Polycystic ovary syndrome (PCOS) is a widespread and complex endocrine disorder affecting women of childbearing potential, characterized by reproductive dysfunction, hyperandrogenism, and metabolic disorders, including insulin resistance. Insulin resistance is a key pathogenetic factor contributing to ovarian dysfunction and reduced fertility. Myo-inositol (MI), a ubiquitous polyol, has earned a reputation as a promising dietary supplement due to its vital role in insulin signaling pathways. This scoping review aimed to map the available scientific literature on the effects of MI supplementation in women with PCOS, with particular emphasis on fertility and ovarian function, and to identify gaps in the current evidence base. This scoping review was conducted in accordance with the methodology developed by the Joanna Briggs Institute (JBI) and presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. A literature search was conducted against six electronic databases: PubMed, Scopus, Web of Science, EBSCO (MEDLINE Complete), Cochrane Library and Google Scholar. Searches were conducted between 10 January and 20 February 2026. Eligibility sources included original articles (observational and randomized controlled trials), meta-analyses, systematic and narrative reviews, published in English with full text available, focusing on adult women with PCOS. Data extraction was performed independently by two reviewers using the Population-Concept-Context (PCC) framework. In accordance with the scope review methodology, no formal critical appraisal of study quality and no quantitative synthesis were performed. This is consistent with JBI methodology, which does not require critical appraisal for scoping reviews unless explicitly justified. Of the 77 records initially identified, 13 studies were included in the review, and no duplicates were found. These potential benefits should be interpreted cautiously, as the available evidence is heterogeneous and varies across study designs. Potential benefits were also reported for hormonal and metabolic parameters, including reductions in hyperandrogenism and the improvement of insulin sensitivity. Some studies suggest benefits for oocyte and embryo quality, but results remain inconsistent. MI supplementation may support PCOS management, particularly in fertility-related outcomes. Its ability to improve ovulation, increase pregnancy rates, optimize ART outcomes, and mitigate the risk of OHSS highlights its clinical utility. However, the evidence remains heterogeneous, and some outcomes, particularly oocyte and embryo quality, remain inconclusive.
Reimão Miller KA et al., 2026·Reproductive biomedicine online
This review explores whether the clomiphene citrate stair-step protocol (SSP) for ovulation induction in patients with polycystic ovary syndrome (PCOS) outperforms the traditional protocol. The following databases were searched: PubMed, Cochrane Library, ClinicalTrials.gov, EMBASE and Google Scholar from inception to 15 June 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and with PROSPERO registration (CRD420251050294). Of 847 screened records, five randomized controlled trials were included (n = 520: n = 255; traditional protocol: n = 265). Analyses were conducted in Review Manager 5.4 using random-effects models. Risk ratios, mean differences and 95% confidence intervals were calculated. Heterogeneity was assessed with I², risk of bias with RoB2, certainty with GRADE and robustness with leave-one-out sensitivity analysis. The SSP increased ovulation rates compared with the traditional protocol (RR 1.28, 95% CI 1.10 to 1.49; five randomized controlled trials [RCTs], n = 520, I² = 0%). Clinical pregnancy also favoured SSP (RR 1.46, 95% CI 1.04 to 2.05; four RCTs, n = 460; I² = 0%), although this result was largely driven by one study. The SSP shortened treatment duration (mean difference -32.59 days, 95% CI -38.66 to -26.52 days; three RCTs, n = 320, I² = 83%). Endometrial thickness was similar (mean difference 0.32 mm, 95% CI -0.95 to 1.59 mm; four RCTs, n = 460, I² = 91%). SSP improves ovulation rate and shortens treatment without affecting endometrial thickness and may increase clinical pregnancy rates.
The present study investigated the role of melatonin (MT) in regulating mitochondrial function via sirtuin 3 (SIRT3) in granulosa cells (GCs) from patients with polycystic ovary syndrome (PCOS), with a focus on mitochondrial protection. Notably, GCs isolated from patients with PCOS exhibited mitochondrial dysfunction. Using an in vitro PCOS model established by treating KGN cells with dihydrotestosterone (DHT), decreased SIRT3 expression, dysregulated mitochondrial dynamics and hyperactivation of mitophagy were observed. Both SIRT3 overexpression and MT treatment restored the mitochondrial membrane potential, rebalanced mitochondrial dynamics and suppressed excessive autophagy in DHT-treated cells. Additionally, MT levels were shown to be reduced in the follicular fluid of patients with PCOS. Notably, the protective effects of MT on proteins associated with both mitochondrial dynamics and autophagy were abolished upon SIRT3 inhibition. In conclusion, mitochondrial dysfunction and aberrant mitophagy in GCs may serve a role in the pathogenesis of PCOS. MT appears to ameliorate these defects by modulating mitochondrial dynamics and function in a SIRT3-dependent manner. Moreover, the current study identified SIRT3 as a key molecular target of MT in PCOS.
Anti-Müllerian hormone (AMH), produced by ovarian granulosa cells, is a key regulator of female reproduction. Traditionally seen as a local follicular brake, emerging evidence calls for a paradigm shift. We propose that AMH acts as a context-dependent signaling hub. It primarily signals via the Smad1/5/8 pathway and interacts with Wnt/β-catenin and MAPK cascades to regulate follicle growth and steroidogenesis. Beyond the ovary, AMH and its receptors are expressed in the hypothalamus, pituitary, uterus, and placenta, modulating the hypothalamic-pituitary-gonadal axis and other reproductive processes. This review provides a comprehensive framework for understanding AMH as a context-dependent signaling hub in female mammals.
Sajjad MU et al., 2026·Archives of gynecology and obstetrics
The human placenta consumes, on average, one third of the glucose from maternal blood. However, the role of placental glucose consumption in the production of estradiol and progesterone remains unclear. We hypothesized that placental glucose consumption in humans is associated with steroid production via a non-glycolytic pathway. We included 41 healthy pregnancies at term. Blood samples were obtained from the maternal radial artery, uterine vein, and from the umbilical artery and vein during scheduled cesarean delivery. Blood flow in the uterine artery and umbilical vein was measured using Doppler ultrasound. Plasma concentrations of estradiol, progesterone, glucose, insulin, lactate, and ketones were analyzed. We calculated uteroplacental uptake and consumption of maternal glucose and ketones, and the loss of uteroplacental lactate in 6-carbon units as well as the release of steroid hormones into maternal circulation. Our data revealed a net placental release of estradiol and progesterone into maternal circulation [24.1 (5.34, 49.8) and 560.3 (61.2, 798.2) nmol/min, respectively]. The release of estradiol was positively associated with uteroplacental glucose uptake (ρ = 0.59, p < 0.001) and consumption (ρ = 0.43, p = 0.005), while progesterone exhibited similar associations (ρ = 0.61, p < 0.001; ρ = 0.43, p = 0.005). Notably, both hormones correlated positively with lactate-adjusted uteroplacental glucose consumption but not with acetate-equivalent uteroplacental ketone consumption. Placental release of estradiol and progesterone correlates with uteroplacental consumption of glucose that primarily occurs via non-glycolytic pathways in the third trimester placenta.
Background Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder characterized by reproductive, hormonal, and metabolic disturbances. This study aimed to evaluate the association between clinical features, anthropometric indices, hormonal parameters, metabolic profile, ultrasonographic findings, and the second-to-fourth digit (2D:4D) ratio in women with PCOS compared to age-matched healthy controls. Methods A case-control study was conducted, including women diagnosed with PCOS and age-matched healthy controls. Clinical features, anthropometric measurements (BMI, waist-hip ratio (WHR), waist-height ratio (WHtR)), hormonal parameters (luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH)), metabolic variables (fasting glucose, lipid profile), ultrasonographic findings, and 2D:4D digit ratio were assessed. Statistical analysis was performed using appropriate tests, and a p-value < 0.05 was considered statistically significant. Results Women with PCOS exhibited a significantly higher prevalence of menstrual irregularity, polycystic ovarian morphology, hirsutism, and acne (p < 0.001). Hormonal analysis showed significantly elevated LH, FSH, and AMH levels in PCOS cases (p < 0.001). Anthropometric indices, including BMI, WHR, and WHtR, were significantly higher among PCOS cases (p < 0.01), indicating increased general and central adiposity. In contrast, fasting glucose and lipid profile levels did not differ significantly between groups. Additionally, the 2D:4D ratio was significantly lower in PCOS cases (p < 0.01) and showed significant negative correlations with BMI, WHR, WHtR, and cholesterol levels. Conclusion The study demonstrates that PCOS is associated with significant hormonal dysregulation, central obesity, and early metabolic alterations. The lower 2D:4D ratio observed in PCOS supports the role of prenatal androgen exposure in disease pathogenesis. These findings highlight the complex interplay between developmental, metabolic, and endocrine factors in PCOS and underscore the importance of early identification and comprehensive management strategies.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, typically characterized by irregular menstrual cycles. Our study found that postpartum menstrual cycles were largely restored in PCOS patients following assisted reproductive technology (ART) therapy. However, this recovery in menstrual cycles was not associated with any specific ART procedures. Using a PCOS mouse model, we demonstrated that elevated progesterone levels during pregnancy were responsible for normalizing estrous cyclicity. Elevated levels of progesterone induce granulosa cell apoptosis and deplete large follicles, which potentially contribute to ovarian function suppression during pregnancy. Mechanistic studies indicated that progesterone decreased follicle-stimulating hormone receptor (FSHR) expression in a GATA binding protein 2 (GATA2)-dependent manner. Interestingly, the capacity of granulosa cells to convert androgens to estrogens significantly increased after progesterone withdrawal, as evidenced by elevated cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) expression in granulosa cells when stimulated with FSH. Additionally, we found that progesterone administration reduced the thickness of the uterine endometrium in PCOS mice. Our findings suggest that sustained high levels of progesterone during pregnancy can enhance ovarian reproductive endocrine capacity and improve endometrial function, thereby facilitating the recovery of postpartum menstrual cycles.
This systematic review and meta-analysis examined the relationship between menstrual cycle phases and the incidence of muscle injuries in female team sport athletes, following PRISMA 2020 and PERSiST guidelines. A comprehensive search was conducted in PubMed, Scopus, and SPORTDiscus from inception to mid-January 2024. Studies were included if they examined female team sport athletes of reproductive age with regular menstrual cycles and compared the occurrence of muscle injuries across at least two menstrual phases. Studies involving hormonal contraceptive use, medications affecting the menstrual cycle or musculoskeletal system, or menstrual dysfunction were excluded. Three studies met the inclusion criteria, involving 318 participants. Meta-analysis yielded a pooled Risk Ratio of 1.18 (95% CI: 0.75 to 1.86, p = 0.46) for injury risk between the luteal and follicular phases, suggesting no statistically significant association. However, the certainty of the cumulative evidence was rated as very low due to methodological limitations, including inconsistent phase classifications and reliance on imprecise methods for identifying menstrual phases. Consequently, no practical or clinical recommendations can be made at this time. Future research employing standardised, physiologically accurate methods for classifying and detecting menstrual cycle phases is necessary to better understand the potential links between hormonal fluctuations and injury risk. Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-36763-0.
Clomiphene citrate (CC) is the first-line medication for inducing ovulation in women with polycystic ovary syndrome (PCOS). However, approximately 20% of patients with PCOS are resistant to CC. This study aims to identify reliable baseline predictors of CC resistance in infertile women with PCOS. A post-hoc analysis of a large, multicenter randomized controlled trial (PCOSAct trial) conducted in China. The current analysis comprised the 471 participants who were randomized to the active CC arm and completed the requisite follow-up. To identify potential candidate variables, we employed multivariable logistic and LASSO regression analyses. Within the framework of a multivariable logistic regression model, we also estimated the independent associations between the identified candidate variables and resistance to CC. Additionally, we plotted the Receiver Operating Characteristic (ROC) curve and utilized the DeLong method to compare the statistical differences in the area under the curve (AUC). Finally, we constructed a restricted cubic spline (RCS) logistic regression model to illustrate the dose-response relationship between continuous predictor variables and CC resistance. CC resistance was identified in 32 (6.8%) participants. Body Mass Index (BMI), Total Testosterone (TT), and Anti-Müllerian Hormone (AMH) were useful predictors of ovarian response to CC. The "T+BMI" dual-factor model demonstrated high discriminative power (AUC = 0.801) and was statistically comparable to the three-factor model including AMH (AUC = 0.818; P = 0.347). TT was the strongest individual predictor (OR = 2.73 per 1-unit), while BMI was the most significant modifiable risk factor (OR = 2.49 per 1-SD). A simplified "T + BMI" assessment provides comparable prognostic utility without the need for AMH testing. For patients at high risk of CC resistance, we recommend upfront use of aromatase inhibitors or low-dose gonadotropins. This strategy avoids ineffective treatment cycles and enables personalized ovulation induction. The study was registered on ClinicalTrials.gov under the identification number NCT01573858 on July 6, 2012.
The corpus luteum is a vital yet temporary organ that plays a crucial role in fertility during the luteal phase. An endocrine structure in females exists within the ovary once the ovarian follicle releases a mature ovum during ovulation. See Image. Anatomy of the Internal Structures of the Ovary. The secretion of hormones from the corpus luteum stops within 14 days after ovulation if the oocyte is not fertilized. It then degenerates into a scar within the ovary, known as corpus albicans. The corpus luteum's role is to maintain a uterine environment that allows for implementation and pregnancy. This occurs by the release of pregnancy-related hormones and regulation of the hypothalamic-pituitary access through inhibition of gonadotropin-releasing hormone from the hypothalamus, which in turn decreases the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) released from the anterior pituitary. The primary hormone produced by the corpus luteum is progesterone, but it also produces inhibin A and estradiol. In the absence of fertilization, the corpus luteum regresses over time. A corpus luteum develops each time a woman ovulates so that she produces a corpus luteum numerous times throughout her lifetime.
Bouchard TP et al., 2025·Preprints.org·
Open Access
Background/Objectives: Quantitative urine monitors are increasingly being used for a personalized approach to improve menstrual cycle knowledge and to manage fertility. Although several studies have evaluated urine fertility monitors in regular cycles, there is limited research in the use of quantitative monitors in reproductive disorders, such as polycystic ovarian syndrome (PCOS). Urine hormone data was collected with the Mira monitor from 20 participants, 10 of whom had PCOS and a matched group who had regular cycles. The main aim of this study was to evaluate the levels of luteinizing hormone (LH), estrone-3-glucuronide (E13G), and pregnanediol glucuronide (PDG) in PCOS menstrual cycles compared to regular cycles. Women with PCOS had higher BMI than regular cycling women (p=0.02). PCOS cycles were longer (p<0.05), peak day was later in the menstrual cycle (p<0.001), and luteal length was shorter (p < 0.01) compared to regular cycles. In whole cycle comparisons, E13G was found to be lower in PCOS cycles (p<0.01) and PDG was found to be higher in PCOS cycles (p<0.05). E13G was also lower in the follicular phase of and late luteal phase of PCOS cycles (p<0.00001). The results of this study demonstrate the feasibility of detecting hormonal differences in PCOS compared to regular cycles with at-home measurements with the Mira monitor. The metabolic dysregulation of PCOS is a possible factor in these hormone changes. Larger studies with different sub-types of PCOS will be needed to further clarify these changes and to understand the pathophysiology behind these hormonal changes.
Brandao BM et al., 2025·Hormones and Behavior·
Open Access
Hormonal contraceptives (HCs) are widely used, yet their effects on emotional and cognitive processes remain poorly understood. This study examined how HC use may influence emotional reactivity, emotion regulation, and emotional memory. Female participants (N = 179), either using HCs (N = 87) or naturally cycling (NC; N = 92), were randomly assigned to one of three groups: no emotion regulation (control), distancing and immersion, or reinterpretation and immersion. The emotion regulation groups completed emotion regulation training in which they viewed emotional images while applying different emotion regulation strategies, followed by a surprise memory test. Overall, HC users showed greater emotional reactivity to emotional images compared to NC participants. Both HC and NC groups successfully applied emotion regulation strategies as measured by changes in emotional affect; however, distancing led to a greater reduction in negative emotions compared to reinterpretation, particularly among HC users. Both HC and NC groups showed better memory for positive images after applying immersion. For negative images, HC users showed reduced memory performance when applying either distancing or reinterpretation, an effect not observed in NC participants. These findings suggest that HC use may influence specific aspects of emotional processing and memory, highlighting the need for more nuanced research on the cognitive and emotional effects of hormonal contraceptives.
Thyroid and Metabolic Function · Insulin and Metabolism
Abstract What gut microbiota and metabolic alterations are associated with Polycystic ovary syndrome (PCOS) and linked to adverse pregnancy outcomes (APOs)? In PCOS, P. merdae decreases, BCAAs increase, raising the risk of APOs. Meanwhile, endometrial senescence and decidualization impairment are found, worsening with higher Ile concentration. PCOS, a prevalent and complex endocrine disorder, stands as the primary cause of anovulatory infertility. The rising prevalence of PCOS in China over the past decade has led to a substantial increase in disease burden. Our previous ten-year retrospective analysis revealed that PCOS patients undergoing their first fresh embryo transfer faced a heightened risk of APOs, such as miscarriage. However, the factors influencing disease progression and future obstetric outcomes in PCOS remain elusive. Study design, size, duration
This prospective cohort study encompassed a diverse cohort of 220 women (110 with PCOS and 110 controls) from 44 cities across China, with a median follow-up duration of 16.6 months. Participants/materials, setting, Women aged < 35 years with PCOS (Rotterdam criteria) and age-/BMI-matched controls were recruited. Fecal microbiomes were analyzed using 16S rRNA sequencing and metagenomics, while serum metabolites were assessed through both untargeted and targeted metabolomics. Endometrial stromal cell senescence was evaluated based on a constellation of markers, including cell proliferation, senescence-associated secretory phenotype factors, cell cycle, ROS levels, and SA-β-Gal activity. Endometrial decidualization was gauged by measuring prolactin and IGFBP-1 levels using ELISA. Main Our study revealed significant gut microbiota alterations, including reduced α-diversity and a notable decline in Parabacteroides merdae (P. merdae), a key species differentiating PCOS from controls. Serum metabolomics identified 45 differential metabolites, with branched-chain amino acids (BCAAs), especially isoleucine (Ile), exhibiting strong diagnostic potential. Targeted metabolomics further validated BCAAs’ (Valine, Leucine, and Ile) upregulation and short-chain fatty acids’ downregulation in PCOS.
During follow - up, PCOS patients had a higher cumulative incidence of APOs despite similar pregnancy rates. And the adjustment for potential confounders did not substantially change the estimates. Intriguingly, individuals who experienced APOs showed a reduction in gut P. merdae levels and an elevation in serum BCAAs, suggesting their potential association with APOs occurrence.
Further analysis revealed increased Ile levels in the endometrial tissue of PCOS (P < 0.05) and higher proportions of cells positive for senescence markers (P21, P16, IL6, and IL1β), indicating aggravated cellular senescence, particularly in endometrial stromal cells (ESCs). ESCs from PCOS patients displayed classical senescence features, including proliferation loss, increased SA-β-Gal activity, cell cycle arrest, and elevated ROS levels. The accumulation of senescent ESCs in PCOS endometrium ultimately resulted in a disrupted decidualization process, which was exacerbated by increasing concentrations of Ile supplementation. Limitations, However, we must acknowledge certain limitations of this study. While our study makes a significant contribution to existing scientific knowledge, it is crucial to validate these findings in diverse populations. In addition, clinical translatability of biomarkers needs further exploration. This study highlights gut microbiota-metabolite crosstalk as a novel axis influencing reproductive health in PCOS. Moreover, the identification of P. merdae and BCAAs as potential biomarkers for PCOS patients and the associated APOs risk opens up new avenues for risk stratification and personalized interventions. No
Karaman E et al., 2025·Vaccines (Basel)·
Open Access
This study aimed to elucidate the effects of messenger RNA (mRNA) and inactivated coronavirus disease 2019 (COVID-19) vaccines on ovarian histology and reserve in rats. Thirty female Wistar albino rats, aged 16-24 weeks, were randomly divided into three groups (n = 10): control, mRNA vaccine, and inactivated vaccine groups. Each vaccine group received two doses (on day 0 and day 28) at human-equivalent doses. Four weeks post-second vaccination, ovarian tissues were harvested for analysis. Immunohistochemical analysis was performed to evaluate the expression of transforming growth factor beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), caspase-3, and anti-Müllerian hormone (AMH) in ovarian follicles. Both vaccines induced significant increases in TGF-β1, VEGF, and caspase-3 expression, with more pronounced effects in the mRNA vaccine group. Conversely, AMH expression in the granulosa cells of primary, secondary, and antral follicles showed marked reductions (p < 0.001). The counts of primordial, primary, and secondary follicles decreased significantly in the inactivated vaccine group relative to controls and further in the mRNA vaccine group compared to the inactivated group (p < 0.001). Additionally, the mRNA vaccine group exhibited a decrease in antral and preovulatory follicles and an increase in atretic follicles compared to the other groups (p < 0.05). The serum AMH level was diminished with the mRNA vaccination in comparison with the control and inactivated groups. Our findings suggest that both mRNA and inactivated COVID-19 vaccines may detrimentally impact ovarian reserve in rats, primarily through accelerated follicular loss and alterations in apoptotic pathways during folliculogenesis. Given these observations in a rat model, further investigations into the vaccines' effects on human ovarian reserve are needed.
Thyroid and Metabolic Function · Insulin and Metabolism
Myrer RS et al., 2025·Utah Womens Health Rev·
Open Access
The objective of this study is to test the association between preconception polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) using Utah's Pregnancy Risk Assessment Monitoring System (2016-2021). In addition, pre-pregnancy hypertension will be tested as a potential effect moderator. This cross-sectional study utilizes data from Phase 8 of the Utah Pregnancy Risk Assessment Monitoring System (PRAMS) survey (2016-2021). The association between PCOS and GDM was tested using Poisson regression to generate adjusted prevalence ratios and 95% confidence intervals. PCOS was associated with higher prevalence of GDM in all models, regardless of whether the outcome data (GDM) came from the infant's birth certificate, the PRAMS survey, or the combined measure. When adjusting for sociodemographic characteristics, lifestyle factors, reproductive history, and comorbidities, women with PCOS were 1.50 (1.16-1.95) times as likely to have GDM (reported on birth certificate and/or survey) compared to women without PCOS. Pre-pregnancy hypertension was not found to be a statistically significant effect moderator. The findings from this study were consistent with the majority of research indicating that women with PCOS have increased risk for GDM. This is also the first known study to test pre-pregnancy hypertension as an effect moderator between PCOS and GDM. More research is needed on the role of comorbidities such as chronic hypertension as effect modifiers between PCOS and GDM.
These findings show that women with PCOS are at high risk for GDM, among a population-based sample of mothers. Interventions to reduce the risk of GDM among women with PCOS need to be developed and evaluated.
Traditionally, taste receptors (TRs) have been understood to reside within the taste buds on the tongue, serving as initiators for different taste perceptions. However, recent research has expanded our understanding, revealing that TRs are found throughout the body and perform a wide range of functions beyond taste perception as non-tasting functions. These receptors, along with their genetic variations, have been linked to various human health conditions. They are activated by an array of substances, including hormones, nutrients, and toxins, indicating their involvement in numerous biological processes. Specifically, in males, TRs are notably present in the testes and epididymis, where they contribute to the hormonal production, spermatogenesis, and sperm maturation. In females, these receptors are found in the ovaries, uterus, and myometrium, playing crucial roles in ovulation, menstrual cycle regulation, and embryo implantation. There are a lot of missed areas regarding TRs research that imposes to fulfill the gaps in the current understanding of their role in reproduction. This review aims to provide a comprehensive overview of the emerging roles of extraoral TRs in reproductive health, highlighting their physiological and pathophysiological significance in various reproductive processes. As well, grabbing the attention towards the release of new pharmacological interventions to manage conception and contraception in male and female was considered.
Senthilkumar H et al., 2025·Journal of translational medicine
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects reproductive-aged women worldwide, causing hormonal imbalances and ovarian dysfunction. PCOS affects metabolic health and increases the risk of obesity, insulin resistance, and cardiovascular disease, in addition to infertility. This review delves deeper into the connections of gut microbiota with PCOS pathophysiology, particularly into its impact on hormone metabolism, obesity, inflammation, and insulin resistance by way of short-chain fatty acids, lipopolysaccharides, and gut-brain axis. Studies also show that changes in the metabolic processes and immune responses are seen in changes in the gut microbiota in PCOS subjects, such as changes in the Bacteroidetes and Firmicutes groups. Some bacteria, like Escherichia and Shigella, have been associated with dysbiosis in patients with PCOS, leading to systemic inflammation and changed hormone levels, which further worsen the clinical symptoms. Therapeutic interventions targeting the gut microbiota comprise probiotics, prebiotics, and fecal microbiota transplantation; these have potential to alleviate the symptoms of PCOS. Other precision microbiome-based therapies include postbiotics, and CRISPR-Cas9 genome editing, which are relatively new avenues toward precision treatment. This complex interlink of gut microbiota and PCOS pathophysiology will open the avenues for possible treatments for hormonal imbalances and metabolic problems that characterize these complex disorders. The review here focuses on the requirement of further studies to be able to elucidate the specific pathways relating gut microbiota dysregulation to PCOS and, thus, improve microbiome-based therapies for better clinical outcomes in affected individuals.
Progesterone supplementation reverses 83% of transcript changes in the secretory endometrium induced by postovulatory mifepristone, potentially mitigating its antiprogestogenic effects. Mifepristone (RU486) antagonizes progesterone signaling in human endometrium interfering in the secretory phenotype after estradiol priming. The objective of the present study was to determine effect in the endometrial transcript profile of progesterone supplementation after the administration of 200 mg of the antiprogestin mifepristone 48 h after the LH peak (LH+2, LH+0 = LH peak). Endometrial samples were obtained on LH+7 after vaginal administration of micronized progesterone 200 mg/day for 3 days in nine women of proven fertility, each one contributing with one cycle treated with progesterone and another with a placebo. In addition, endometrial samples were obtained in LH+7 from a subgroup of four women with no administration of mifepristone, with each one contributing with one cycle treated with vaginal progesterone supplementation or placebo as a reference. RNA-seq was used to identify transcripts significantly regulated under the administration of progesterone vs placebo with or without postovulatory mifepristone. We observed that 713 transcripts changed significantly in the endometrium under mifepristone after progesterone supplementation in group A. Of these, progesterone reversed approximately 83% of the transcripts affected by mifepristone in the secretory endometrium. Bioinformatic analyses revealed that these transcripts were enriched in genes associated with mitochondrial function, particularly oxidative phosphorylation. In addition, NR2C2 and DLX1 were identified as potential transcription factors that may mediate the effects of progesterone in the endometrium. We conclude that progesterone supplementation after postovulatory mifepristone administration can reverse the antiprogestogenic effects for most of the affected endometrial transcripts.
1. Define premature ovarian insufficiency, diagnostic criteria, risk factors and comorbidities.
2. Discuss health concerns, as well as health and hormone management of patients suffering with POI.
3. Discuss restorative fertility approaches to those with POI.
Lara HE et al., 2025·Frontiers in endocrinology·
Open Access
Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?Summary answerThe current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI. Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline. Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. Main s and the role of chanceNew data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. Limitations reasons for cautionThe guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. Wider s of the findingsThe guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.Study funding/competing interestsThe guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR-research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017-2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR-HTA Reference Number: NIHR133461; NIHR-HTA Reference Number: NIHR128757; Action Medical Research and Borne: GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women's health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare.DisclaimerThis guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).
Huang Y et al., 2024·Front Endocrinol (Lausanne)·
Open Access
Premature ovarian insufficiency/failure (POI/POF) is a significant issue for women of reproductive age. Anti-Müllerian hormone (AMH) is a potential biomarker of ovarian reserve, but its clinical value in diagnosing and predicting POI/POF remains unclear. This study aimed to analyze the correlation between AMH and basal follicle-stimulating hormone (FSH) levels in women aged 18 to 40 and evaluate AMH's predictive value for POI/POF. A total of 21,143 participants aged 18-40 who visited the gynecology department or underwent physical examinations at the International Peace Maternity and Child Health Hospital in Shanghai, China, from July 2016 to June 2021 were enrolled. Demographic information and laboratory test results were collected, including age, FSH, AMH, E2 and test dates. Participants were grouped by FSH and AMH levels, and subgroup analyses were performed to investigate the relationship between these hormones and age. The AMH level associated with POI risk was evaluated using restricted cubic splines (RCS) and logistic regression. Clinical benefit was assessed by decision curve analysis (DCA). Participants with higher FSH levels had significantly lower median AMH levels and vice versa(p<0.001). At AMH ≥ 0.5 ng/mL, FSH levels were normal or slightly elevated with age. At AMH level below 0.5ng/ml,basal FSH increased significantly with age. At FSH <10 IU/L, AMH levels show a trend of rising and then decreasing with age, reaching a peak at approximately 25 years old and gradually decreasing with age. At FSH ≥10 IU/L, AMH levels show a gradual downward trend with age, and at FSH >40 IU/L, AMH levels remain very low to undetectable values. The RCS showed that the risk of POI/POF in the overall population sharply increased until serum AMH reached a low level (below 0.5ng/ml). DCA showed that a low AMH level had good clinical diagnostic utility in predicting POI/POF. Our analysis of a large dataset suggests that serum AMH levels are inversely correlated with FSH levels and that AMH is a good predictor of POI until it drops to a low level.
Del Río JP et al., 2024·Front Psychol·
Open Access
Hormones produced by the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis are crucial for modulating central nervous system (CNS) function and development throughout a person's life. Disruptions in HPAG function can impact psychological development, particularly during adolescence-a period marked by psychological growth and the maturation of the HPAG axis. An early indicator of HPAG alterations is ovulatory dysfunction (OD), a common condition among adolescents. This study explored the associations between neuroactive hormones and personal growth in adolescents with OD. Female participants aged 12-25 years with OD were recruited, and assessments were conducted to profile their basic hormonal levels and various dimensions of individual development, including self-concept clarity, sense of coherence, self-esteem, perfectionism, self-control, and mood states. Adolescents with OD (n = 117) had lower self-concept clarity and self-esteem compared to reference data. A significant portion of the sample displayed elevated levels of tension (71.25%), confusion (62.5%), fatigue (58.22%), and depression (52.6%). Self-esteem scores were negatively correlated with DHEAS (r = -0.224; p = 0.026) and glucose (r = -0.249; p = 0.010). Higher levels of free testosterone were associated with increased depression scores (coef = 0.2398; p = 0.002), whereas higher estradiol levels were linked to lower aggressiveness scores (coef = -0.0648; p = 0.001). These findings indicate that hormonal imbalances in adolescents with OD could affect personal growth. Further research is needed to establish causal relationships between the variables considered.
Boyle PC et al., 2024·Front Med (Lausanne)·
Open Access
Hypoandrogenemia is not usually considered as a potential cause of recurrent miscarriage. We present the case of a 30-year-old female with 6 previous pregnancies resulting in one live birth and 5 pregnancy losses, including fetal demise at 24 weeks gestation. She had standard investigations after her 4th loss, at a specialized miscarriage clinic. Lupus anticoagulant, anticardiolipin antibodies, thyroid function, parental karyotypes were all normal. Fetal products confirmed triploidy for her 4th miscarriage at 16 weeks gestation. She was reassured and advised to conceive again but had fetal demise after 24 weeks gestation. This was her 5th pregnancy loss with no explanation. She attended our Restorative Reproductive Medicine (RRM) clinic in January 2022. In addition to poor follicle function, we found hypoandrogenemia for the first time. Treatment included follicle stimulation with clomiphene and DHEA 25 mg twice daily pre-conception with DHEA 20 mg once daily maintained throughout pregnancy. She delivered a healthy baby boy by cesarean section at 36 weeks gestation in November 2023. Hypoandrogenemia should be considered as a contributory factor for women with recurrent miscarriage or late pregnancy loss. Restoration of androgens to normal levels with oral DHEA is safe and can improve pregnancy outcome.
Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with an adverse cardiometabolic profile early in life. Increasing evidence links cardiovascular risk factors, such as diabetes and hypertension, to accelerated cognitive aging. However, less is known about PCOS and its relationship to brain health, particularly at midlife. Our goal was to investigate possible associations between PCOS and midlife cognitive function and brain MRI findings in an ongoing prospective study. We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a geographically diverse prospective cohort study of individuals who were 18-30 years at baseline (1985-1986) and followed for 30 years. We identified women with PCOS from an ancillary study (CARDIA Women's study (CWS); n = 1,163) as those with elevated androgen levels and/or hirsutism in conjunction with symptoms of oligomenorrhea. At year 30, participants completed cognitive testing, including the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory), Digit Symbol Substitution Test (processing speed and executive function), Stroop test (attention and cognitive control), and category and letter fluency tests (semantics and attention). A subset completed brain MRI to assess brain structure and white matter integrity. Multivariable linear regression models estimated the association between PCOS and outcomes, adjusting for age, race, education, and study center. Of the 1163 women in CWS, 907 completed cognitive testing, and of these, 66 (7.1%) met criteria for PCOS (age 54.7 years). Women with and without PCOS were similar for age, BMI, smoking/drinking status, and income. At year 30, participants with PCOS performed lower (mean z score; 95% CI) on Stroop (-0.323 (-0.69 to -7.37); p = 0.008), RAVLT (-0.254 (-0.473 to -0.034); p = 0.002), and category fluency (-0.267 (-0.480 to -0.040); p = 0.02) tests. Of the 291 participants with MRI, 25 (8.5%) met PCOS criteria and demonstrated lower total white matter fractional anisotropy, a measure of white matter integrity (coefficient (95% CI) -0.013 (-0.021 to -0.005); p = 0.002), though not abnormal white matter. Our results suggest that women with PCOS have lower cognitive performance and lower white matter integrity at midlife. Additional research is needed to confirm these findings and to determine potential mechanistic pathways including potential modifiable factors.
Boyle P et al., 2024·Frontiers in Reproductive Health
Low serum estradiol in early pregnancy is associated with an elevated risk of miscarriage. We sought to determine whether efforts to restore low blood estradiol via estradiol or dehydroepiandrosterone (DHEA) supplementation would reduce the risk of miscarriage as part of a multifactorial symptom-based treatment protocol. This retrospective cohort study included women with low serum estradiol levels in early pregnancy, defined as ≤50% of reference levels by gestational age. Estradiol or DHEA were administered orally, and the primary outcome measure was serum estradiol level, in reference to gestational age. The secondary outcome measures included miscarriage, birth weight, and gestational age at birth. We found no significant effect of estradiol supplementation on serum estradiol levels referenced to gestational age, while DHEA supplementation strongly increased estradiol levels. For pregnancies with low estradiol, the miscarriage rate in the non-supplemented group was 45.5%, while miscarriage rate in the estradiol and DHEA supplemented groups were 21.2% (p = 0.067) and 17.5% (p = 0.038), respectively. Birth weight, size, gestational age, and preterm deliveries were not significantly different. No sexual abnormalities were reported in children (n = 29) of DHEA-supplemented patients after 5-7 years follow-up. In conclusion, DHEA supplementation restored serum estradiol levels, and when included in the treatment protocol, there was a statistically significant reduction in miscarriage.
Thyroid and Metabolic Function · Insulin and Metabolism
Dhar S et al., 2024·Journal of human reproductive sciences
Zinc is an essential micronutrient, a vital stabiliser and a cofactor in many enzymes such as superoxide dismutase and phospholipase C and also acts as an antioxidant by protecting the sulfhydryl groups of different proteins and enzymes against free radicals. It is unclear if serum zinc levels are correlated with polycystic ovary syndrome (PCOS) and its pathophysiology, although relation between diabetes and insulin resistance has been established. This study aimed to investigate circulating serum zinc levels in PCOS subjects compared with non-PCOS subjects. In this cohort study, PCOS subjects were compared with normal subjects aged between 18 and 35. All the included subjects underwent measurement of anthropometric parameters, fasting insulin, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, progesterone, oestrogen and serum zinc levels. These values were taken on days 2-5 of the menstrual cycle. Univariate analysis and linear regression were performed for serum zinc levels and fasting insulin levels in PCOS subjects and non-PCOS subjects using SPSS (version 21) and Microsoft Excel (2019). Serum zinc levels in the PCOS group were lower than in the control group (P = 0.012). Fasting insulin levels in the PCOS group were higher than in non-PCOS subjects (P = 0.001). We found a negative correlation between zinc and fasting insulin (r = -0.580, P < 0.0001) in the normal group and (r = -0.332, P = 0.019) in the PCOS group. A positive correlation was found between body mass index (BMI) and fasting insulin levels in both the PCOS group (r = 0.227, P = 0.112) and normals (r = 0.612, P < 0.0001). A negative statistically significant correlation between BMI and zinc in both the PCOS group (r = -0.378, P = 0.007) and the non-PCOS group (r = -0.7452, P < 0.0001) was seen. The data suggest that serum zinc levels were found to be lower in PCOS subjects as compared to normal controls and evaluation of these levels may indicate that zinc has a vital role in PCOS pathophysiology.
Chiarella SE et al., 2023·The journal of allergy and clinical immunology. In practice
Progestogen hypersensitivity (PH) is a heterogeneous disease characterized by diverse cutaneous manifestations, bronchospasm, and/or anaphylaxis. Possible triggers include ovarian progesterone and exogenous progestogens. The timing of symptoms is critical to diagnose PH: during the luteal phase of the menstrual cycle for the endogenous form and after exposure to progestins for exogenous PH. Diagnostic modalities such as progesterone skin testing have low sensitivity and specificity for PH. When exogenous PH is suspected, the allergist should consider a progestogen challenge. Treatment strategies should be tailored for each patient, including symptom-directed therapies, ovulation suppression, and progesterone desensitization. Future studies should explore the mechanisms of PH, validation of diagnostic criteria, and standardization of treatment strategies.
The use of platelet-rich plasma (PRP) has become popular as an adjunct to fertility treatment for women with infertility, particularly those with low ovarian reserve and premature ovarian insufficiency. Recent data in a polycystic ovary syndrome (PCOS) animal model demonstrated that intraovarian PRP administration improved folliculogenesis, ovarian antioxidant potential, and serum hormonal imbalance, suggesting that PRP could be considered a novel technique to alleviate PCOS-induced pathogenesis. With injection of PRP into the ovaries, it has been hypothesized that the infusion of cytokines and growth factors may exhibit a local effect that changes the expression of genes important in folliculogenesis and steroidogenesis, decreases inflammation, and partially restores normal ovarian function. This report is the first to present a case of a long-term amenorrheic woman with PCOS who has been trying to conceive, who resumed spontaneous ovulatory cycles, and had improvement in several aspects of her hormonal imbalance following intraovarian PRP administration. The purpose of this case report is to increase awareness regarding the possible benefits of intraovarian PRP injections for women with PCOS. There is a clear need for larger prospective studies to properly elucidate the effect of intraovarian PRP administration on both the reproductive and metabolic dysfunctions observed in women with PCOS.
Meyers M et al., 2023·Medicina (Kaunas)·
Open Access
The fertility tracking of menstrual cycles during perimenopause with a quantitative hormone monitor is a novel undertaking. Women in regular menstrual cycles have been tracking their fertility using different biomarkers since the 1960's. Presently, there are newer electronic hormonal devices used to track fertility that provide more exact and objective data to help delineate the fertile time frame of a woman's cycle. These devices measure quantitative levels of estrogen, the luteinizing hormone, progesterone, and follicle-stimulating hormone, all of which occur at varying levels during the menstrual cycle. As women advance toward menopause, their cycles vary in length, and their hormones fluctuate. In this retrospective analysis, forty-two women aged 40 to 50 tracked their cycles over time, and eight of these forty-two women used the quantitative hormonal device. With the use of this device, the perimenopausal period has revealed distinct hormonal cycle characteristics that are unique to this group of women. It is the purpose of this paper to discuss these cycle's characteristics during perimenopause, which were found with the use of the quantitative hormonal device.
Thyroid and Metabolic Function · Thyroid Disorders
Moon KY et al., 2023·Taiwan J Obstet Gynecol·
Open Access
This study aimed to investigate the impact of thyroid autoantibodies and serum TSH levels on clinical IVF outcomes. This study included 260 Korean women scheduled for their first IVF between 2013 and 2017. Serum levels of thyroid hormone, TSH, and antibody for thyroid peroxidase and thyroglobulin were measured just before the first ovarian stimulation. Clinical pregnancy rate (PR), ongoing PR, and miscarriage rate were analyzed according to thyroid autoimmunity and serum TSH levels. The primary outcome was ongoing PR beyond 12 weeks of gestation. The ongoing PR and miscarriage rates were similar between women with positive (n = 29) and negative autoantibodies (n = 186). In women with subclinical hypothyroidism (serum TSH ≥4.2 μIU/mL), ongoing PR was significantly lower than euthyroid women (22.2%, vs. 44.7%, p = 0.045), but miscarriage rate was similar. The group with serum TSH ≥3.4 μIU/mL showed a significantly lower ongoing PR (23.9% vs. 46.7%, p = 0.005) and significantly higher miscarriage rate (38.9% vs. 14.1%, p = 0.020). In multivariate logistic regression analysis, serum TSH ≥3.4 μIU/mL was an independent unfavorable predictor for ongoing PR (odds ratio 0.375, p = 0.013). Thyroid autoantibodies did not affect clinical IVF outcomes, but women with serum TSH ≥3.4 μIU/mL demonstrated poor IVF outcomes.
Zhang P et al., 2023·International journal of molecular sciences
Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance.
Kicińska AM et al., 2023·Healthcare (Basel)·
Open Access
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Absent, impaired, or rare ovulation induces progesterone deficiency in the luteal phase, which is a critical problem in PCOS. A usual pattern of progesterone administration from a fixed and arbitrary pre-determined day of a menstrual cycle may preserve infertility but can easily be avoided. We present the case of a 29-year-old infertile woman who had been ineffectively treated for over two years. We introduced a line of therapy that was suited to her individual menstrual cycle by implementing biomarker recording. Supplementation based on a standardized observation of the basal body temperature (BBT) and cervical mucus stopped the vicious circle of absent ovulation and hyperandrogenism, restoring regular bleeding, ovulation cycles, and fertility. The implementation of a reliable fertility awareness method (FAM), accompanied by a standardized teaching methodology and periodic review of the observations recorded by the patient, validated through an ultrasound examination and plasma gonadotropins, estrogens, and progesterone concentrations, is key to achieving therapeutic success. The presented case is an example of a clinical vignette for many patients who have successfully managed to improve their fertility and pregnancy outcomes by applying the principles of a personalized treatment approach together with gestagens by recording their fertility biomarkers.
Background Polycystic ovary syndrome (PCOS) presents clinical symptoms of menstrual abnormalities, excessive hair growth (hirsutism), scalp hair loss, acne and infertility. Metabolic abnormalities such as obesity, insulin resist‑ ance, glucose intolerance and cardiovascular problems constitute an essential part of PCOS, all of which can have significant long-term health consequences. Low-grade chronic inflammation demonstrated by persistent moderately elevated serum levels of inflammatory and coagulatory markers plays a critical role in the pathogenesis of PCOS. Oral contraceptive pills (OCPs) constitute the mainstay of pharmacologic therapy for women with PCOS to regularize cyclicity and ameliorate androgen excess. On the other hand, OCP use is associated with various venous thromboem‑ bolic and proinflammatory events in the general population. PCOS women always carriers the increased lifetime risk of these events. The studies on the effect of OCPs on inflammatory, coagulation and metabolic parameters in PCOS are less robust. Therefore in this study, we investigated and compared the messenger RNA (mRNA) expression profiles of genes implicated in inflammatory and coagulation pathways between drug-naive and OCP-treated PCOS women. The selected genes include intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), mono‑ cyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1). Furthermore, the correlation between the selected markers and various metabolic indices in the OCP group has also been explored. Method The relative amounts of ICAM-1, TNF-α, MCP-1 and PAI-1 mRNA in peripheral blood mononuclear cells from 25 drug-naive PCOS subjects (controls) and 25 PCOS subjects who received OCPs containing 0.03 mg-ethinyl-estra‑ diol and 0.15 mg-levonorgestrel for at least six months (cases) were estimated using real-time qPCR. The statistical Open Access Background Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases, involving 6–20% percent of women of reproductive age [ 1 ], with an even greater incidence among Kashmiri women [ 2 ]. Apart from the symptoms of hyperandrogenism and infertility, PCOS is associated with several metabolic abnormalities, including obesity, insulin resistance (IR), hyperlipidemia, systemic inflammation and functional atherosclerosis [ 3 – 5 ]. Elevated inflammatory and coagulatory markers characterize this low-grade inflammation and endothelial dysfunction. Intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) are potent biological markers for the development of inflammatory and metabolic diseases which may include PCOS [ 6 – 8 ]. ICAM-1 belongs to the super immunoglobulin family and is produced mainly on cell surfaces of endothelial cells, smooth muscle cells, macrophages and activated lymphocytes. It is required for the adhesion of freely moving leukocytes to blood vessel walls and trans-endothelial migration to the vascular intima. This action is crucial in the evolution of atheroma from early to advanced stages. Cleavage of membranebound ICAM-1 results in circulating soluble ICAM-1 (sICAM-1) [ 9 , 10 ]. In prospective epidemiologic investigations, its levels in serum have been linked to abdominal obesity, insulin resistance and cardiovascular disease (CVD) [ 11 ]. TNF-α, a cytokine released by adipose tissue, instigates insulin resistance. In the endothelium, the TNF-α signaling pathway, which is regulated by nuclear factor kappa B (NF-KB), governs the expression of adhesion molecules such as sICAM-1 [ 12 ]. Many studies have found that women with PCOS have significantly higher ICAM-1, MCP-1 and TNF-α than women without PCOS [ 13 , 14 ]. interpretation was conducted using SPSS version 20.0 (SPSS, Inc, Chicago, IL), Epi Info version 2002 (Disease Control and Prevention Centres, Atlanta, GA) and GraphPad Prism 5 (GraphPad Software, La Jolla, CA) software. Result Six months of OCP therapy enhanced the expression of inflammatory genes viz ICAM-1, TNF-α and MCP-1 mRNA in PCOS women by 2.54, 2.05 and 1.74 folds, respectively, in this study. However, PAI-1 mRNA in the OCP group showed no significant increase. Furthermore, in cases, ICAM-1 mRNA expression positively correlated with body mass index (BMI) (p = 0.01), fasting insulin (p = 0.01), insulin 2 h p = 0.02), glucose 2 h (p = 0.01) and triglycerides (p = 0.01). TNF-α mRNA expression positively correlated with fasting insulin (p = 0.0007). MCP-1 mRNA expression positively cor‑ related with (BMI) (p = 0.002). Conclusion OCPs helped reduce clinical hyperandrogenism and regularise menstrual cycles in women with PCOS. [truncated]
Miao C et al., 2023·Front Endocrinol (Lausanne)·
Open Access
Primary ovarian insufficiency (POI) is a common gynecological disease with serious ramifications including low pregnancy rate and low estrogen symptoms. Traditional Chinese medicine is regarded as an effective treatment for POI. However, the therapeutic mechanism of it is unclear. In this study, a mouse model of primary ovarian insufficiency was established by intraperitoneal injection of cyclophosphamide (CTX) and He's Yang Chao Recipe (HSYC) concentrate was used for intragastric administration. Serum hormone levels (Anti-Müllerian Hormone, Estradiol, Progesterone, Luteinizing Hormone and Follicle Stimulating Hormone) and Oxidative Stress (OS) related products, superoxide dismutase (SOD), GSH-Px, and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Pathological changes in ovarian tissue were evaluated by hematoxylin and eosin staining, and flow cytometry was used to determine reactive oxygen species content and mitochondrial membrane potential levels in granulosa cells. Mitochondrial distribution and morphology were investigated using immunofluorescence staining. The level of mitophagy was evaluated by LC3 immunofluorescence staining and autophagosome counts using electron microscopy. Western blotting and qPCR were used to detect the expression of proteins and genes related to mitophagy and the NLRP3 inflammasome. After HSYC treatment, the ovarian damage was milder than in the CTX group. Compared with the CTX group; SOD, GSH-Px, and the total antioxidant capacity were significantly increased, while MDA and ROS were decreased in the HSYC treatment groups. Furthermore, mitochondrial distribution and membrane potential levels were improved after HSYC treatment compared to the CTX group. After the HSYC treatment, the LC3 fluorescent intensity and autophagosome counts were decreased. Similarly, mitophagy related markers PINK1, Parkin, LC3, and Beclin1 were decreased, while p62 was significantly increased, compared with the CTX groups. The mRNA and protein expression of NLRP3 inflammasome, NLRP3, caspase-1, GSDMD, IL-18, and IL-1β were significantly decreased in the HSYC treatment groups. This is the first study in molecular mechanisms underlying HSYC against granulosa cell injury in POI. HSYC protects ovaries from CTX-induced ovarian damage and oxidative stress. HSYC enhanced ovarian function in mice with primary ovarian insufficiency by inhibiting PINK1-Parkin mitophagy and NLRP3 inflammasome activation.
The number of sperm that reaches the oocytes in mammalian species is limited. In mice, 8-10 oocytes are ovulated, a similar number of sperm reaches the oocytes, and nearly all oocytes are fertilized via natural mating. Meanwhile, our improved superovulation technique (ultrasuperovulation: administration of inhibin antiserum and equine chorionic gonadotropin [IASe]) produced 100 oocytes from a single female C57BL/6 mouse but resulted in only approximately 20 fertilized oocytes via mating. We hypothesized that sperm shortage in the ampulla might cause this low fertilization rate. Mice were mated in the proestrus stage or after hormone injection, but ovulation timing was not considered. In clinical application, the rhythm method supports fertilization by testing the ovulation period and synchronizing the ovulation and copulation timings. Therefore, this study examined the effects of ovulation and copulation timings on in vivo fertilization in female mice with IASe. Synchronization of the ovulation and copulation timings increased fertilization efficiency in female mice with ultrasuperovulation. The number of embryos obtained post ovulation was three times higher than that obtained pre ovulation. This study suggests that synchronized ovulation and copulation timings improve the efficiency of in vivo fertilization in IASe-treated female mice. This technique can be used to produce genetically modified mice and develop technologies for infertility treatment.
We sought to better understand factors associated with ovarian aging in women with HIV (WWH).
HIV has been associated with diminished fertility, younger age at menopause, and shorter leukocyte telomere length (LTL), a marker of cellular aging. We herein examine cross-sectional and longitudinal associations between LTL, anti-Müllerian hormone (AMH), and HIV. We included WWH and HIV-negative women 12-50 years of age in the CARMA cohort with one or more study visit(s). LTL and AMH were measured by qPCR and ELISA, respectively. Women were analyzed in peak reproductive (<35 years) vs. late reproductive (≥35 years) life phases. Using multivariable mixed-effect linear or logistic regressions, we assessed factors associated with AMH and ΔAMH/year while adjusting for relevant confounders. WWH had shorter LTL and lower AMH levels compared to HIV-negative controls despite being of similar age. After adjusting for relevant factors, HIV was associated with 20% lower AMH levels in women under 35 years of age and shorter LTL was associated with AMH levels below 2 ng/ml among women aged 35 years or older. Longitudinally, ΔAMH/year was largely related to initial AMH level among older women, and to age in younger women. Factors associated with AMH change across women's reproductive lifespan. Lower AMH among peak reproductive aged WWH suggests that HIV may have an initial detrimental effect on ovarian reserve, an observation that may warrant counseling around pregnancy planning. In women aged 35 years or older, the association between shorter LTL and lower AMH suggests that the immune and reproductive aging connections are more important in this age group.
Brouillard A et al., 2023·Frontiers in endocrinology
Endogenous sex hormones and oral contraceptives (OCs) have been shown to influence key regions implicated in fear processing. While OC use has been found to impact brain morphology, methodological challenges remain to be addressed, such as avoiding selection bias between OC users and non-users, as well as examining potential lasting effects of OC intake. We investigated the current and lasting effects of OC use, as well as the interplay between the current hormonal milieu and history of hormonal contraception use on structural correlates of the fear circuitry. We also examined the role of endogenous and exogenous sex hormones within this network. We recruited healthy adults aged 23-35 who identified as women currently using (n = 62) or having used (n = 37) solely combined OCs, women who never used any hormonal contraceptives (n = 40), or men (n = 41). Salivary endogenous sex hormones and current users' salivary ethinyl estradiol (EE) were assessed using liquid chromatography - tandem mass spectrometry. Using structural magnetic resonance imaging, we extracted surface-based gray matter volumes (GMVs) and cortical thickness (CT) for regions of interest of the fear circuitry. Exploratory whole-brain analyses were conducted with surface-based and voxel-based morphometry methods. Compared to men, all three groups of women exhibited a larger GMV of the dorsal anterior cingulate cortex, while only current users showed a thinner ventromedial prefrontal cortex. Irrespective of the menstrual cycle phase, never users exhibited a thicker right anterior insular cortex than past users. While associations with endogenous sex hormones remain unclear, we showed that EE dosage in current users had a greater influence on brain anatomy compared to salivary EE levels and progestin androgenicity, with lower doses being associated with smaller cortical GMVs. Our results highlight a sex difference for the dorsal anterior cingulate cortex GMV (a fear-promoting region), as well as a reduced CT of the ventromedial prefrontal cortex (a fear-inhibiting region) specific to current OC use. Precisely, this finding was driven by lower EE doses. These findings may represent structural vulnerabilities to anxiety and stress-related disorders. We showed little evidence of durable anatomical effects, suggesting that OC intake can (reversibly) affect fear-related brain morphology.
Is sequential letrozole/human menopausal gonadotrophin (HMG) superior to letrozole alone in ovulation induction and pregnancy promotion among infertile women with polycystic ovary syndrome (PCOS)?
This open-label randomized controlled trial comparing sequential letrozole/HMG and letrozole alone included 174 participants enrolled from August 2019 to January 2020 at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. Infertile women aged between 18 and 40 years who met Rotterdam criteria for PCOS and without other known causes of infertility were selected for this study. Patients were randomly assigned at a 1:1 ratio to receive 2.5 mg letrozole on cycle days 3-7 (n = 87) or 2.5 mg letrozole on cycle days 3-7 with a sequential injection of 75 IU HMG on cycle days 8-10 for one treatment cycle (n = 87). The pregnancy outcome was recorded after one treatment cycle.
Women receiving sequential treatment achieved a significantly higher ovulation rate than those in the letrozole group (90.8% versus 70.1%, P = 0.001) and the live birth rate of the sequential group was significantly higher than that of the letrozole protocol (23.0% versus 10.3%, P = 0.025); there was no statistical variation with respect to adverse events. The data suggest that the sequential letrozole/HMG protocol may be superior to the letrozole alone protocol in terms of ovulation induction and pregnancy promotion among infertile women with PCOS.
Duane M et al., 2022·BMC Pregnancy Childbirth·
Open Access
Miscarriage is defined as spontaneous loss of pregnancy prior to 20 weeks gestation. With an estimated risk of 15% of clinically confirmed pregnancies ending in miscarriage, it is the most common adverse event in pregnancy. Woman's age is the primary risk factor for miscarriage, while medical conditions, including hormonal abnormalities, are also associated. Progesterone is essential for maintaining pregnancy. A short luteal phase may reflect inadequate levels of progesterone production, but it is unclear whether a short luteal phase correlates with an increase in the risk of miscarriage. Using a cohort study design, we conducted a secondary data analysis from four cohorts of couples who used a standardized protocol to track biomarkers of the female cycles. A short luteal phase was defined as less than 10 days, with < 11, < 9, and < 8 days as alternate definitions in sensitivity analyses. We included women who experienced a pregnancy with a known outcome, identified the length of the luteal phase in up to 3 cycles prior to conception and assessed the relationship with miscarriage using a modified Poisson regression analysis, adjusting for demographic characteristics, smoking, alcohol use and previous pregnancy history. In our sample of 252 women; the overall miscarriage rate was 18.7%. The adjusted incident risk ratio of miscarriage in women who had at least one short luteal phase < 10 days, compared to those who had none, was 1.01 (95% CI: 0.57, 1.80) Similar null risk was found when assessing alternative lengths of short luteal phase. Women who had short luteal phases < 10 days in all 3 cycles prior to the conception cycle had an incident risk ratio of 2.14 (95% CI: 0.7, 6.55). Our study found that a short luteal phase in the three cycles prior to conception was not associated with higher rates of miscarriage in an international cohort of women tracking their cycles, but our sample size was limited. Further research to determine if short luteal phases or luteal phase deficiency is associated with early pregnancy losses among preconception cohorts with daily tracking of cycle parameters, in addition to progesterone and human chorionic gonadotropin levels, is warranted. Additionally, future studies should include women with recurrent short luteal phases as a more likely risk factor than isolated short luteal phases.
Thyroid and Metabolic Function · Insulin and Metabolism
Endocrine disorders negatively influence the ovarian function, and increasing incidence of endocrine diseases with age may have further negative effects on pregnancy rate. Prospective cohort study of 231 consecutively enrolled patients underwent IVF treatment. In patients with known endocrine disorders, the laboratory parameters were corrected before IVF treatment. One hundred sixty one patients (69.7%) had at least one known and treated endocrine disorder (study group), and 70 patients were endocrine negative (control group). Endocrine disorders diagnosed were thyroid disorders (32.5%), diminished ovarian reserve (23.8%), insulin resistance (22.5%), PCOS (15.2%), hyperprolactinaemia (13.4%), obesity (12.1%), hypogonadotropic hypogonadism (0.8%) and congenital adrenal hyperplasia (0.2%). Before the IVF treatment, systematic endocrine laboratory examinations were performed in all patients. Higher age, BMI and FSH were found in the study group, while AMH level was lower. There were no differences in LH, E2, prolactin, TSH, FT3, FT4, TT, DHEAS, androstendione, 17-OHP and SHBG level between the study and control groups. The study group had higher baseline glucose, baseline insulin, 120-min glucose and 120-min insulin level after oral glucose tolerance test. With no difference in the IVF cycles performed, pregnancy rate was lower in the study group (61.43% vs. 34.16%; p = 0.003), and this difference (p = 0.0151) remained in age-corrected rates, as well. The analyses were also performed in individual endocrinology groups. The prevalence of endocrine disorders is high in females participating in IVF programs, and they are often accompanying each other. Even after proper correction, the presence of the endocrine disorder negatively influences the pregnancy rate in IVF treatment.
Vigil P et al., 2022·Front Endocrinol (Lausanne)·
Open Access
Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.
Premature ovarian insufficiency (POI) is a disorder of ovarian function, which occurs in approximately 3.7% of women younger than 40 years of age.1 The aetiologies of most cases were unknown and usually manifest as isolated organ senescence at early stage of diagnosis, only with long-term consequences of increased risk of metabolic syndrome or disease.2 We tried to explore the essence of POI from multiple dimensions. First, we found that upregulated genes in POI patients' ovarian granulosa cells were mainly enriched in metabolic pathways. Then, we profiled metabolites in the patients' sera and identified some metabolites with changed levels, including fumarate, arachidonate and acetoacetate, and the combination of hyodeoxycholic acid (HDCA) and acetoacetate may be used as one of potential biomarkers for POI. In addition, we found genes with upregulated transcription levels and differential methylated levels were enriched in oxidative stress pathways, which can be also elucidated from abnormal metabolism.The transcriptomes of patient and control granulosa cells were profiled, and 3966 differentially expressed genes (DEGs) (fold change > 2, Padj < .05) were identified (Table S1). Gene ontology analyses found that downregulated DEGs were mainly related to extracellular matrix/structure organization and different types of junctions. The upregulated DEGs were enriched in various catabolic/metabolic/biosynthetic/processes (Figure 1A). KEGG (Kyoto Encyclopaedia of Genes and Genomes) analysis showed that cytokine–cytokine receptor interaction, PI3K-Akt-signalling pathway and MAPK-signalling pathway were enriched in the downregulated genes, whereas the metabolic pathway was the most enriched in the upregulated genes. Moreover, other pathways, such as amino acid degradation, synthesis, peroxisome and oxidative phosphorylation, were also enriched in upregulated DEGs (Figure 1B). Several previous studies present valuable information about metabolic features of POI, which mainly focus on total cholesterol, lipoprotein cholesterol and glucose metabolism.3-6 Elevated levels of free fatty acids in follicular fluid were also reported as a potential driver of human POI.7 However, many of these results were inconsistent and not so comprehensive, although they have been noteworthy. Therefore, we carried out metabolomic analyses on serum samples from POI patients and controls. The outlined demographic characteristics of all recruited patients and controls were shown (Table 1). Two cohorts were enrolled in the metabolomic analyses in this study (Figure 2A). In the discovery cohort, a total of 6 categories of 181 features were reliably detected. POI patients could be clearly distinguished from controls by conducting multivariate statistical analysis (Figure 2B). Sixty-two features with VIP (variable importance in projection) values greater than 1 were identified and considered as differential metabolites (DMets). Subsequently, 26 of the 63 DMets were found to be significantly different between POI patients and controls using univariate t test analysis (p < .05) (Figure 2C; Table S2). Next, 32 out of the 62 features were validated using the validation cohort (Table S3). The numbers of metabolites in the union and intersections of the DMets identified from the discovery and validation cohorts were 39 and 13, respectively. Pearson's correlation coefficient figure and heat map analysis of the 39 DMets are shown (Figure S1). Enrichment and pathway analysis of the 39 DMets are shown respectively (Figure 2D,E). Out of the 13 validated DMets, 5 (acetoacetate, glutamate, C22:1, arachidonate and succinate) and 4 (HDCA, C22:0, homocitrulline [Hcit] and fumarate) were increased and decreased in the sera of POI patients, respectively. In addition, ROS and LDH (lactic dehydrogenase) were increased, and NADH and ATP were decreased in patients (Figure 2F). Receiver-operating characteristic (ROC) analysis was performed and 8 metabolites had area under curve (AUCs) greater than .7. In addition, the top two combinations with the highest AUCs were NADH plus acetoacetate (.868) and HDCA plus acetoacetate (.955) (Figure 2G,H). Furthermore, we reanalysed the human granulosa cell whole-genome DNA methylation profiling data that we previously generated.7 A number of 536 genes were hypermethylated in their differentially methylated regions (DMRs), whereas 1583 genes with hypomethylated DMRs were identified (Table S4; Figure S2). Integrating our transcriptomic and methylomic data, we found that 240 differentially expressed and methylated genes (DEMGs) were mainly enriched in response to oxidative stress, response to chemical stress, reactive oxygen species and hydrogen peroxide (Table S5; Figure S3A,B). DNMT3, DNMT1, methylenetetrahydrofolate reductase) and 5-methyltetrahydrofolate–homocysteine methyltransferase reductase, involved in methionine cycle, were differently expressed in POI patients' granulosa cells (Figure S3C). We next conducted network analysis on these DEMGs and the metabolites we detected (Table S6; Figure S4). The top five DMets were ATP, arachidonate, serotonin, glutamate and citrate. Glutamine synthetase (GLUL) and FOS were revealed as the top two hub genes in terms of connectivity with metabolites. GLUL, which catalyses the ATP-dependent conversion of glutamate and ammonia to glutamine, is related to 9 metabolites and was significantly upregulated and hypomethylated in exonic regions and the 3′UTRs. In-line with this, metabolic profiling showed decreased ATP and increased glutamate in POI patients. FOS was related to 8 metabolites and significantly upregulated and hypomethylated in exonic and 3′UTR regions (Figure 3A). It was also recently reported as a hub gene in the gene regulatory network of antioxidant in aged monkeys and human ovaries.8 In addition, we searched the human metabolome database for the associated enzymes/proteins of the 39 DMets. Changes in the expression and methylation status of these genes were displayed using Cytoscape software (Table S7; Figure S4). Joint-pathway analysis of DEMGs and DMets showed pathways those were impacted (Figure 3B). All the previous analyses were summarized as a metabolic network composed of DMets and enzymes of DEMGs that may contribute to the aetiology of POI (Figure 3C). Genes for NMNAT, PAR3 and NAMPT, enzymes involved in the synthesis or consumption of nicotinamide adenine dinucleotide (NAD+), which were reported associated with POI or ovarian ageing,9, 10 were upregulated or downregulated DEGs. In summary, the integrated analyses of transcriptomic and methylomic data from granulosa cells of the human ovary and the metabolomic data from human sera have identified increased levels of acetoacetate and arachidonate and disturbances in the TCA (tricarboxylic acid) cycle, fatty acids, ketone bodies and antioxidative processes, all of which contribute to decreased levels of NADH and ATP, increased oxidative stress and eventually ovarian premature senescence. Our data not only yielded valuable fundamental insights into its pathological mechanism but also would aid in the development of new therapeutic targets for POI. The causal effect relationship between gene expression and metabolic changes warrants further investigation in the future. This work was supported by the National Natural Science Foundation of China (81971349 and 81300456 to Cuiling Lu) and National Key Research and Development Program of China (2018YFE0201100 to Chunsheng Han and 2016YFC1000302 to Xiumei Zhen). The authors declare that there is no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Check JH et al., 2022·Gynecol Reprod Health·
Open Access
Many infertility specialists advise women with diminished oocyte reserve (DOR) that their remaining oocytes probably are of poor quality similar to women of advanced reproductive age. There have been studies, especially employing in vitro fertilization-embryo transfer (IVF-ET), showing very poor live delivered pregnancy rates despite the transfer of morphologically normal embryos in women even with mild DOR. However, other data suggests that the low pregnancy rates are related to the use of high dosages of follicle stimulating hormone (FSH) drugs which down-regulate some key FSH dependent enzymes, cytokines, or proteins required for proper embryo implantation. Some studies have shown that techniques that favor FSH receptor up-regulation, rather than down-regulation, can provide the chance of live delivery 80% as well in women ≤ 35 with DOR, 70% for women 36-39, and 50% for women 40-42. Though some infertility specialists will encourage women whose only infertility issue is DOR, who reject the initial suggestion to consider donor oocytes, to proceed immediately with IVF-ET to maximize success, pregnancies are quite possible with natural conception. Thus, it seems imprudent to make couples undergo the financial burden of IVF-ET in the absence of a significant tubal or male factor problem. Not only have live deliveries occurred in women with DOR, using the principle described to achieve a mature dominant follicle followed by proper luteal phase support, with serum FSH levels over 100 mIU/mL, but also serum Anti-Mullerian Hormone (AMH) levels that were undetectable. This even applies to women in overt menopause where FSH up-regulation was achieved by negative feedback to the pituitary using ethinyl estradiol inhibiting FSH release, or down-regulation of hypothalamic-pituitary stimulation of FSH production by using gonadotropin releasing hormone agonists or antagonists.
Gao Y et al., 2022·Frontiers in Endocrinology·
Open Access
Polycystic ovary syndrome (PCOS) is one of the most common reasons for infertility. The consensus of the treatment of infertile women with PCOS is ovulation induction (OI) for six to nine attempts beforein vitrofertilization (IVF)/intracytoplasmic sperm injection (ICSI). Nowadays, more attention was paid to a rising, noninvasive treatment, intrauterine insemination (IUI), as some experts claimed IUI could benefit PCOS patients with infertility. Our study means to investigate the outcomes of IUI for PCOS patients and if patients’ previous OI cycles can be a predictive factor for IUI outcomes. A total of 1,086 PCOS patients was included and 1,868 IUI cycles were performed between January 2007 and July 2021 in the department of assisted reproduction in Shanghai Ninth People’s Hospital. All included patients underwent IUI treatments with letrozole+human menopausal gonadotropin (LE+hMG) for ovarian stimulation. The pregnancy outcomes were not associated with the attempts of failed OI cycles previously. Specifically, the clinical pregnancy rate was 21.14% for PCOS patients without previous OI cycles, 21.95% for PCOS patients with 1-2 previous OI cycles and 23.64% for PCOS patients with 3 or more previous OI cycles (p=0.507). The corresponding live birth rate was 16.64%, 18.06%, and 18.68%, respectively, of which the difference was not statistically significant (p=0.627). The cumulative rate per patient was 38.59% for clinical pregnancy and 31.03% for live birth, and approximately 98% of the pregnancies occurred in the first 3 cycles of IUI. PCOS women with different attempts of OI cycles had similar pregnancy outcomes after IUI, thus a history of repeated failures of OI treatments was not a predictive factor for the pregnancy outcomes in IUI cycles. Most pregnancies occurred in the first three cycles of IUI, so we strongly recommended three attempts of IUI for PCOS women before they switched to IVF/ICSI. Generally, IUI might be an assist for infertile women with PCOS before IVF/ICSI and might accelerate pregnancy for target women without invasive manipulations.
Peters BA et al., 2022·International Journal of Women's Health
The gut microbiome is an important contributor to human health, shaped by many endogenous and exogenous factors. The gut microbiome displays sexual dimorphism, suggesting influence of sex hormones, and also has been shown to change with aging. Yet, little is known regarding the influence of menopause - a pivotal event of reproductive aging in women - on the gut microbiome. Here, we summarize what is known regarding the interrelationships of female sex hormones and the gut microbiome, and review the available literature on menopause, female sex hormones, and the gut microbiome in humans. Taken together, research suggests that menopause is associated with lower gut microbiome diversity and a shift toward greater similarity to the male gut microbiome, however more research is needed in large study populations to identify replicable patterns in taxa impacted by menopause. Many gaps in knowledge remain, including the role the gut microbiome may play in menopause-related disease risks, and whether menopausal hormone therapy modifies menopause-related change in the gut microbiome. Given the modifiable nature of the gut microbiome, better understanding of its role in menopause-related health will be critical to identify novel opportunities for improvement of peri- and post-menopausal health and well-being.
Prior JC, 2022·The Cambridge Handbook of Evolutionary Perspectives on Sexual Psychology·
Periodic vaginal bleeding occurs in humans (who are henceforth called “women,” a word describing culture as well as biology), old-world apes, and few other mammals. By current concepts, women’s menstrual cycles provide estrogen for thirty to fifty years; following one year of no flow they become menopausal and “estrogen deficient.” By contrast we now know that the purpose of menstrual cycles is to supply all cells and tissues with the balanced essential actions of estradiol (E2) and progesterone (P4) produced in feedback-controlled patterns to facilitate fecundability and preserve younger women’s well-being. We also now know that menopausal women’s health is negatively affected (by increased osteoporosis, heart disease, breast and endometrial cancers) if those past menstrual cycles produced inadequate net P4 to counterbalance and complement E2’s actions. Menstrual periodicity, flow, and ovulatory characteristics in women reflect the integrated actions/interactions of the central nervous system through the hypothalamus and pituitary, ideally leading to each cycle’s stimulation of a dominant egg-containing follicle. That follicle, by central complex feedback loops, produces the cyclic, graded amounts of estradiol (E2) and progesterone (P4) for that threeto five-week period and releases a viable egg. Central reproductive connections allow adult premenopausal women’s menstrual cycle periodicity, ovulation or not, and luteal phase lengths, that can be adapted to the challenges and demands of each woman’s current physiological and sociocultural/emotional environments. These new ideas are based on the differing and complementary cellular and tissue actions of E2 and P4. E2 is essential for cell growth and stimulates cell proliferation. P4 uniquely counterbalances and controls proliferation while stimulating cell differentiation and tissue maturation. Thus, E2–P4 actual and relative productions integrate cycles within each woman’s reproductive lifecycle (adolescent, premenopausal, perimenopausal), and are related to her nutrition, illness, energy expenditure, and social/emotional/spiritual environments. The subtlest indication of a stressed reproductive system is truncated P4 production in the short luteal phase within a normal-length, ovulatory menstrual cycle. This adaptation protects a woman from pregnancy when she has inadequate net energy balance or is under emotional/social/spiritual or physical duress. Thus, a normal luteal phase length within a threeto five-week regular menstrual cycle is a bellwether of women’s well-being. By contrast, regular cycles with ovulatory disturbances (anovulation or short luteal phases; E2>P4) predict current decreased well-being and poor later life health. The purpose of this review is to provide a practical approach to understanding this new women’s menstrual cycle balanced E2–P4 paradigm applied to common clinical situations including subfertility with regular cycles, premenstrual symptoms, and heavy menstrual flow.
Ranisavljevic N et al., 2022·Front Endocrinol (Lausanne)·
Open Access
Progesterone plays a key role in implantation. Several studies reported that lower luteal progesterone levels might be related to decreased chances of pregnancy. This systematic review was conducted using appropriate key words, on MEDLINE, EMBASE, and the Cochrane Library, from 1990 up to March 2021 to assess if luteal serum progesterone levels are associated with ongoing pregnancy (OP) and live birth (LB) rates (primary outcomes) and miscarriage rate (secondary outcome), according to the number of corpora lutea (CLs). Overall 2,632 non-duplicate records were identified, of which 32 relevant studies were available for quantitative analysis. In artificial cycles with no CL, OP and LB rates were significantly decreased when the luteal progesterone level falls below a certain threshold (risk ratio [RR] 0.72; 95% confidence interval [CI] 0.62-0.84 and 0.73; 95% CI 0.59-0.90, respectively), while the miscarriage rate was increased (RR 1.48; 95% CI 1.17-1.86). In stimulated cycles with several CLs, the mean luteal progesterone level in the no OP and no LB groups was significantly lower than in the OP and LB groups [difference in means 68.8 (95% CI 45.6-92.0) and 272.4 (95% CI 10.8-533.9), ng/ml, respectively]. Monitoring luteal serum progesterone levels could help in individualizing progesterone administration to enhance OP and LB rates, especially in cycles without corpus luteum. SYSTEMATIC REVIEW Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=139019, identifier 139019.
Bouchard TP et al., 2022·J Womens Health (Larchmt)·
Some studies have suggested minor changes in the menstrual cycle after COVID-19 vaccination, but more detailed analyses of the menstrual cycle are needed to evaluate more specific changes in the menstrual cycle that are not affected by survey-based recall bias. Using a pretest-post-test quasi-experimental evaluation of menstrual cycle parameters before and after COVID-19 vaccination, we conducted an anonymous online survey of two groups of North American women who prospectively monitor their menstrual cycle parameters daily including bleeding patterns, urinary hormone levels using the ClearBlue Fertility Monitor, or cervical mucus observations. The primary outcome measures were cycle length, length of menses, menstrual volume, estimated day of ovulation (EDO), luteal phase length, and signs of ovulation. Perceived (subjective) menstrual cycle changes and stressors were also evaluated in this study as secondary outcome measures. Of the 279 women who initiated the survey, 76 met the inclusion criteria and provided 588 cycles for analysis (227 pre-vaccine cycles, 145 vaccine cycles, 216 post-vaccine cycles). Although 22% of women subjectively identified changes in their menstrual cycle, there were no significant differences in menstrual cycle parameters (cycle length, length of menses, EOD, and luteal phase length) between the pre-vaccine, vaccine, and post-vaccine cycles. COVID-19 vaccines were not associated with significant changes in menstrual cycle parameters. Perceived changes by an individual woman must be compared with statistical changes to avoid confirmation bias.
Yin WW et al., 2022·BMC Endocr Disord·
Open Access
The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin (MET), Gonadotropin-releasing hormone agonist (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET). Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. The extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis. After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD = -1.43, 95% CI: -2.05 to -0.80, P < 0.00001). After MET treatment, the serum AMH decreased in polycystic ovary syndrome (PCOS) patients (WMD = -1.79, 95% CI: -2.32 to -1.26, P < 0.00001), in both obese and non-obese patients. GnRH-a treatment in endometriosis patients led to dynamic changes in the serum AMH levels, that is, ascent at 1 month (P = 0.05), and descent at 3 months (P = 0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD = 0.18, 95% CI: 0.09 to 0.27, P < 0.0001). After VD treatment the serum AMH increased, and it was obvious in non-PCOS patients (WMD = 0.78, 95% CI: 0.34 to 1.21, P = 0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD = -1.24, 95% CI: -1.87 to -0.61, P = 0.0001). Serum AMH levels may be affected in the short term after drug application. Specifically, OC, MET and CC lead to decreased AMH level, DHEA and VD lead to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medications should be taken into consideration when AMH is used as a marker of ovarian reserve.
Vigil P et al., 2022·Front Glob Womens Health·
Open Access
Stress is known to be associated with adverse health outcomes. The COVID-19 pandemic and its associated lockdowns are examples of chronic stressors. Lockdown measures inadvertently caused significant psychological distress and became a powerful source of anxiety/stress, sleep disturbances, nutritional changes and weight gain. Stress is known to impact women's health specifically, through hypothalamic-pituitary-gonadal (HPG) axis dysfunction and resultant ovulatory dysfunction. Such dysfunction may manifest in menstrual irregularities and/or infertility due to hypothalamic hypogonadism. Here, we review the key physiological mediators of stress and associated ovulatory dysfunction. The kisspeptinergic system is comprised of sets of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and the arcuate nucleus (ARC). This system links nutrition, reproductive signals and stress. It plays a key role in the function of the HPG axis. During chronic stress, the kisspeptinergic system affects the HPG axis, GnRH pulsatility, and, therefore, ovulation. Leptin, insulin and corticotrophin-releasing hormone (CRH) are thought to be additional key modulators in the behavioral responses to chronic stress and may contribute to stress-related ovulatory dysfunction. This mini-review also summarizes and appraises the available evidence on the negative impact of chronic stress as a result of the COVID-19 pandemic lockdowns. It proposes physiological mechanisms to explain the observed effects on women's reproductive health and well-being. The review suggests areas for future research.
Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women's lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.
Iwasa T et al., 2022·Reproductive medicine and biology
It is known that metabolic and nutritional disturbances induce reproductive dysfunction in females. The main cause of these alterations is reduced gonadotrophin-releasing hormone (GnRH) secretion from the hypothalamus, and the underlying mechanisms have gradually been elucidated. The present review summarizes current knowledge about the effects of nutrition/metabolism on reproductive functions, especially focusing on the GnRH regulation system. Various central and peripheral factors are involved in the regulation of GnRH secretion, and alterations in their activity combine to affect GnRH neurons. Satiety-related factors, i.e., leptin, insulin, and alpha-melanocyte-stimulating hormone, directly and indirectly stimulate GnRH secretion, whereas orexigenic factors, i.e., neuropeptide Y, Agouti-related protein, orexin, and ghrelin, attenuate GnRH secretion. In addition, kisspeptin, which is a potent positive regulator of GnRH, expression is reduced by metabolic and nutritional disturbances. These neuroendocrine systems may be defensive mechanisms, which help organisms to survive adverse conditions by temporarily suppressing reproduction.
Thyroid and Metabolic Function · Insulin and Metabolism
Cabre HE et al., 2022·Deutsche Zeitschrift fur Sportmedizin
If athletes develop low energy availability (LEA), it can lead to a Relative Energy Deficiency in Sport (RED-S) syndrome which has severe health consequences if not treated. A narrative review of the most recent and pertinent literature on the topic, with special emphasis on women. In assessing the current literature, we have synthesized: i) the scientific implications of LEA and RED-S, ii) the clinical manifestations of the conditions currently available for detection, as well as iii) the practical implications for healthcare and support for female athletes and teams in planning intervention or prevention strategies (maintaining EA >45 kcal/kg FFM/day). The 'Female Athlete Triad" emerged in the 1990s as researchers understood more of the etiological adaptation of female athlete health to sports training. In the last 10 years, the scientific community has recognized that the 'Triad' approach was too narrow in focus, and the broader concept of RED-S emerged. Both the Triad and RED-S are consequences of a frequently prevalent LEA in athletes (<30 kcal/kg FFM/day). Developing LEA and RED-S compromises training adaptation, performance capacity, and health in athletes. For these reasons, it is critical that an athlete's support team recognize the behaviors that may indicate RED-S evolution. In this way, we can assist female athletes in reaching their full potential in sports while protecting their health. Kommt es bei männlichen oder weiblichen Athleten zu einer dauerhaft niedrigen Energieverfügbarkeit (low energy availability, LEA), steigt das Risiko eines Relative Energy Deficiency in Sports (RED-S) Syndroms, welches unbehandelt schwerwiegende kurz- wie langfristige gesundheitliche Konsequenzen haben kann. Ein narratives Review der aktuellsten und relevantesten Literatur mit besonderem Fokus auf weibliche Betroffene. Aus der verfügbaren Literatur haben wir i) wissenschaftliche Implikationen von LEA und RED-S, ii) klinische Manifestationen und iii) praktische Implikationen für die medizinische Behandlung, Unterstützung betroffener Teams, sowie präventive Strategien herausgearbeitet. In den 1990er Jahren erfasste mit zunehmendem Verständnis um die frauen-spezifischen Anpassungen an sportliche Aktivität das Phänomen der “Female Athlete Triad” die Aufmerksamkeit von Wissenschaftlern und Medizinern. In der vergangenen 10 Jahren zeigte sich, dass der “Triad”-Ansatz zu kurz greift und es wurde stattdessen das breiter gefasste Konzept des RED-S etabliert. Sowohl die “Female Athlete Triad”, als auch RED-S sind letztendlich Konsequenzen der häufig prävalenten LEA in Athletinnen mit weitreichenden Konsequenzen auf die Trainingsadaptation, Wettkampfleistung und kurz-, wie langfristige Gesundheit der Betroffenen. Aus diesem Grund ist das Erkennen von Verhaltensweisen, welche auf ein RED-S hindeuten durch Trainer und weiterer Stakeholder einer Athletin beziehungsweise eines Teams essenziell für eine gesundheitsund leistungserhaltende Betreuung von betroffenen Athletinnen.
Thyroid and Metabolic Function · Insulin and Metabolism
Westerman R et al., 2021·Reprod Biomed Soc Online·
Open Access
Metabolic risk factors such as obesity are considered major obstacles to female fertility. Chronic infertility imposes psychological and social burdens on women because infertility violates societal gender roles. Although the prevalence of obesity among women is expected to increase in the future, the relevance of metabolic status for fertility is still underestimated. However, the assessment of metabolic risk factors is highly relevant for understanding fertility disorders and improving infertility treatment. This narrative review discusses the associations of metabolic risk factors (e.g. obesity, female athlete triad, oxidative stress) with significant infertility. An electronic search was conducted for studies published between 2006 and 2020 in Cumulative Index to Nursing and Allied Health Literature, ScienceDirect, PubMed, Scopus, Google Scholar and related databases. In total, this search identified 19,309 results for polycystic ovary syndrome, 28,969 results for endometriosis, and only 1611 results for idiopathic and/or unknown infertility. For the present narrative review, 50 relevant studies were included: 19 studies were on obesity, 24 studies investigated the female athlete triad, and seven studies addressed other risk factors, including reactive oxygen species. This narrative review confirms the direct impact of obesity on female infertility, while the effect of other risk factors needs to be confirmed by large-scale population studies.
Cumulus cells (CCs) originating from undifferentiated granulosa cells (GCs) differentiate in mural granulosa cells (MGCs) and CCs during antrum formation in the follicle by the distribution of location. CCs are supporting cells of the oocyte that protect the oocyte from the microenvironment, which helps oocyte growth and maturation in the follicles. Bi-directional communications between an oocyte and CCs are necessary for the oocyte for the acquisition of maturation and early embryonic developmental competence following fertilization. Follicle-stimulation hormone (FSH) and luteinizing hormone (LH) surges lead to the synthesis of an extracellular matrix in CCs, and CCs undergo expansion to assist meiotic resumption of the oocyte. The function of CCs is involved in the completion of oocyte meiotic maturation and ovulation, fertilization, and subsequent early embryo development. Therefore, understanding the function of CCs during follicular development may be helpful for predicting oocyte quality and subsequent embryonic development competence, as well as pregnancy outcomes in the field of reproductive medicine and assisted reproductive technology (ART) for infertility treatment.
Estradiol, an estrogen steroid hormone, serves as the dominant female hormone and its levels fluctuate during lifetime. In women, after the menopause, all estrogens and almost all androgens are locally developed in the peripheral tissues from dehydroepiandrosterone (DHEA). However, the effect of DHEA supplementation on estradiol levels in women is unclear as previously published data has resulted in conflicting findings. Thus, we conducted the present dose-response meta-analysis of randomized controlled trials (RCTs) evaluating the influence of DHEA on estradiol concentrations in women. The PubMed/Medline, Embase, Web of Science and Scopus databases were systematically searched for articles published on this topic until May 10, 2021. No time or language restrictions were applied. The data were expressed as weighted mean differences (WMDs) and 95% confidence intervals (CI), and a P-value of less than 0.05 was considered to be statistically significant. The pooled results were obtained using the generic inverse of variance method with a random effects model. A total of 21 arms, including 1223 participants (case = 610, and control = 613), reported estradiol concentrations as an outcome measure. The overall results demonstrated that estradiol significantly increased following the administration of DHEA (WMD: 7.02 pg/mL, 95% CI: 5.43, 8.62, P = 0.000). The stratified analyses revealed that the elevation of estradiol concentrations was more pronounced in subjects aged ≥60 years old (WMD: 8.56 pg/mL, 95% CI: 6.97, 10.16, I2 = 94%) and in those receiving DHEA supplements for ≥26 weeks (WMD: 7.30 pg/mL, 95% CI: 6.28, 8.32, I2 = 61%). Moreover, estradiol levels increased significantly with DHEA dosages of 50 mg/day (WMD: 7.75 pg/mL, 95% CI: 9.12, 9.39, I2 = 94%) and when DHEA was prescribed to postmenopausal women (WMD: 7.61 pg/mL, 95% CI: 5.97, 9.24, I2 = 93%). This meta-analysis has provided a comprehensive overview of the effects of DHEA administration on circulating estradiol levels, far beyond the available evidence from different RCTs. Subsequent subgroup analyses revealed that postmenopausal women, females aged 60 years and above, those on DHEA dosages of 50 mg/day and those receiving DHEA for ≥26 weeks registered a more pronounced elevation of the circulating estradiol levels.
This study was designed to investigate if whole dimension subcortical ovarian administration of platelet-rich plasma with gonadotropin, in proximity to most ovarian follicles, is effective in restoring ovarian functions in women during early menopause. Platelet-rich plasma, prepared from 40 mL of autologous peripheral blood using the buffy coat method, was injected into extended subcortical area of bilateral ovaries along with recombinant follicle-stimulating hormone (rFSH) (Gonal-F 300IU) under laparoscopic guidance. The posttreatment ovarian folliculogenesis and serum levels of FSH, luteinizing hormone (LH), and estradiol were followed up for 6 months at weekly to monthly intervals. IVF was carried out in women resuming ovulatory functions. Twelve early menopausal women with mean age of 44.42 ± 2.84 were enrolled. After treatment, 11 women resumed their menstrual period in 37.1 ± 23.5 days. Their average serum FSH was 70.47 ± 20.92 and 26.22 ± 17.55 IU/L, luteinizing hormone was 34.81 ± 11.86 and 14.3 ± 12.8 IU/L, before and after treatment, respectively. The mid-cycle E2 was 251.1 ± 143.8 pg/mL. Ten oocyte retrievals were carried out among six participants, four of them received controlled ovarian stimulation and another two using natural ovulation cycles. Thirteen mature eggs were retrieved which were then ICSI fertilized to obtain 10 normally fertilized 2PN oocytes. Two participants had cleavage stage embryos transferred of which one achieved clinical pregnancy. Whole dimension subcortical ovarian administration of platelet-rich plasma with gonadotropin was shown to restore ovarian functions, at least temporarily, and could increase the probability of pregnancy using autologous oocytes in women with early menopause.
Thyroid and Metabolic Function · Thyroid Disorders
Saei Ghare Naz M et al., 2021·Int J Endocrinol Metab·
Open Access
Menstrual cycle is considered the fifth vital sign among women. This study aimed to summarize the menstrual disturbances in different endocrine disorders.
Evidence Acquisition: In this narrative review, relevant studies (up to December 2019) were searched based on the MeSH keywords diabetes, polycystic ovary syndrome, Cushing's syndrome, thyroid dysfunction, hyperprolactinemia, menstrual cycle, uterine bleeding, and menstruation. Databases used for searching articles included Google Scholar, Scopus, PubMed, and Web of science for observational, experimental, and review studies. Endocrine disorders trigger the onset of menstrual disturbance across the reproductive lifespan of women. Endocrine glands (pituitary, thyroid, pancreas, adrenal, and ovaries) have a functional role in endocrine regulation of the menstrual cycle. According to available evidence, oligomenorrhea (cycles longer than 35 days) is the most common menstrual disturbance among endocrine disorders (thyrotoxicosis, hypothyroidism, polycystic ovary syndrome, Cushing's syndrome, and diabetes). Complex endocrine pathways play an essential role in a women's menstrual calendar. The menstrual cycle length and amount of bleeding can be indicative of endocrine disorders. Further studies are needed to identify the unknowns about the association between endocrine disorders and the menstrual cycle.
This paper reviews the recent literature on menstrual cycle phase effects on outcomes relevant to anxiety and PTSD, discusses potential neurobiological mechanisms underlying these effects, and highlights methodological limitations impeding scientific advancement. The menstrual cycle and its underlying hormones impact symptom expression among women with anxiety and PTSD, as well as psychophysiological and biological processes relevant to anxiety and PTSD. The most consistent findings are retrospective self-report of premenstrual exacerbation of anxiety symptoms and the protective effect of estradiol on recall of extinction learning among healthy women. Lack of rigorous methodology for assessing menstrual cycle phase and inconsistent menstrual cycle phase definitions likely contribute to other conflicting results. Further investigations that address these limitations and integrate complex interactions between menstrual cycle phase-related hormones, genetics, and psychological vulnerabilities are needed to inform personalized prevention and intervention efforts for women.
Lisova KM et al., 2021·Journal of medicine and life
The purpose of the study was TO analyze the fetoplacental complex hormone levels and changes in their dynamics in pregnant women with miscarriage and the impact of these features on the subsequent course of pregnancy. Hormone levels were determined at different stages of gestation in 50 healthy women with a physiological course of pregnancy (control group) and 50 pregnant women with a history of miscarriage (main group). The women of the main group had a significantly slower rate of increase in hormones and a lag in quantitative indicators than the control group. The estradiol level indicators were 4.1 times (76.0%) and 2.89 times (65.5%) lower in women with miscarriage in the embryonic and late fetal period, respectively, compared to healthy women. Indicators of the level of placental lactogen and chorionic gonadotropin in the embryonic period in women with miscarriage were lower by 39.1% and 50.9%, respectively, compared to healthy women. In the late fetal period, the level of these hormones was lower by 72.9% and 35.4%, respectively. In the embryonic and late fetal periods, progesterone levels were lower by 67.4% and 68.4%, respectively, compared to the control group. The data obtained are evidence of a pronounced hormonal abnormality of the placenta, and hence a marker of fetoplacental dysfunction, which on the background of miscarriage develops at the early stages and continues to progress with the course of pregnancy.
The reference range and potential value of inhibin B are still unclear and controversial. This study aimed to define the variation trend of inhibin B in healthy women with age and explore its value in the reflection of ovarian reserve. A total of 2524 healthy reproductive age women from eight medical institutes nationwide were recruited. The variation tendency of inhibin B with age was primarily established in the first group of 948 women and validated in another 605. We evaluated the relationship between inhibin B and classic ovarian reserve and function markers. The potency of inhibin B in predicting AFC <5-7 was also estimated and compared with FSH. The nomogram showed that serum levels of inhibin B rapidly decreased after the age of 40. Inhibin B was positively correlated with AMH (R = 0.57, P < 0.001), AFC (R = 0.34, P < 0.001) and testosterone (R = 0.10, P = 0.002), and negatively correlated with FSH (R = -0.41, P < 0.001) and LH (R = -0.20, P < 0.001) and FSH/LH (R=-0.18, P < 0.001), while no correlation was found with PRL. Unexpectedly, Inhibin B (AUC = 0.74, P < 0.001 for the establishment population; AUC = 0.78, P < 0.001 for the validation population) had a slightly higher value than FSH (AUC = 0.71, P < 0.001 for the establishment population; AUC = 0.72, P < 0.001 for the validation population) in diagnosing AFC <5-7. For healthy reproductive age women, the decline of inhibin B can reflect decreased ovarian reserve effectively, having a good consistency with AMH and AFC. More importantly, inhibin B had an advantage in predicting AFC <5-7 compared with FSH, which suggested the potential of inhibin B in predicting ovarian response.
Androgenic Polycystic Ovary Syndrome (PCOS) creates physical/emotional burdens in 4-20% of premenopausal women living with PCOS (WLWP) including: few menstruations per year, subfertility, hirsutism/acne and low quality of life by validated PCOS Questionnaire (PCOSQ). Combined hormonal contraceptives (CHC), the current standard-of-care, improve PCOSQ only 16%; with stopping CHC, benefits disappear within 6-months. We hypothesize too-fast brain/luteinizing hormone (LH) pulses cause PCOS. Progesterone (P4) slows LH when testosterone (FreeT) is normal. Combining two approved medications, Cyclic P4 with anti-androgen, Spironolactone (Sp), will likely provide effective, durable benefits. WLWP lit-review suggested significant P4 7-14-day benefits. A 6-month prospective feasibility study of CyclicP4/Sp is necessary. Overall Perform a pilot study in 40 WLWP on Cyclic P4 (300 mg/bedtime, 14 days/month) plus Spironolactone (Sp, 200 mg/d). Feasibility: Assess longitudinal within-WLWP 6-month changes in: 1) PCOSQ; 2) FreeT, HbA1c, and LH; plus 3) WLWP's acceptance of CyclicP4/Sp. Single-centre, prospective, longitudinal single cohort study. Recruit \~7-8 WLWP/month over 4-6 months; 85% retention. Eligible WLWP have physician-diagnosed PCOS, are 1-month off CHC/metformin, ages 19-35 (avoiding adolescence/perimenopause), HbA1c <6.4% (no diabetes) and commit to non-hormonal contraception, if needed. Recruitment uses online, internet, strategic ads and tear-tab posters. Measures at 0 and 6 months: as above plus K+ (safety assessment). Menstrual Cycle Diary monitoring (flow, adherence), 2 visits, monthly telephone/emails for support and assessment of any adverse effects. Statistical analysis: changes by paired T-test.
A feasibility 6-month study of CyclicP4/Sp will facilitate a CIHR-funded RCT of CHC versus this innovative and likely beneficial treatment for WLWP.
Sims ST et al., 2021·BMJ open sport & exercise medicine
As the number of female athletes competing rises globally, training methodologies should reflect sex differences across critical metrics of adaptation to training. Surrogate markers of the autonomic nervous system (ANS) used for monitoring training load are heart rate variability (HRV) and resting heart rate (RHR). The aim was to investigate ovarian hormone effects on standard recovery metrics (HRV, RHR, respiratory rate (RR) and sleep duration) across a large population of female athletes. A retrospective study analysed 362 852 days of data representing 13 535 menstrual cycles (MC) from 4594 respondents (natural MC n=3870, BC n=455, progestin-only n=269) for relationships and/or differences between endogenous and exogenous ovarian hormones on ANS. HRV and return to baseline (recovery) decreased as resting HR and RR increased (p<0.001) from the early follicular to the late luteal phase of the MC. Patterning was paradoxical across phases for users of combined hormonal contraception (BC) as compared with the patterning of the MC. HRV and recovery start elevated and drop off quickly during the withdrawal bleed, rising through the active pill weeks (p<0.001). Progestin-only users had similar patterning as the MC. The relationship between normalised recovery and previous day strain is modulated by birth control type. BC exhibited steeper declines in recovery with additional strain-normalised recovery decreases by an additional 0.0055±0.00135 (p<0.001) per unit of strain; with no significant difference between MC and progestin-only (p=0.19). The patterning of ANS modulation from ovarian hormones is significantly different between naturally cycling women and those on BC, with the patterning dependent on the type of contraception used.
Chaer R et al., 2020·Diseases (Basel, Switzerland)
Reproductive health is compromised during anorexia nervosa (AN). However, it is still unclear whether this medical complication is reversible after recovery from AN. The purpose of this paper was to conduct a systematic review of the major reproductive health outcomes in females after recovery from AN. The review was conducted in adherence to preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines. Data were collated using meta-analysis and a narrative approach. Of the 1186 articles retrieved, five studies met the inclusion criteria and were reviewed. These studies monitored weight-restored females who had recovered from AN for a follow-up period of between six and 18 years. Their narrative analysis revealed that appropriate treatment of AN leads to the normalization of reproductive function, especially in terms of fertility, pregnancy, and childbirth rates. The meta-analysis confirmed this finding, where the pooled odds of childbirth rates between the AN group and the general population was not statistically significant (OR = 0.75, 95% CI: 0.43-1.29, p = 0.41). We conclude that if patients undergo appropriate eating-disorder treatment and weight restoration, it appears to be unlikely that reproductive health is affected by AN. However, since this finding is derived from only a few studies, it requires replication and confirmation.
Larsen SV et al., 2020·Acta Psychiatr Scand·
Open Access
Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging. [(11)C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions. We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate region-based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (-12.8% (95% CI [-21.0; -3.9], P(corrected) = 0.03). We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.
Sundström-Poromaa I et al., 2020·Front Neuroendocrinol·
Open Access
Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
DeMayo FJ et al., 2020·Journal of molecular endocrinology
Progesterone's ability to maintain pregnancy in eutherian mammals highlighted this steroid as the 'hormone of pregnancy'. It was the unique 'pro-gestational' bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses ('progestational proliferation') of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone's involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focuses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics which reveal the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.
Sfakianoudis K et al., 2020·Journal of clinical medicine
Intraovarian platelet-rich plasma (PRP) infusion was recently introduced in the context of addressing ovarian insufficiency. Reporting on its effectiveness prior to adopting in clinical routine practice is imperative. This study aims to provide pilot data regarding PRP application for ovarian rejuvenation. Four pilot studies were conducted on poor ovarian response (POR), premature ovarian insufficiency (POI), perimenopause, and menopause, respectively. Each pilot study reports on thirty patients, 120 participants were recruited in total. All participants provided written informed consent prior to treatment. Primary outcome measures for the POR pilot study were levels of anti-müllerian hormone (AMH), antral follicle count (AFC) and oocyte yield. For the POI, perimenopausal and menopausal pilot studies primary outcome measures were restoration of menstrual cycle, and Follicle Stimulating Hormone (FSH) levels. A significant improvement on the hormonal profile and the ovarian reserve status was noted, along with improved intracytoplasmic sperm injection (ICSI) cycle performance concerning POR participants. Menstruation recovery was observed in 18 out of 30 POI patients, along with a statistically significant improvement on levels of AMH, FSH, and AFC. Similarly, 13 out of 30 menopausal women positively responded to PRP treatment. Finally, menstruation regularity, improved hormonal levels and AFC were reported for 24 out of 30 perimenopausal women. To conclude, PRP infusion appears to convey promising results in addressing ovarian insufficiency.
This study reports on 632 cycles from 105 women who were using the CREIGHTON MODEL FertilityCare™ System to avoid pregnancy and had either a serious reason to avoid pregnancy or some degree of a lack of confidence. A progesterone level was drawn on the third day after the Peak Day as they were charting, and if the progesterone level was 2.3 ng/mL or greater, then ovulation was determined to have passed. If the level was greater than 3.0 ng/mL, this indicated that an absolute period of infertility had begun. In these cases, no pregnancies were observed. In the 27 cycles in which a specific follow-up relative to pregnancy could not be definitively determined, the progesterone levels in all cases were 2.3 ng/mL or greater with 23 of the 27 cycles being 3.1 ng/mL or greater. It is highly unlikely that any of those became pregnant as well. These cycles were collected over thirteen years (2004-2016). Two case presentations are also a part of this article of two families in which the couples had very serious reasons to avoid pregnancy. In these two couples, each of the women was multi-gravid and had no evidence of subfertility or infertility. They used the family planning progesterone level (the Peak Day +3 progesterone level) for a total of 167 cycles over a number of years successfully without a subsequent pregnancy.
This article presents a thirteen-year effort to evaluate the serum progesterone level on the third day after the Peak Day as observed by women charting the CREIGHTON MODEL FertilityCare™ System. It is known that the Peak Day is associated with ovulation, and if the progesterone reaches a certain level, then an absolute period of infertility should follow. In fact, this is what this study reflects.
Women living with androgenic PCOS (WLWP) experience unpredictable oligomenorrhea1 and are at increased risk for endometrial cancer2. Oral micronized progesterone (OMP) given cyclically (14 days/cycle or 4 weeks, Cyclic OMP), in luteal phase doses3 (300 mg at bedtime) as a “luteal phase replacement” therapy would be likely to effectively treat both. In addition, evidence suggests PCOS is causally related to rapid pulsing of GnRH and LH 4; OMP normalizes LH pulsatility if androgen levels are not elevated 4. Previous searches did not find progesterone therapy for PCOS 5. Our Does the peer-reviewed literature provide evidence for prescribing cyclic progesterone therapy in PCOS? Literature search methods used Medline (Ovid) and PubMed for published articles. Our search terms were: “polycystic ovary syndrome”, “androgenic PCOS”, and, “micronized progesterone.” We sought publications with eligible women participants having androgenic PCOS, drug exposures (cyclic
OMP, vaginal progesterone, and in varying doses and durations) and specific outcomes (biochemical or patient-reported data or both) in all languages. We excluded reviews and practice guidelines but searched bibliographies for missed citations. Results discovered 18 articles in combined Medline (n=6) and PubMed (12) searches. After excluding duplicates, articles on estradiol (E2) alone E2 with OMP therapy, five eligible articles remained. We read all in full detail.
Progesterone therapy was beneficial for WLWP as, even in sub-therapeutic doses (<300 mg at bedtime) and in cycles of too short durations (<14 days), it decreased luteinizing hormone (LH) 6,7 and total testosterone 7 levels. Vaginal progesterone (200 mg, b.i.d for 2 to 12 weeks) added to letrozole ovulation induction increased the pregnancy rate from 0 to 21% 8. Although present data suggest Cyclic OMP withdrawal predictively causes flow, we found no evidence it improved women’s cycle-related experiences nor decreased acne and hirsutism. Women-reported data on Cyclic OMP for improving androgenic PCOS cycle regularity, daily experiences and risks for endometrial cancer are needed.
Reference: 1Azziz R Nat Rev Dis Primers 2016;2:16057. 2Barry J Hum Reprod Update 2014; 20:748. 3Simon J Fertil Steril 1993;60:26. 4Blank S Hum Reprod Update 2006;12:351. 5Teede H Clin Endocrinol (Oxf) 2018;89:251. 6Livadas S Fertil Steril 2010;94:242. 7Bagis T J Clin Endocr Met 2002;87:4536. 8Montville C Fertil Steril. 2010;94:678.
Başar Gökcen B et al., 2020·Gynecological Endocrinology
Data on eating disorders in women with PCOS is insufficient. The objective of this case study was to examine the hypothesis that women with PCOS exhibit more impaired eating than healthy women. Women diagnosed with PCOS under the 2003 Rotterdam Diagnostic Criteria (n = 40) were compared with a healthy control group (n = 40). The groups also were divided into two as normal body weight and overweight/obese. The Eating Disorders Assessment Questionnaire (EDE-Q) and the Three Factor Eating Questionnaire (TFEQ-R21), were completed by all participants in order to evaluate eating behaviors in addition to eating disorders. Among the overweight/obese group, the average total and subscale scores of the EDE-Q as well as the total and sub-factor scores of the TFEQ-R21 were higher in women with PCOS compared to controls (p < .05). However, this statistically significant result was not shown among the women with normal weight (p > .05). In comparison to the controls, the PCOS women displayed higher values of the tool scores indicating abnormal restraint eating, body shape concern and weight concern subscale scores (p < .05). This result suggests that the evaluation of eating disorders should be added to routine screening and the monitoring of women with PCOS.
The conception rates among women with premature ovarian insufficiency (POI) remain extremely low. To achieve a successful pregnancy, most of these women have to receive donor oocytes through IVF treatment. Ovarian administration of platelet-rich plasma (PRP) has been recently applied to enhance the ovulatory function in women with poor ovarian response. However, no live birth has been reported for this application in patients with POI. In this study, we present a 37-year-old woman with POI who had secondary amenorrhea for 6 months. The clinical manifestations and evaluation of this women with a diminished ovarian function were an undetectable serum level of AMH (<0.02 ng/mL) and an elevated serum level of FSH (63.65 mIU/mL). A single dose of autologous PRP (extracted from 40 mL of peripheral blood) in combination with gonadotropin (150IU rFSH/75 IU rLH) was directly injected into the stroma of bilateral ovaries via vaginal sonographic guidance. Following the treatment, this patient received controlled ovarian stimulation and IVF during the successive months. Following embryo culture, three cleavage-stage embryos were transferred, leading to a successful pregnancy, which later resulted in the live birth of twins. This case report provides one example of alternative therapy that allows POI patients to use autologous oocytes in IVF treatment.
Thyroid and Metabolic Function · Insulin and Metabolism
Roseff S et al., 2020·International journal of endocrinology
The aim of this paper is to critically analyze the composition of many inositol-based products currently used to treat Polycystic Ovary Syndrome (PCOS). Several different combinations of myo-inositol and D-chiro-inositol, with and without additional compounds such as micro- and macroelements, vitamins, and alpha-lipoic acid, have been formulated over the years. Such therapeutic proposals do not take various features of inositol stereoisomers into consideration. As an example, it is important to know that D-chiro-inositol treatment may be beneficial when administered in low doses, yet the progressive increase of its dosage results in the loss of its advantageous effects on the reproductive performance of women and a deterioration in the quality of blastocysts created via in vitro fertilization (IVF). In addition, we have to consider that the intestinal absorption of myo-inositol is reduced by the simultaneous administration of D-chiro-inositol since the two stereoisomers compete with each other for the same transporter that has similar affinity for each of them. A decrease in myo-inositol absorption is also found when it is coadministered with inhibitors of sugar intestinal absorption and/or types of sugars such as sorbitol, maltodextrin, and sucralose. The combination of these may require higher amounts of myo-inositol in order to reach a therapeutic dosage compared to inositol administration alone, a particularly important fact when physicians strive to obtain a specific plasma level of the stereoisomer. Finally, we must point out that D-chiro-inositol was found to be an aromatase inhibitor which increases androgens and may have harmful consequences for women. Therefore, the inositol supplements used in PCOS treatment must be carefully defined. Clinical evidence has demonstrated that the 40 : 1 ratio between myo-inositol and D-chiro-inositol is the optimal combination to restore ovulation in PCOS women. Therefore, it is quite surprising to find that inositol-based treatments for PCOS seem to be randomly chosen and are often combined with useless or even counterproductive molecules, all of which can weaken myo-inositol's efficacy. Such treatments clearly lack therapeutic rationale.
Prior JC, 2020·Drug Discovery Today: Disease Models·
Open Access
This review is to challenge current concepts of women’s reproduction with its cultural over-emphasis on estrogen and positive actions, while progesterone tends to be ignored or associated with negative effects. To explore the physiology, and the clinical implications of understanding that progesterone and estradiol interact in counterbalancing and complementary ways within a complex system that is Women’s Reproductive Health. Fundamental, descriptive, quantitative and experimental data all show that estradiol’s important cellular action is to promote growth and proliferation; by contrast, despite short-term proliferative effects, progesterone’s dominant actions are to inhibit proliferation, to enhance differentiation and promote maturation. Estradiol and progesterone variably interact in every cell and tissue in women’s bodies and across the life cycle. Since ovulation and thus progesterone’s presence is subclinical in normal-length cycles, we urgently need a convenient, home, once/cycle, inexpensive test of normal ovulation. Major funding is needed for ovulation-testing cycle-by-cycle over months or years in large population-based cohorts of adolescent, premenopausal and perimenopausal women. These women need to be followed for fertility and their later-life experiences of osteoporotic fracture, myocardial infarction, breast and endometrial cancers. In addition, all research with menstruating women participants and female mammals needs cycle-phase specific testing. It is difficult to perceive, much less to change, a current paradigm. With this journal issue, however, we have begun the important tasks of transforming concepts about women’s health, and setting the research agenda to advance the innovative understanding that women's reproductive and overall health becomes optimal when premenopausal menstrual cycle estradiol and progesterone actions are balanced within this complex system.
For more than a half century the hormone melatonin has been associated with vertebrate reproduction, particularly in the context of seasonal breeding. This association is due in large measure to the fact that melatonin secretion from the pineal gland into the peripheral circulation is a nocturnal event whose duration is reflective of night length, which of course becomes progressively longer during winter months and correspondingly shorter during the summer months. The nocturnal plasma melatonin signal is conserved in essentially all vertebrates and is accessed not just for reproductive rhythms, but for seasonal cycles of metabolic activities, immune functions, and behavioral expression. A vast literature on melatonin and vertebrate biology has accrued over the past 60 years since melatonin's discovery, including the broad topic of animal reproduction, which is far beyond the scope of this human-focused review. Although modern humans in the industrialized world appear in general to have little remaining reproductive seasonality, the relationships between melatonin and human reproduction continue to attract widespread scientific attention. The purpose of this chapter is to draw attention to some newer developments in the field, especially those with relevance to human fertility and reproductive medicine. As the vast majority of studies have focused on the female reproductive system, a discussion of the potential impact of melatonin on human male fertility will be left for others.
Landersoe SK et al., 2019·Eur J Contracept Reprod Health Care·
The aim of the study was to assess whether the ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) were lower among women using the progestin-only pill (POP) or levonorgestrel-releasing intrauterine system (LNG-IUS) and similar to the decrease observed in combined oral contraceptive (COC) pill users. This retrospective study comprised 565 hormonal contraceptive users (COC, POP, LNG-IUS or contraceptive vaginal ring) and 983 non-hormonal contraceptive users, who were seen in two Danish fertility assessment and counselling clinics between 2015 and 2019. Adjusted multiple regression analysis was used to examine the differences in AMH and AFC between hormonal and non-hormonal contraceptive users. Compared with non-hormonal contraceptive users, AMH was 31.1% lower among COC users [95% confidence interval (CI) -39.6%, -25.9%; p < 0.001], 35.6% lower among POP users (95% CI -49.0%, -18.6%; p < 0.001) and 17.1% lower among LNG-IUS users (95% CI -31.4%, 0.002%; p = 0.052); no significant differences were seen among vaginal ring users. Compared with non-hormonal contraceptive users, AFC was 31.3% lower among COC users (95% CI -35.0%, -25.3%; p < 0.001) and 29.7% lower among POP users (-39.1%, -17.9%; p < 0.001); no significant differences were seen among LNG-IUS or vaginal ring users. Ovarian volume was more than 50% reduced among COC and vaginal ring users (p < 0.001) but was unchanged among POP and LNG-IUS users. Assessment of ovarian reserve markers among users of all types of hormonal contraception should be interpreted cautiously and the type of contraceptive method considered.
Yen JY et al., 2019·International journal of environmental research and public health
: Objective/introduction: The dynamics of ovarian hormone fluctuations during the luteal phase of the menstruation cycle were previously suggested to contribute to the development of premenstrual dysphoric disorder (PMDD) symptoms, but adequate empirical evidence has not been obtained from hormone concentration studies. We prospectively evaluated estrogen and progesterone levels in the early luteal (EL) and late luteal (LL) phases in women with PMDD and the association of these levels with PMDD symptom severity. 63 women with PMDD and 53 controls without such severe symptoms were evaluated for the estrogen and progesterone levels, and PMDD severity in the EL and LL phases. The results demonstrated that the women with PMDD had a lower EL-phase estrogen level than the controls. Covariant analysis demonstrated that the interaction term between EL-phase estrogen and EL-phase progesterone level was associated with PMDD severity. Among women with lower EL estrogen levels, higher EL-phase progesterone was observed among the women with PMDD versus controls. These results suggest that low EL-phase estrogen level could moderate the provoking effect of EL progesterone in women with PMDD. Overall, these data suggest a possible role of estrogen and progesterone in the development of PMDD symptoms.
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder associated with hyperandrogenism and anovulation. Although a spectrum disorder, many women with PCOS exhibit elevated luteinizing hormone (LH) pulse frequency and an elevated LH to follicle stimulating hormone ratio. This aberrant pattern of gonadotrophin signalling drives many of the downstream ovarian features of PCOS, including increased androgen synthesis, and indicates neuroendocrine impairments upstream. Decreased responsiveness to gonadal steroid hormone negative feedback in PCOS patients points toward dysfunction within the gonadotropin-releasing hormone (GnRH) neuronal network in the brain. Excessive androgen exposure during development or over pubertal onset can recapitulate the neuroendocrine pathology of PCOS in pre-clinical models, and these models have been fundamental in beginning to pick apart the specific central mechanisms involved. This mini-review will briefly describe the pathology of PCOS associated with high frequency GnRH/LH pulses and then highlight what is currently known, and yet to be discovered, about the central mechanisms involved.
Astapova O et al., 2019·Endocrinology·
Open Access
Androgens, although traditionally thought to be male sex steroids, play important roles in female reproduction, both in healthy and pathological states. This mini-review focuses on recent advances in our knowledge of the role of androgens in the ovary. Androgen receptor (AR) is expressed in oocytes, granulosa cells, and theca cells, and is temporally regulated during follicular development. Mouse knockout studies have shown that AR expression in granulosa cells is critical for normal follicular development and subsequent ovulation. In addition, androgens are involved in regulating dynamic changes in ovarian steroidogenesis that are critical for normal cycling. Androgen effects on follicle development have been incorporated into clinical practice in women with diminished ovarian reserve, albeit with limited success in available literature. At the other extreme, androgen excess leads to disordered follicle development and anovulatory infertility known as polycystic ovary syndrome (PCOS), with studies suggesting that theca cell AR may mediate many of these negative effects. Finally, both prenatal and postnatal animal models of androgen excess have been developed and are being used to study the pathophysiology of PCOS both within the ovary and with regard to overall metabolic health. Taken together, current scientific consensus is that a careful balance of androgen activity in the ovary is necessary for reproductive health in women.
The relation between excessive prolactin and endometriosis-related infertility is debatable. Anovulation or defective luteal phase occurs frequently due to hyperprolactinemia in subfertile women. In this investigation, we evaluated the association between serum prolactin levels and the severity of endometriosis. This retrospective cohort study carried out at the Babol Infertility Research Center looked into the baseline serum prolactin levels of 114 infertile women with endometriosis and compared them to the levels seen in 101 infertile women without endometriosis (controls). Statistical analysis included independent t-test, chi-square, Welch test and ROC curve analysis. Infertile women with endometriosis had significantly higher serum prolactin levels than infertile women without endometriosis (p=0.003). A significant difference was detected between controls and individuals with endometriosis stages III/IV (p-value=0.009). Prolactin was found to have diagnostic value to detect endometriosis stages III/IV vs. stages I/II in AUC=0.65, 95% CI (0.55, 0.76). Prolactin values with a cut off set at 20.08 ng/mL had a sensitivity of 0.74 and specificity of 0.54 in detecting disease stages III/IV vs. I/II. The prognostic capability of prolactin in detecting endometriosis in cases vs. controls by ROC curve analysis had an AUC=+0.67, 95% CI (0.60, 0.74). Prolactin values with a cut off set at 17.5 ng/mL had a sensitivity of 0.64 and specificity of 0.63 in segregating subjects with and without endometriosis. Higher prolactin levels were observed in infertile women with more severe endometriosis when compared to infertile women without endometriosis. Prolactin levels act as a probable prognostic biomarker to detect endometriosis stages III/IV vs. I/II and segregate infertile women with endometriosis from subjects without endometriosis.
Thyroid and Metabolic Function · Insulin and Metabolism
Abedini M et al., 2019·Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
Several studies have investigated serum zinc levels in patients with polycystic ovarian syndrome (PCOS), but the results of these studies remain inconclusive. Therefore, to derive a more precise estimation, we conducted a meta-analysis to investigate serum zinc concentrations in women with PCOS in comparison with healthy subjects. Electronic search was performed in PubMed, Scopus, and Google scholar up to April; 4, 2018 without any restriction. Eligible studies that evaluated the levels of zinc status in subjects with PCOS were included. Weighted mean differences (WMDs) with corresponding 95% CIs in serum zinc levels were initially estimated using a random-effects model. Eight studies, measuring circulating zinc levels in 552 PCOS and 464 control subjects, were included. Pooled effect size suggested that serum zinc levels in women with PCOS were not statistically different than their controls (WMD = -4.43 mg/dL; 95% CI = [-10.30, 1.44]; P = 0.139). Exclusion of one study revealed that women with PCOS significantly have lower serum zinc levels compared to healthy controls (WMD: -6.60 mg/dL; 95% CI = [-12.43, -0.76], P = 0.027). Our study indicated that circulating zinc levels in women with PCOS were significantly lower than those in healthy controls when detailed analysis is conducted. Large scale studies are needed to elucidate clear relation between zinc status and etiology of PCOS.
The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options.
Sfakianoudis K et al., 2019·Gynecologic and obstetric investigation
Poor responders are described as those In Vitro Fertilization (IVF) patients who are failing to respond to controlled ovarian stimulation protocols. Extensive research has focused on crafting the optimal treatment. However, it appears that each approach fails to be established as effective or guaranteed towards successful management. Platelet-Rich Plasma (PRP) is a novel, highly promising approach that has been successfully applied for an array of medical issues. In this case series, we present 3 poor responder patients with the common denominator of: failed IVF attempts, poor oocyte yield, and poor embryo quality. The option of oocyte donation was rejected. All patients were treated with autologous PRP ovarian infusion following written consent. Within a 3-month interval, follicle-stimulating hormone decreased by 67.33%, while Anti-Müllerian hormone increased by 75.18%. These impressive results on the biochemical infertility markers alone are classified as a complete biological paradox, coupled by improved embryo quality. Results report a natural conception at 24 weeks, an uncomplicated healthy pregnancy at 17 weeks and a successful live birth. To our knowledge, this is the first time such an approach and results are reported, where PRP treatment on poor responders lead to overcoming their challenging reproductive barrier.
The purpose of this review was to determine whether there is evidence that ovulation can occur in women using hormonal contraceptives and whether these drugs might inhibit implantation. We performed a systematic review of the published English-language literature from 1990 to the present which included studies on the hormonal milieu following egg release in women using any hormonal contraceptive method. High circulating estrogens and progestins in the follicular phase appear to induce dysfunctional ovulation, where follicular rupture occurs but is followed by low or absent corpus luteum production of progesterone. Hoogland scoring of ovulatory activity may inadvertently obscure the reality of ovum release by limiting the term "ovulation" to those instances where follicular rupture is followed by production of a threshold level of luteal progesterone, sufficient to sustain fertilization, implantation, and the end point of a positive β-human chorionic gonadotropin. However, follicular ruptures and egg release with subsequent low progesterone output have been documented in women using hormonal contraception. In the absence of specific ovulation and fertilization markers, follicular rupture should be considered the best marker for egg release and potential fertilization. Women using hormonal contraceptives may produce more eggs than previously described by established criteria; moreover, suboptimal luteal progesterone production may be more likely than previously acknowledged, which may contribute to embryo loss. This information should be included in informed consent for women who are considering the use of hormonal contraception. For this study, the authors looked at English-language research articles that focused on how hormonal birth control, such as the birth control pill, may affect very early human embryos. The authors found that abnormal ovulation, or release of an egg followed by abnormal hormone levels, may often occur in women using hormonal birth control. This may increase the number of very early human embryos who are lost before a pregnancy test becomes positive. For women who are thinking about using hormonal birth control, this is important information to consider.
To assess prospectively luteinized unruptured follicle (LUF) syndrome in juvenile idiopathic arthritis (JIA) patients with and without non-steroidal anti-inflammatory drugs (NSAIDs) and healthy controls. Twenty-three adolescent and young adult female JIA patients (ILAR criteria) and 11 female healthy subjects were studied by pelvic ultrasound monitoring for follicular development and ovulation in one menstrual cycle. LUF syndrome was prospectively investigated by pelvic ultrasound with a dominant ovarian follicle without signs of follicular rupture, with elevation of serum progesterone in the luteal phase of the menstrual cycle and luteinizing hormone (LH) detected in the urine. Comparison between JIA patients with (n = 8) vs. without NSAIDs (n = 15) and healthy controls (n = 11) revealed that LUF syndrome was significantly higher in the former group (2 (25%) vs. 0% vs. 0%, p = 0.049). These two patients with LUF syndrome had normal menstrual cycles without reduced ovarian reserve, and they were under naproxen 500 mg bid during the menstrual cycle. Disease duration was comparable in JIA with and without NSAIDs [19.8 (4.4-25) vs. 13 (3.1-33) years, p = 0.232]. Further comparison between JIA patients with and without NSAIDs and healthy controls showed similar mean anti-Müllerian hormone levels (p = 0.909), estradiol (p = 0.436), FSH (p = 0.662), LH (p = 0.686), and mean antral follicle count (p = 0.240) and ovarian volume (p = 0.363). No differences were evidenced in three groups regarding Caucasian race, body mass index, duration, and length of menstrual cycles (p > 0.05). This is the first study to identify that JIA patients have a high frequency of LUF without impaired ovarian reserve. Future prospective studies are necessary to determine if chronic/continuous use of NSAIDs in JIA will have an impact in these patients' fertility.
Del Río JP et al., 2018·Front Public Health·
Open Access
Sex hormones significantly impact women's lives. Throughout the different stages of life, from menarche to menopause and all stages in between, women experience dramatic fluctuations in the levels of progesterone and estradiol, among other hormones. These fluctuations affect the body as a whole, including the central nervous system (CNS). In the CNS, sex hormones act via steroid receptors. They also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate. Additionally, studies show that sex hormones and their metabolites influence brain areas that regulate mood, behavior, and cognitive abilities. This review emphasizes the benefits a proper hormonal balance during the different stages of life has in the CNS. To achieve this goal, it is essential that hormone levels are evaluated considering a woman's age and ovulatory status, so that a correct diagnosis and treatment can be made. Knowledge of steroid hormone activity in the brain will give women and health providers an important tool for improving their health and well-being.
Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.
Namavar Jahromi B et al., 2018·Iranian journal of medical sciences
Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovulation induction that usually occurs after gonadotropin stimulation, followed by human chorionic gonadotropin administration, for infertility treatment. The existing knowledge about the pathophysiology, risk factors, and primary and secondary methods for the prevention of OHSS is reviewed in this manuscript. The clinical manifestations and characteristics of mild, moderate, severe, and critical forms of the syndrome are defined. The methods of handling affected cases as outpatient or in-hospital management methods as well as indications for hospitalization are summarized in this review. The clinical and biochemical routes of assessing and monitoring hospitalized patients with OHSS, various drugs and medical treatment strategies including indications for aspiration of the ascitic fluid and pleural effusion, and also rare indications for surgery are briefly explained in this article. Severe OHSS, which two decades ago was considered an iatrogenic life-threatening condition, can now be effectively prevented or managed during the early stages. An OHSS-free clinic can be established nowadays by carefully considering the endocrinology of ovulation and using appropriate and dose-adjusted pharmaceutical agents, which are summarized and discussed in this review.
Kurdi MS et al., 2018·Indian journal of anaesthesia
The menstrual cycle is a physiological phenomenon that is accompanied by several hormonal fluctuations involving oestrogen and progesterone. Oestrogen and progesterone exert several physiological effects. There are many questions pertaining to the influence of the physiology of menstruation on anaesthesia. We attempted to find out whether the phase of the menstrual cycle can alter the physiological functions during anaesthesia, the perioperative management and outcomes. We performed a literature search in Google Scholar, PubMed and Cochrane databases for original and reviewed articles on the phases of the menstrual cycle and their relation to anaesthesia-related physiological parameters to find an answer to these questions. Many studies have shown that women, perimenstrually, may have increased pain perception, exacerbation of systemic diseases, vocal cord/peripheral oedema and post-operative nausea and vomiting (PONV). Some of the other notable findings in most studies were sleep disturbances in the luteal phase (LP), increased occurrence of PONV in the ovulatory phase and a lower requirement of intravenous sedative and anaesthetic drug requirements in the LP. We found contradictory results concerning pain perception and PONV in relation to the follicular and LPs. However, we found that literature regarding the phase of the menstrual cycle and the haemodynamic response to intubation, anaesthesia-induced hypnosis and perioperative blood loss is relatively scarce. Thus, there is a need to conduct good quality research on these topics.
What is the optimal endometrial preparation protocol for a frozen embryo transfer (FET)?Summary answerAlthough the optimal endometrial preparation protocol for FET needs further research and is yet to be determined, we propose a standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials. Amid a continuous increase in the number of FET cycles, determining the optimal endometrial preparation protocol has become paramount to maximize ART success. In current daily practice, different FET preparation methods and timing strategies are used.Study design, size, durationThis is a review of the current literature on FET preparation methods, with special attention to the timing of the embryo transfer.Participants/materials, setting, methodsLiterature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017.Main results and the role of chanceThe number of high quality randomized controlled trials (RCTs) is scarce and, hence, the evidence for the best protocol for FET is poor. Future research should compare both the pregnancy and neonatal outcomes between HRT and true natural cycle (NC) FET. In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively.Limitations reasons for cautionAs only a few high quality RCTs on the optimal preparation for FET are available in the existing literature, no definitive conclusion for benefit of one protocol over the other can be drawn so far.Wider implications of the findingsCaution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports.Study funding/competing interest(s)S.M. is funded by the Research Fund of Flanders (FWO). H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study.Trial registration numberNot applicable.
Herzberg SD et al., 2017·Orthopaedic journal of sports medicine
Women are at substantially greater risk for anterior cruciate ligament (ACL) injuries than are men. To conduct a systematic review and meta-analysis of the literature to clarify the effect of the menstrual cycle and contraceptives on the laxity of and noncontact injuries to the ACL. Systematic review; Level of evidence, 4. Searches were conducted using MEDLINE (1946-August 2016), the Cochrane Library Database, clinical trial registries, and related reference lists. Search terms included athletic injuries, knee injuries, ligaments, joint instability, menstrual cycle, ovulation, hormones, and contraceptives. Investigators independently dually abstracted and reviewed study details and quality using predefined criteria and evaluated overall strength of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Twenty-one studies totaling 68,758 participants were included: 5 on the menstrual cycle and ACL injury, 7 on hormonal contraceptives and ACL injury, as well as 13 on menstrual cycle and ligament laxity. Four of 5 studies of women not using hormonal contraception indicated that the luteal phase was the least associated with ACL injuries. The 2 largest and highest quality studies on hormonal contraceptives suggested that hormonal contraceptives may be protective against ACL injury. Six of 12 studies on ACL laxity provided quantitative data for meta-analysis, finding significantly increased laxity during the ovulatory phase compared with the follicular phase. The literature suggests an association between hormonal fluctuations and ACL injury. Recent studies have suggested that oral contraceptives may offer up to a 20% reduction in risk of injury. The literature on ACL injuries and the menstrual cycle has more than doubled over the past decade, permitting quantitative analysis for the first time. However, the overall strength of this evidence is low. Promising potential directions for future research include long-term observational studies with ongoing hormonal assays and large interventional trials of follicular suppression, including newer hormonal methods.
Malaria is prevalent in Nigeria, and artemether + lumefantrine (artemisinin-based combination therapy [ACT]) is drug of choice in treatment of uncomplicated cases. ACT is contraindicated in early pregnancy. They release-free radicals that can compromise female fertility. Infertility and its associated complications such as miscarriages, abnormal gestation, and unstable marriages seem to be on the increase. This study aims at evaluating the effect of ACT on female fertility. The significance of this research is to draw the attention of fertility care givers to this possible cause of infertility and fertility challenges. Subjects and Creighton Model FertilityCare System and NaProTECHNOLOGY are simply technologies that can be used to assess female fertility. They are used in this study to assess the effect of ACT administered at different stages of menstrual cycles of three selected fertile adult females. The results are interpreted on the background of standard Creighton model chart. This study has shown that ACT has a significant fertility deteriorating effect on the women. It caused ovulation defect and diagnosed as partial rupture syndrome in the very cycle of use and in the first cycle after use. It also significantly reduced cervical mucus production and significantly reduced luteal phase progesterone production with an associated significant increase of luteal phase estrogen production. ACT use as antimalarial may be a possible cause of infertility and fertility challenges in women.
Patel BG et al., 2017·Acta obstetricia et gynecologica Scandinavica
Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital "preconditioning", whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment.
Ibrahim Y et al., 2017·Journal of assisted reproduction and genetics·
Open Access
The purpose of the study was to examine the association between serum progesterone levels on the day of hCG administration and birth weight among singleton live births after fresh embryo transfer. This study was conducted as a retrospective cohort database analysis on patients who underwent IVF treatment cycles from January 2004 to April 2012. The study was performed at a University affiliated private infertility practice. All cycles that had achieved a singleton live birth after fresh embryo transfer and for which progesterone was measured on the day of hCG administration were examined. Generalized linear models were used to calculate mean birth weight and z-scores. We analyzed 817 fresh IVF embryo transfers in which birth weight, gestational age, and progesterone (ng/mL) level on day of hCG administration were documented. While there was a decrease in birth weight as progesterone quartile [≤0.54; >0.54 to ≤0.81; >0.81 to ≤1.17; >1.17 ng/mL] increased, the difference in mean birth weights among the four quartiles was not statistically significant (p = 0.11) after adjusting for maternal age and peak estradiol levels. When dichotomizing based on a serum progesterone considered clinically elevated, cycles with progesterone >2.0 ng/mL had a significantly lower mean singleton birth weight (2860 g (95% CI 2642 g, 3079 g)) compared to cycles with progesterone ≤2.0 ng/mL (3167 g (95% CI 3122 g, 3211 g) p = 0.007)) after adjusting for maternal age and estradiol. We demonstrated that caution should be exercised when performing fresh embryo transfers with elevated progesterone levels and in particular with levels (>2.0 ng/mL) as this may lead to lower birth weight.
To our knowledge, data on comparison of myo-inositol and metformin on clinical, metabolic and genetic parameters in subjects with polycystic ovary syndrome (PCOS) are limited. This study was carried out to compare myo-inositol and metformin on clinical, metabolic and genetic parameters in subjects with PCOS. DESIGN, This randomized controlled trial was conducted among 60 subjects with PCOS aged 18-40 years. Subjects were randomly allocated into two groups to receive either myo-inositol (N=30) or metformin (N=30) for 12 weeks. Gene expression of inflammatory cytokines was assessed in peripheral blood mononuclear cells (PBMCs) of PCOS women by RT-PCR. After the 12-week intervention, compared with metformin, myo-inositol intake significantly decreased serum total testosterone (-1.4±4.2 vs +0.7±1.4 nmol/L, P=.03), modified Ferriman-Gallwey (mF-G) scores (-1.1±0.7 vs -0.5±0.8, P=.01) and serum high-sensitivity C-reactive protein (hs-CRP) levels (-2.6±3.9 vs +0.2±1.5 mg/L, P<.001). RT-PCR demonstrated that compared with metformin, myo-inositol downregulated gene expression of interleukin-1 (IL-1) (P=.02) in PBMCs of subjects with PCOS. We did not observe any significant effect of myo-inositol intake compared with metformin on other hormonal profiles, plasma nitric oxide (NO) or gene expression of IL-8 and tumour necrosis factor alpha (TNF-α). Overall, taking myo-inositol, compared with metformin, for 12 weeks in patients with PCOS with hyperinsulinism and normoinsulinism had beneficial effects on total testosterone, mFG scores, serum hs-CRP levels and gene expression of IL-1, but did not affect other hormonal profiles, NO levels or gene expression of IL-8 and TNF-α.
Thyroid and Metabolic Function · Insulin and Metabolism
Are maternal preconception lipid levels associated with fecundability?Summary answerFecundability was reduced for all abnormal female lipid levels including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total triglyceride levels. Subfecundity affects 7-15% of the population and lipid disorders are hypothesized to play a role since cholesterol acts as a substrate for the synthesis of steroid hormones. Evidence illustrating this relationship at the mechanistic level is mounting but few studies in humans have explored the role of preconception lipids in fecundity.Study design, size, durationA secondary analysis of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (2007-2011), a block-randomized, double-blind, placebo-controlled trial. Participants/materials, setting, methodsA total of 1228 women, with 1-2 prior pregnancy losses and without a diagnosis of infertility, attempting pregnancy for up to six menstrual cycles were recruited from clinical sites in Utah, New York, PA and Colorado. Time to pregnancy was the number of menstrual cycles to pregnancy as determined by positive hCG test or ultrasound. Individual preconception lipoproteins were measured at baseline, prior to treatment randomization and dichotomized based on clinically accepted cut-points as total cholesterol ≥200 mg/dl, LDL-C ≥130 mg/dl, HDL-C Main results and the role of chanceThere were 148 (12.3%) women with elevated total cholesterol, 94 (7.9%) with elevated LDL-C, 280 (23.2%) with elevated triglycerides and 606 (50.7%) with low HDL-C. The fecundability odds ratio (FOR) was reduced for all abnormal lipids before and after confounder adjustment, indicating reduced fecundability. Total cholesterol ≥200 mg/dl was associated with 24% (For: 0.76, 95% CI: 0.59, 0.97) and 29% (For: 0.71, 95% CI: 0.55, 0.93) reduced fecundability for hCG-detected and ultrasound-confirmed pregnancy, respectively, compared with total cholesterol Limitations, reasons for cautionAlthough the FOR is a measure of couple fecundability, we had only measures of female lipid levels and can therefore not confirm the findings from a previous study indicating the independent role of male lipids in fecundity. The attenuated estimates and decreased precision after adjustment for central adiposity and obesity indicate the complexity of potential causal lipid pathways, suggesting other factors related to obesity besides dyslipidemia likely contribute to reduced fecundability. Wider s of the findingsOur results are consistent with one other study relating preconception lipid concentrations to fecundity and expand these findings by adding critically important information about individual lipoproteins. As lipid levels are modifiable they may offer an inexpensive target to improve female fecundability.Study funding and competing interest(s)This study was funded by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have declared that no conflicts of interest exist.Trial registration number#NCT00467363.
Semen liquefaction changes semen from a gel-like to watery consistency and is required for sperm to gain mobility and swim to the fertilization site in the Fallopian tubes. Kallikrein-related peptidases 3 (KLK3) and other kallikrein-related peptidases from male prostate glands are responsible for semen liquefaction by cleaving gel-forming proteins (semenogelin and collagen). In a physiological context, the liquefaction process occurs within the female reproductive tract. How seminal proteins interact with the female reproductive environment is still largely unexplored. We previously reported that conditional genetic ablation of Esr1 (estrogen receptor α) in the epithelial cells of the female reproductive tract (Wnt7aCre/+;Esr1f/f) causes female infertility, partly due to a drastic reduction in the number of motile sperm entering the oviduct. In this study, we found that post-ejaculated semen from fertile wild-type males was solidified and the sperm were entrapped in Wnt7aCre/+;Esr1f/f uteri, compared to the watery semen (liquefied) found in Esr1f/f controls. In addition, semenogelin and collagen were not degraded in Wnt7aCre/+;Esr1f/f uteri. Amongst multiple gene families aberrantly expressed in the absence of epithelial ESR1, we have identified that a lack of Klks in the uterus is a potential cause for the liquefaction defect. Pharmacological inhibition of KLKs in the uterus replicated the phenotype observed in Wnt7aCre/+;Esr1f/f uteri, suggesting that loss of uterine and seminal KLK function causes this liquefaction defect. In human cervical cell culture, expression of several KLKs and their inhibitors (SPINKs) was regulated by estrogen in an ESR1-dependent manner. Our study demonstrates that estrogen/ESR1 signaling in the female reproductive tract plays an indispensable role in normal semen liquefaction, providing fundamental evidence that exposure of post-ejaculated semen to the suboptimal microenvironment in the female reproductive tract leads to faulty liquefaction and subsequently causes a fertility defect.
The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.
To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.
Gibson-Helm M et al., 2016·J Clin Endocrinol Metab·
Open Access
Polycystic ovary syndrome (PCOS) is a complex, chronic, and under-recognized disorder. Diagnosis experience may have lasting effects on well-being and self-management. To investigate PCOS diagnosis experiences, information provided, and concerns about PCOS.
Cross-sectional study using an online questionnaire.
Recruitment via support group web sites in 2015 to 2016. There were 1385 women with a reported diagnosis of PCOS who were living in North America (53.0%), Europe (42.2%), or other world regions (4.9%); of these, 64.8% were 18 to 35 years of age. Satisfaction with PCOS diagnosis experience, satisfaction with PCOS information received at the time of diagnosis, and current concerns about PCOS. One-third or more of women reported >2 years (33.6%) and ≥3 health professionals (47.1%) before a diagnosis was established. Few were satisfied with their diagnosis experience (35.2%) or with the information they received (15.6%). Satisfaction with information received was positively associated with diagnosis satisfaction [odds ratio (OR), 7.0; 95% confidence interval (CI), 4.9 to 9.9]; seeing ≥5 health professionals (OR, 0.5; 95% CI, 0.3 to 0.8) and longer time to diagnosis (>2 years; OR, 0.4; 95% CI, 0.3 to 0.6) were negatively associated with diagnosis satisfaction (independent of time since diagnosis, age, and world region). Women's most common concerns were difficulty losing weight (53.6%), irregular menstrual cycles (50.8%), and infertility (44.5%). In the largest study of PCOS diagnosis experiences, many women reported delayed diagnosis and inadequate information. These gaps in early diagnosis, education, and support are clear opportunities for improving patient experience.
Recent studies have identified that levonorgestrel administered orally in emergency contraception (LNG-EC) is only efficacious when taken before ovulation. However, the drug does not consistently prevent follicular rupture or impair sperm function. The present systematic review is performed to analyze and more precisely define the extent to which pre-fertilization mechanisms of action may explain the drug's efficacy in pregnancy avoidance. We also examine the available evidence to determine if pre-ovulatory drug administration may be associated with post-fertilization effects. The mechanism of action of LNG-EC is reviewed. The drug has no ability to alter sperm function at doses used in vivo and has limited ability to suppress ovulation. Our analysis estimates that the drug's ovulatory inhibition potential could prevent less than 15 percent of potential conceptions, thus making a pre-fertilization mechanism of action significantly less likely than previously thought. Luteal effects (such as decreased progesterone, altered glycodelin levels, and shortened luteal phase) present in the literature may suggest a pre-ovulatory induced post-fertilization drug effect. Plan B is the most widely used emergency contraceptive available. It is important for patients and physicians to clearly understand the drug's mechanism of action (MOA). The drug was originally thought to work by preventing fertilization. Recent research has cast doubt on this. Our review of the research suggests that it could act in a pre-fertilization capacity, and we estimate that it could prevent ovulation in only 15 percent or less of cases. The drug has no ability to alter sperm function and limited ability to suppress ovulation. Further, data suggest that when administered pre-ovulation, it may have a post-fertilization MOA.
This paper is a response to Dr. Kathleen Raviele's recent article on her critical analysis of the use of levonorgestrel given to women postsexual assault and her suggestion that the use of Meloxicam may be an ethical alternative.
Regidor PA et al., 2016·Int J Endocrinol·
Open Access
The use of 2 × 2000 mg myoinositol + 2 × 200 μg folic acid per day is a safe and promising tool in the effective improvement of symptoms and infertility for patients with a polycystic ovary syndrome (PCOS). Using a questionnaire an observational study was performed under German gynecologists to collect data on ovulation and pregnancy rates in PCOS patients with infertility. In this observational study, 3602 infertile women used myoinositol and folic acid between 2 and 3 months in a dosage of 2 × 2000 mg myoinositol + 2 × 200 μg folic acid per day. In a subgroup of 32 patients, hormonal values for testosterone, free testosterone, and progesterone were analyzed before and after 12 weeks of treatment. The mean time of use was 10.2 weeks. During this time 70% of these women had a restored ovulation, and 545 pregnancies were obtained. This means a pregnancy rate of 15.1% of all the myoinositol and folic acid users. In 19 cases a concomitant medication with clomiphene or dexamethasone was used. One twin pregnancy was documented. Testosterone levels changed from 96.6 ng/ml to 43.3 ng/ml and progesterone from 2.1 ng/ml to 12.3 ng/ml (p < 0.05) after 12 weeks of treatment. No relevant side effects were present among the patients. This study could show that a new treatment option for patients with a PCOS and infertility is available. The achieved pregnancy rates are at least in an equivalent or even superior range than those reported by the use of metformin.
El Tokhy O et al., 2016·Women's Health·
Open Access
Ovarian hyperstimulation syndrome is a potentially life-threatening, but preventable iatrogenic complication of in vitro fertilisation treatment. In recent years, new strategies have been developed to minimise the risk of ovarian hyperstimulation syndrome after in vitro fertilisation, including better at-risk patient identification prior to starting treatment, the use of a lower human chorionic gonadotrophin dose or alternative medication instead of human chorionic gonadotrophin to induce final oocyte maturation such as gonadotrophin-releasing hormone agonist and kisspeptin in antagonist cycles, cryopreservation of all embryos and delayed embryo transfer, and the use of oral dopamine agonists after oocyte retrieval. In this article, the advantages and limitations of those new developments are discussed and future directions towards establishment of an ovarian hyperstimulation syndrome–free in vitro fertilisation clinic are explored.
Brents LK, 2016·The Yale journal of biology and medicine
Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.
Studies with animals of both sexes show that the adrenal glands release progesterone in addition to cortisol in response to stress. However, little is known about the progesterone response to stress in naturally cycling women. We investigated the effect of stress on estradiol, progesterone, and cortisol levels in women during the follicular phase of the menstrual cycle. We found that physical stress (the cold pressor test) had no effect on estradiol levels, but increased progesterone and cortisol. We also found positive correlations between baseline progesterone and cortisol levels, as well as between the change in progesterone and cortisol before and after water exposure in both the stress and control sessions. Mediation analyses revealed during the stress session, the change in progesterone from baseline to 42-min post-stress onset was mediated by the magnitude of change in cortisol levels across the same time span. Overall, these findings reveal that progesterone released in response to stress as observed in animals and men extends to women during the low ovarian output follicular phase of the menstrual cycle, and that the mechanism of release may be similar to the mechanism of cortisol release.
Jamilian M et al., 2016·Biological trace element research
The current study was conducted to evaluate the effects of zinc supplementation on endocrine outcomes, biomarkers of inflammation, and oxidative stress in patients with polycystic ovary syndrome (PCOS). This study was a randomized double-blind, placebo-controlled trial. Forty-eight women (18-40 years) with PCOS diagnosed according to Rotterdam criteria were randomly assigned to receive either 220 mg zinc sulfate (containing 50 mg zinc) (group 1; n = 24) and/or placebo (group 2; n = 24) for 8 weeks. Hormonal profiles, biomarkers of inflammation, and oxidative stress were measured at study baseline and after 8-week intervention. After 8 weeks of intervention, alopecia (41.7 vs. 12.5%, P = 0.02) decreased compared with the placebo. Additionally, patients who received zinc supplements had significantly decreased hirsutism (modified Ferriman-Gallwey scores) (-1.71 ± 0.99 vs. -0.29 ± 0.95, P < 0.001) and plasma malondialdehyde (MDA) levels (-0.09 ± 1.31 vs. +2.34 ± 5.53 μmol/L, P = 0.04) compared with the placebo. A trend toward a significant effect of zinc intake on reducing high-sensitivity C-reactive protein (hs-CRP) levels (P = 0.06) was also observed. We did observe no significant changes of zinc supplementation on hormonal profiles, inflammatory cytokines, and other biomarkers of oxidative stress. In conclusion, using 50 mg/day elemental zinc for 8 weeks among PCOS women had beneficial effects on alopecia, hirsutism, and plasma MDA levels; however, it did not affect hormonal profiles, inflammatory cytokines, and other biomarkers of oxidative stress.
Azmoodeh A et al., 2015·Glob J Health Sci·
Open Access
Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes. The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups. For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18-23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38-40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured, a third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome. There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p < 0.001). The results of our multivariate logistic regression indicate that size 18-19.9 mm leads to the complete LUF less than ≥22 mm [AOR: 0.25, P = 0.005], and in size 20- 21.9 mm as well [AOR: 0.17, P = 0.002]. Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of ≥22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF.
Zarek SM et al., 2015·J Clin Endocrinol Metab·
Open Access
The objective of the study was to evaluate whether anti-Müllerian hormone (AMH) is associated with fecundability among women with proven fecundity and a history of pregnancy loss.
This was a prospective cohort study within a multicenter, block-randomized, double-blind, placebo-controlled clinical trial ( clinicaltrials.gov , number NCT00467363).
The study was conducted at four US medical centers (2006-2012). Participating women were aged 18-40 years, with a history of one to two pregnancy losses who were actively attempting pregnancy. Time to human chorionic gonadotropin detected and clinical pregnancy were assessed using Cox proportional hazard regression models to estimate fecundability odds ratios (fecundability odds ratios with 95% confidence interval [CI]) adjusted for age, race, body mass index, income, low-dose aspirin treatment, parity, number of previous losses, and time since most recent loss. Analyses examined by preconception AMH levels: low (<1.00 ng/mL, n = 124); normal (referent 1.00-3.5 ng/mL, n = 595); and high (>3.5 ng/mL, n = 483). Of the 1202 women with baseline AMH levels, 82 women with low AMH (66.1%) achieved an human chorionic gonadotropin detected pregnancy, compared with 383 with normal AMH (65.2%) and 315 with high AMH level (65.2%). Low or high AMH levels relative to normal AMH (referent) were not associated with fecundability (low fecundability odds ratios 1.13, 95% CI 0.85-1.49; high FOR 1.04, 95% CI 0.87-1.24). Lower and higher AMH values were not associated with fecundability in unassisted conceptions in a cohort of fecund women with a history of one or two prior losses. Our data do not support routine AMH testing for preconception counseling in young, fecund women.
Schliep KC et al., 2015·Am J Clin Nutr·
Open Access
Although habitual low-to-moderate alcohol intake has been linked with reduced all-cause mortality and morbidity, the effect of recent alcohol intake on female reproductive function has not been clearly established. We assessed the relation between acute alcohol consumption, reproductive hormones, and markers of menstrual cycle dysfunction including sporadic anovulation, irregular cycle length, luteal phase deficiency, long menses, and heavy blood loss.
A total of 259 healthy, premenopausal women from Western New York were followed for ≤2 menstrual cycles (2005-2007) and provided fasting blood specimens during ≤8 visits/cycle and four 24-h dietary recalls/cycle. Linear mixed models were used to estimate associations between previous day's alcohol intake and hormone concentrations, whereas Poisson regression was used to assess RR of cycle-average alcohol intake and menstrual cycle function. For every alcoholic drink consumed, the geometric mean total and free estradiol, total and free testosterone, and luteinizing hormone were higher by 5.26% (95% CI: 1.27%, 9.41%), 5.82% (95% CI: 1.81%, 9.99%), 1.56% (95% CI: 0.23%, 2.90%), 1.42% (95% CI: 0.02%, 2.84%), and 6.18% (95% CI: 2.02%, 10.52%), respectively, after adjustment for age, race, percentage of body fat, perceived stress, pain-medication use, sexual activity, caffeine, and sleep. Binge compared with nonbinge drinking (defined as reporting ≥4 compared with <4 drinks/d, respectively) was associated with 64.35% (95% CI: 18.09%, 128.71%) and 63.53% (95% CI: 17.41%, 127.73%) higher total and free estradiol. No statistically significant associations were shown between cycle-average alcohol intake and menstrual cycle function. Although recent moderate alcohol intake does not appear to have adverse short-term effects on menstrual cycle function, including sporadic anovulation, potential protective and deleterious long-term effects of alterations in reproductive hormones on other chronic diseases warrant additional investigation.
Thyroid and Metabolic Function · Cushing Syndrome and Pituitary Disorders
Abdel Hamid AM et al., 2015·Int J Gynaecol Obstet·
To evaluate the prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding (AUB) compared with matched controls. In 2013-2014, an observational study of women with AUB (group A) and women with regular menstruation (group B) was undertaken at one center in Egypt and one in the United Arab Emirates. Eligible women were aged 20-35 years and were not obese. Participants underwent clinical examinations, vaginal ultrasonography, office hysteroscopy (in selected cases), and measurement of hormone levels. Hyperprolactinemia was present in 17 (16.2%) of 105 patients in group A and 4 (3.2%) of 125 patients in group B (P=0.009). In group A, a high thyroid-stimulating hormone (TSH) level was observed in 8 (7.6%) patients and low levels of free triiodothyronine/thyroxine were found in 5 (4.8%) patients, compared with 2 (1.6%) patients and 1 (0.8%) patient in group B (P=0.012 and P=0.008, respectively). Polymenorrhea was the most frequent presentation of AUB (n=60 [57.1%]). Five (29.4%) patients with hyperprolactinemia had galactorrhea. In group A, 8 (47.1%) patients with a high TSH had hyperprolactinemia, whereas 1 (1.1%) patient with a high TSH had a normal prolactin value (P=0.008). Screening by evaluating prolactin and thyroid hormone levels is recommended for all patients with AUB, even in the absence of galactorrhea.
The onset of puberty has been a fascinating topic for reproductive endocrinologists for decades; however, its underlying physiological mechanisms have remained elusive until recently. The discovery and understanding of the effects exerted by the peptide hormone kisspeptin have shed light on this research area. This review is aimed to discuss the functions of kisspeptin, with special focus on its role in the onset of puberty and in the ovulatory mechanism. The points under discussion are (1) the characteristics of kisspeptin and its receptor, (2) the relevance of this hormone and its interaction with leptin in the onset of puberty, (3) the role of kisspeptin in the ovulatory mechanism based on its differential expression at hypothalamic nuclei, which is modulated by sex steroid hormones, and (4) the clinical relevance of kisspeptin and its antagonists in new therapeutic strategies for the treatment of various reproductive pathologies. All of this explains the revolution that kisspeptin has caused among researchers working in the field of gynecological endocrinology and reproductive biology.
Does use of commonly used over-the-counter (OTC) pain medication affect reproductive hormones and ovulatory function in premenopausal women? Few associations were found between analgesic medication use and reproductive hormones, but use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for potential confounders. Analgesic medications are the most commonly used OTC drugs among women, but their potential effects on reproductive function are unclear. STUDY DESIGN, SIZE, Duration: The BioCycle Study was a prospective, observational cohort study (2005-2007) which followed 259 women for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS, SETTING, Two hundred and fifty-nine healthy, premenopausal women not using hormonal contraception and living in western New York state. Study visits took place at the University at Buffalo. Main During study participation, 68% (n = 175) of women indicated OTC analgesic use. Among users, 45% used ibuprofen, 33% acetaminophen, 10% aspirin and 10% naproxen. Analgesic use during the follicular phase was associated with decreased odds of sporadic anovulation after adjusting for age, race, body mass index, perceived stress level and alcohol consumption (OR 0.36 [0.17, 0.75]). Results remained unchanged after controlling for potential confounding by indication by adjusting for 'healthy' cycle indicators such as amount of blood loss and menstrual pain during the preceding menstruation. Moreover, luteal progesterone was higher (% difference = 14.0, -1.6-32.1, P = 0.08 adjusted) in cycles with follicular phase analgesic use, but no associations were observed with estradiol, LH or FSH. LIMITATIONS, Self-report daily diaries are not validated measures of medication usage, which could lead to some classification error of medication use. We were also limited in our evaluation of aspirin and naproxen which were used by few women. The observed associations between follicular phase analgesic use and higher progesterone and a lower probability of sporadic anovulation indicate that OTC pain medication use is likely not harmful to reproduction function, and certain medications possibly improve ovulatory function. This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275200403394C). The authors have no conflicts of interest to disclose.
Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.
There has been much debate regarding levonorgestrel emergency contraception's (LNG-EC's) method of action since 1999 when the Food and Drug Administration first approved its use. Proponents of LNG-EC have argued that they have moral certitude that LNG-EC works via a non-abortifacient mechanism of action, and claim that all the major scientific and medical data consistently support this hypothesis. However, newer medical data serve to undermine the consistency of the non-abortifacient hypothesis and instead support the hypothesis that preovulatory administration of LNG-EC has significant potential to work via abortion. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room protocols. In the future, technology such as the use of early pregnancy factor may have the potential to quantify how frequently preovulatory LNG-EC works via abortion. Lay How Plan B (levonorgestrel emergency contraception) works has been vigorously debated ever since the Food and Drug Administration approved it in 1999. Many doctors and researchers claim that it has either no-or at most-an extremely small chance of working via abortion. However, the latest scientific and medical evidence now demonstrates that levonorgestrel emergency contraception theoretically works via abortion quite often. The implications of the newer data have important ramifications for medical personnel, patients, and both Catholic and non-Catholic emergency room rape protocols.
Luteal phase deficiency (LPD), while commonly observed and managed in stimulated in-vitro fertilisation cycles, is a more contentious phenomenon in natural cycles. The challenge arises in the definition and diagnosis of LPD. Controversy regarding the clinical significance of LPD is due in part to the lack of a reliable test to diagnose the disorder.2 Jones first described LPD based on temperature criteria, urinary pregnanediol studies and histological appearance of the endometrium in 1949. 3 In current practice, timing of the luteal phase from which an evaluation of its length and hormonal parameters can be made are problematic. Ovulation and thereby the length of the luteal phase can reliably and reproducibly be determined by teaching women to identify their Peak Symptom Day (PSD) of cervical mucus (the last day of any mucus discharge that is clear, stretchy, or lubricative). 4 There is an abrupt and dramatic change in the characteristic fertile pattern of pre-ovulatory mucus that is due to the effects of progesterone post-ovulation. Correlation with ultrasound and hormonal evaluation indicates that the mucus observation occurs within 2 days of ovulation. Using such a fertility awareness based method, the American Academy of Fertility Care Professionals has defined a luteal phase deficiency as a deficiency in the length of the luteal phase, or a deficiency of the hormones progesterone and oestradiol that occurs during the luteal phase. Women presenting with infertility or recurrent miscarriages to the Fertility Assessment and Research Clinic of the Mater Mothers' Hospital (Brisbane, Australia) were instructed in the Sympto-Thermal Method. This allowed for accurate documentation of ovulation and the luteal phase. Luteal phase hormone levels were collected 5, 7 and 9 days after ovulation. Women were allocated a luteal phase status using the definition below for luteal phase defect. This data is part of the recruitment phase of the Pregnancy Achieving Trials (Mater Health Services HREC no. 1618M). By the definition above, a luteal phase deficiency exists in 36% (100) of 279 infertile couples who presented to our clinic, in preparation for involvement in the Pregnancy Achieving Trials. Of 16 infertile women who had previously experienced both a miscarriage and an ectopic pregnancy, 75% (12) met the criteria for a luteal phase deficiency. Ectopic pregnancy is known to be associated with infectious history, smoking, age, previous spontaneous miscarriage, history of infertility, previous use of an intrauterine device and prior history of medical termination of pregnancy (mifepristone + misoprostol). Previous research has suggested an association between luteal phase defect (LPD) and ectopic pregnancy in subfertile couples." All stimulated cycles of in-vitro fertilisation have abnormal luteal phases.' There exists a high rate of ectopic pregnancy among women undergoing in-vitro fertilization. The high proportion of ectopic pregnancies among women who fall pregnant on progestogen-only contraceptives also suggests an hormonal association." Women who are heavy smokers, another risk factor associated with ectopic pregnancy, has been shown to have lower urinary progesterone metabolite levels in the luteal phase compared with non-smokers. 10 There appears to be an association between prior miscarriage, prior ectopic pregnancy and luteal phase deficiency in subfertile couples. Could luteal phase deficiency, an hormonal disorder, be useful in the definition of ectopic pregnancy risk?
To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression. A prospective cohort of 248 regularly menstruating women, aged 18 to 44 years (27.3 ± 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (<16, no depressive symptoms [92%] vs. ≥ 16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to eight times per cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations, whereas generalized linear mixed models assessed their relationship with sporadic anovulation. No significant associations were identified between depressive symptoms and reproductive hormone levels (all P > .05) or the odds of sporadic anovulation (adjusted odds ratio, 1.1; 95% confidence interval, [0.02-5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption. Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly menstruating women with no recent (within 1 year) self-reported history of clinical depression.
To compare previously used algorithms to identify anovulatory menstrual cycles in women self-reporting regular menses.
Prospective cohort study.
Western New York. PATIENT(S): Two hundred fifty-nine healthy, regularly menstruating women followed for one (n=9) or two (n=250) menstrual cycles (2005-2007). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of sporadic anovulatory cycles identified using 11 previously defined algorithms that use E2, P, and LH concentrations. RESULT(S): Algorithms based on serum LH, E2, and P levels detected a prevalence of anovulation across the study period of 5.5%-12.8% (concordant classification for 91.7%-97.4% of cycles). The prevalence of anovulatory cycles varied from 3.4% to 18.6% using algorithms based on urinary LH alone or with the primary E2 metabolite, estrone-3-glucuronide, levels. CONCLUSION(S): The prevalence of anovulatory cycles among healthy women varied by algorithm. Mid-cycle LH surge urine-based algorithms used in over-the-counter fertility monitors tended to classify a higher proportion of anovulatory cycles compared with luteal-phase P serum-based algorithms. Our study demonstrates that algorithms based on the LH surge, or in conjunction with estrone-3-glucuronide, potentially estimate a higher percentage of anovulatory episodes. Addition of measurements of postovulatory serum P or urine pregnanediol may aid in detecting ovulation.
To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level. Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited. Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night. MAIN OUTCOME MEASURE(S): Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs. RESULT(S): The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ. CONCLUSION(S): Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided.
We investigated whether sexual activity was associated with reproductive function in the BioCycle Study, a prospective cohort study that followed 259 regularly menstruating women aged 18 to 44years for one (n=9) or two (n=250) menstrual cycles in 2005-2007. Women were not attempting pregnancy nor using hormonal contraceptives. History of ever having been sexually active was assessed at baseline and frequency of sexual activity, defined as vaginal-penile intercourse, was self-reported daily throughout the study. Serum concentrations of estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were measured up to 8times/cycle. Sporadic anovulation was identified using peak progesterone concentration. Linear mixed models were used to estimate associations between sexual activity and reproductive hormone concentrations and generalized linear models were used to estimate associations with sporadic anovulation. Models were adjusted for age, race, body mass index, perceived stress, and alcohol consumption and accounted for repeated measures within women. Elevated concentrations of estrogen (+14.6%, P<.01), luteal progesterone (+41.0%, P<.01) and mid-cycle LH (+23.4%, P<.01), but not FSH (P=.33) or testosterone (P=.37), were observed in sexually active women compared with sexually inactive women (no prior and no study-period sexual activity); sexually active women had lower odds of sporadic anovulation (adjusted odds ratio=0.34, 95% confidence interval: 0.16-0.73). Among sexually active women, frequency of sexual activity was not associated with hormones or sporadic anovulation (all P>.23). Findings from our study suggest that ever having been sexually active is associated with improved reproductive function, even after controlling for factors such as age.
Sjaarda LA et al., 2014·J Clin Endocrinol Metab·
Open Access
Hyperandrogenism is a hallmark of polycystic ovary syndrome (PCOS) in women with irregular menses, yet the relationship between androgens and ovarian dysfunction remains poorly understood in eumenorrheic women. The objective of the study was to evaluate whether sporadic anovulation was associated with higher T and anti-müllerian hormone (AMH; marker of ovarian follicle count) concentrations in eumenorrheic women.
This was a prospective cohort study from 2005 to 2007.
The study was conducted at the University of Buffalo in western New York state. A total of 259 eumenorrheic women without a self-reported history of infertility, PCOS, or other endocrine disorder participated in the study. Total T and AMH were measured five to eight times per cycle for one (n = 9) or two (n = 250) cycles per woman (n = 509 cycles) with timing of menstrual cycle phase assisted by fertility monitors. Anovulatory cycles were defined biochemically by progesterone and LH concentrations. Repeated-measures ANOVA was conducted on log-transformed data with adjustment for age. Compared with ovulatory cycles (n = 467), sporadic anovulatory cycles (n = 42) had marginally higher total and significantly higher free T [mean 23.7 ng/dL (95% confidence interval [CI] 21.4-26.3) vs 21.6 ng/dL (95% CI 20.9-22.3), P = .08, and 0.36 ng/dL (95% CI 0.33-0.40) vs 0.32 ng/dL (95% CI 0.31-0.33), P = .02, respectively] during menses and also throughout the luteal phase (P < .01 for all). Women with higher T had elevated AMH concentrations, increased reporting of a history of acne requiring medical treatment, but not increased hirsutism. Mechanisms of androgen-related ovulatory dysfunction that characterize PCOS in women with menstrual disturbances may occur across a continuum of T concentrations, including in eumenorrheic women without clinical hyperandrogenism.
Thyroid and Metabolic Function · Insulin and Metabolism
Guler I et al., 2014·Biological trace element research
In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.
Merhi Z et al., 2014·The Journal of clinical endocrinology and metabolism·
Open Access
Vitamin D deficiency is common among reproductive-aged women and has a role in female reproduction. This study evaluated the role of 1,25-dihydroxyvitamin D3 (vit D3) in ovarian follicular development and steroidogenesis by using a human granulosa cell (GC) model. DESIGN, SETTING, Fifty-four women who underwent in vitro fertilization were enrolled. Follicular fluid (FF) and mural and cumulus GCs were collected from small and large follicles. In separate experiments, primary cumulus GCs were cultured with or without vit D3 followed by RT-PCR for mRNA expression levels. The effect of recombinant anti-Mullerian hormone (AMH) on nuclear localization of phospho-Smad 1/5/8 was evaluated in the presence or absence of vit D3 by using immunofluorescence. 25-Hydroxyvitamin D levels in FF as well as cell culture media AMH, progesterone, and estradiol (E2) concentrations were determined by ELISA and RIA. The following were measured: 1) mRNA expression levels; 2) 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme activity; 3) FSH-induced aromatase mRNA and E2 production; and 4) nuclear localization of phospho-Smad 1/5/8. In a multivariate analysis, 25 OH-D levels in FF negatively correlated with AMH and AMH receptor (AMHR)-II mRNA levels in cumulus GCs of small follicles. Compared with women with replete 25-hydroxyvitamin D levels in FF, those with insufficient/deficient levels had a 2-fold increase in AMHR-II mRNA levels in cumulus GCs of small follicles (P = .02). Treatment with vit D3 caused a decrease in AMHR-II and FSH receptor mRNA but an increase in 3-βHSD mRNA levels compared with control (P < .05). Vit D3 enhanced 3-βHSD enzyme activity as assessed by increasing progesterone release; however, vit D3 did not affect FSH-induced aromatase mRNA and E2 production, but it decreased the phosphorylation of Smad 1/5/8 and its nuclear localization. These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation.
Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼ 24 nM for transactivation of the anti-inflammatory GILZ gene and ∼ 4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.
Schliep KC et al., 2014·J Clin Endocrinol Metab·
Open Access
Although adequate luteal hormone production is essential for establishing pregnancy, luteal phase deficiency (LPD) is poorly characterized among eumenorrheic women. We assessed the prevalence and overlap of two established LPD diagnostic criteria: short luteal phase duration less than10 days (clinical LPD) and suboptimal luteal progesterone of 5 ng/mL or less (biochemical LPD) and their relationship with reproductive hormone concentrations.
Design, Setting, and We conducted a prospective study in western New York (2005-2007) following 259 women, aged 18-44 years, for up to two menstrual cycles. Among ovulatory cycles with recorded cycle lengths (n = 463), there were 41 cycles (8.9%) with clinical LPD, 39 cycles (8.4%) with biochemical LPD, and 20 cycles (4.3%) meeting both criteria. Recurrent clinical and biochemical LPD was observed in eight (3.4%) and five (2.1%) women, respectively. Clinical and biochemical LPD were each associated with lower follicular estradiol (both P ≤ .001) and luteal estradiol (P = .03 and P = .02, respectively) after adjusting for age, race, and percentage body fat. Clinical, but not biochemical, LPD was associated with lower LH and FSH across all phases of the cycle (P ≤ .001). Clinical and biochemical LPD were evident among regularly menstruating women. Estradiol was lower in LPD cycles under either criterion, but LH and FSH were lower only in association with shortened luteal phase (ie, clinical LPD), indicating that clinical and biochemical LPD may reflect different underlying mechanisms. Identifying ovulation in combination with a well-timed luteal progesterone measurement may serve as a cost-effective and specific tool for LPD assessment by clinicians and researchers.
Ahrens K et al., 2014·Am J Obstet Gynecol·
Open Access
The purpose of this study was to investigate the role of leptin on reproductive hormones and ovulation. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for ≤2 menstrual cycles (n = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone, and testosterone were measured ≤8 times per cycle. The association of time-varying leptin and reproductive hormones over the cycle was estimated with the use of linear mixed models that were adjusted for percent body fat and age with inverse probability weighting for time-varying physical activity, caloric intake, and other reproductive hormones. The odds ratio for sporadic anovulation (n = 42 cycles) was estimated with the use of generalized linear models that were adjusted for percent body fat and age. Geometric mean serum leptin levels increased from menses to the late luteal phase (16.7-20.4 ng/mL; P < .01), with a mid-cycle peak (21.7 ng/mL) at the time of the LH surge (P < .01). A 10% higher leptin level across the menstrual cycle was associated with higher estradiol levels (2.2%; 95% CI, 1.5-3.0), luteal progesterone levels (2.1%; 95% CI, 0.5-3.7), ovulatory LH levels (1.2%; 95% CI, 0-2.3), testosterone levels (0.6%; 95% CI, 0.3-0.9), and lower follicle-stimulating hormone levels (-0.7%; 95% CI, -1.1 to -0.4). Leptin at the time of the expected LH surge was moderately inversely associated with sporadic anovulation (per log increase in leptin; adjusted odds ratio, 0.58; 95% CI, 0.28-1.22). The association that was observed between leptin level and reproductive function points to a possible relationship between serum leptin level and enhanced fertility.
Zimmerman Y et al., 2014·Human reproduction update
BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T. A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T. A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18-40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) -0.49 nmol/l (-0.55, -0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20-25 µg EE had similar effects on total and free T compared with COCs with 30-35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20-25 µg EE) were found to have less impact on SHBG concentrations. The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.
Wunderle K et al., 2014·The Journal of head trauma rehabilitation
To determine whether menstrual cycle phase in women at the time of mild traumatic brain injury (mTBI) predicts 1-month outcomes. Six emergency departments; 5 in Upstate New York, and 1 in Pennsylvania. One hundred forty-four female participants (age, 16-60) who presented to participating emergency departments within 4 hours of mTBI. Nested cohort study with neurologic and quality-of-life outcome assessment, 1 month after enrollment. Female subjects aged 16 to 60 enrolled in the parent cohort study, with 1-month neurological determination data available, were classified into menstrual cycle groups by serum progesterone concentration and self-reported contraceptive use. Rivermead Post Concussion Questionnaire and EuroQoL/EQ5D. Women injured during the luteal phase of their menstrual cycle, when progesterone concentration is high, had significantly lower EuroQoL General Health Ratings and Index Scores than women injured during the follicular phase of their cycle or women taking oral contraceptives. Multivariate analysis confirmed a significant independent effect of menstrual cycle phase on EuroQoL Index Score and the Rivermead Post Concussion Questionnaire Somatic Subscore. Menstrual cycle phase and progesterone concentration at the time of mTBI affect 1-month quality-of-life and neurologic outcomes. This association has important implications for treatment and prognosis after mTBI.
Takasaki A et al., 2013·Journal of ovarian research
Clomiphene citrate (CC) is most commonly used as a first-line treatment of infertility. However, a disturbance of endometrial growth by the adverse effects of the CC has been recognized. Since a thin endometrium is recognized as a critical factor of implantation failure, preventing CC-induced thinning of the endometrium is important. This study was undertaken to investigate whether the modified CC treatments are useful to prevent a thin endometrium in patients undergoing CC treatments. This study is a prospective, randomized controlled study. The study was performed at the Saiseikai Shimonoseki General Hospital during a 4-month period (May 2012 to September 2012). Sixty-six infertile women who had a thin endometrium (< 8 mm) during the standard CC treatment (50 mg/day on days 5-9 of the menstrual cycle) were enrolled. The patients were randomly divided into three groups: 22 patients were given 25 mg/day CC on days 5-9 (half-dose group), 22 patients were given 50 mg/day CC on days 1-5 (early administration group) and 22 patients received a standard CC treatment again (control group). Endometrial thickness at the induction of ovulation was assessed by ultrasonography. The primary endpoint of this study was an endometrial thickness. Half dose administration and early administration improved the endometrial thickness (≥ 8 mm) in 14 patients (70%) and in 19 patients (90%) respectively, while only 3 patients (15%) improved in endometrial thickness in the control group. The mean endometrial thickness was also significantly higher in the half dose group (8.6 ± 1.5 mm) and early administration group (9.4 ± 1.5 mm) compared to the control group (6.7 ± 1.8 mm). No side effect was observed in this study. The modified treatment with a half-dose or early administration of CC significantly increased endometrial thickness in patients with a history of thin endometrium caused by the standard CC regimen. The modified CC treatments in this study can be beneficial for patients with a thin endometrium as a result of standard CC treatment. CLINICAL UMIN000007959.
Urinary hormonal markers may assist in increasing the efficacy of Fertility Awareness Based Methods (FABM). This study uses urinary pregnanediol-3a-glucuronide (PDG) testing to more accurately identify the infertile phase of the menstrual cycle in the setting of FABM. Secondary analysis of an observational and simulation study, multicentre, European study. The study includes 107 women and tracks daily first morning urine (FMU), observed the changes in cervical mucus discharge, and ultrasonography to identify the day of ovulation over 326 menstrual cycles. The following three scenarios were tested: (A) use of the daily pregnandiol-3a-glucuronide (PDG) test alone; (B) use of the PDG test after the first positive urine luteinizing hormone (LH) kit result; (C) use of the PDG test after the disappearance of fertile type mucus. Two models were used: (1) one day of PDG positivity; or (2) waiting for three days of PDG positivity before declaring infertility. After the first positivity of a LH test or the end of fertile mucus, three consecutive days of PDG testing over a threshold of 5μg/mL resulted in a 100% specificity for ovulation confirmation. They were respectively associated an identification of an average of 6.1 and 7.6 recognized infertile days. The results demonstrate a clinical scenario with 100% specificity for ovulation confirmation and provide the theoretical background for a future development of a competitive lateral flow assay for the detection of PDG in the urine.
Fusi FM et al., 2013·Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
The aim of this article is to describe unexpected spontaneous pregnancies in poor responder patients with long-term infertility, when treated with dehydroepiandrosterone (DHEA) supplementation prior to in vitro fertilization (IVF). Our evaluation was carried out in two groups of women. The first group included 39 young women with <40 years, all treated with DHEA because of a previous poor response. The second group included 38 women over 40 years who received DHEA supplementation. Controls for latter group were 24 comparable women who had not been treated with DHEA before the first IVF cycle to evaluate the spontaneous pregnancy rate during preparation to IVF. Three tablets daily of 25 mg micronized DHEA were administered for at least 12 weeks before starting a long stimulation protocol for IVF. Surprisingly, spontaneous pregnancy rate significantly increased after DHEA treatment, allowing to achieve 10 spontaneous pregnancies and 9 spontaneous ongoing pregnancies among young poor responders. Pregnancy rate and ongoing pregnancy rate obtained before starting the IVF cycle were also significantly higher in older women treated with DHEA than in the control group: 21.05% and 13.15% and 4.1% and 0, respectively. Our results show that DHEA supplementation improves the ovarian function in poor responders and in women over 40 years, suggesting that this molecule alone can raise fecundity and fertility treatment success in women with poor prognosis for pregnancy.
Fouany MR et al., 2013·Journal of assisted reproduction and genetics·
Open Access
Poor ovarian reserve and poor ovarian response presents a challenge to IVF centers. Dehydroepiandrosterone (DHEA) supplementation is increasingly being used by many IVF centers around the world in poor responders despite the lack of convincing data. We therefore examined the rationale for the use of DHEA in poor responders, address the relevant studies, present new data, and address its potential mechanisms of action. All published articles on the role of DHEA in infertile women from 1990 to April 2013 were reviewed. Several studies have suggested an improvement in pregnancy rates with the use of DHEA. Potential mechanisms include improved follicular steroidogenesis, increased IGF-1, acting as a pre-hormone for follicular testosterone, reducing aneuploidy, and increasing AMH and antral follicle count. While the role of DHEA is intriguing, evidence-based recommendations are lacking. While nearly 25 % of IVF programs use DHEA currently, large randomized prospective trials are sorely needed. Until (and if) such trials are conducted, DHEA may be of benefit in suitable, well informed, and consented women with diminished ovarian reserve.
AMH levels are commonly measured in fertility clinics to assess ovarian reserve and give an indication of female fertility potential. AMH levels are useful in deciding on stimulation protocols for IVF cycles. High AMH levels are useful to confirm a diagnosis of polycystic ovaries. Currently AMH levels cannot be used to predict a couple's ability to conceive naturally.
Majumdar A et al., 2013·Journal of human reproductive sciences
Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the 'big big molecule of prolactin' that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management.
To determine patterns of usage of clomiphene citrate (CC) by primary care providers (obstetrician-gynecologists, family physicians, and other providers) within University of Utah Community Clinics. We performed a retrospective chart review (n = 79) and followup telephone survey of patients (n = 43) who were prescribed CC in the University of Utah Community Clinics in 2006. Most women who were prescribed CC had appropriate indications for therapy (65% with a diagnosis related to irregular menses and 33% with a diagnosis of female infertility), but there was variable and inconsistent monitoring of ovulation (much of which was apparently initiated by the patients). In the interview, 24 of the women (56%) said they would be fine having twins, and 14 (33%) said they would prefer to have twins if possible. In this primary care setting, clomiphene was prescribed for appropriate indications, but the monitoring of treatment could be improved. The preference of some patients for twin gestations represents a challenge for optimum clinical care and public health.
Klump KL et al., 2013·Journal of abnormal psychology
Studies suggest that within-person changes in estrogen and progesterone predict changes in binge eating across the menstrual cycle. However, samples have been extremely small (maximum N = 9), and analyses have not examined the interactive effects of hormones that are critical for changes in food intake in animals. The aims of the current study were to examine ovarian hormone interactions in the prediction of within-subject changes in emotional eating in the largest sample of women to date (N = 196). Participants provided daily ratings of emotional eating and saliva samples for hormone measurement for 45 consecutive days. Results confirmed that changes in ovarian hormones predict changes in emotional eating across the menstrual cycle, with a significant estradiol × progesterone interaction. Emotional eating scores were highest during the midluteal phase, when progesterone peaks and estradiol demonstrates a secondary peak. Findings extend previous work by highlighting significant interactions between estrogen and progesterone that explain midluteal increases in emotional eating. Future work should explore mechanisms (e.g., gene-hormone interactions) that contribute to both within- and between-subjects differences in emotional eating.
Okeke T et al., 2013·Annals of medical and health sciences research
Premature menopause affects 1% of women under the age of 40 years. The women are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. There is need to use simplified protocols and improved techniques in oocyte donation to achieve pregnancy and mother a baby in those women at risk. Review of the pertinent literature on premature menopause, selected references, internet services using the PubMed and Medline databases were included in this review. In the past, pregnancy in women with premature menopause was rare but with recent advancement in oocyte donation, women with premature menopause now have hoped to mother a child. Hormone replacement therapy is beneficial to adverse consequences of premature menopause. Women with premature menopause are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. Public enlightenment and education is important tool to save those at risk.
Shamim N et al., 2012·Indian J Endocrinol Metab·
Open Access
Polycystic Ovary Syndrome (PCOS) is a leading cause of infertility. We studied the rheological properties of cervical-vaginal secretions in five PCOS patients during variable treatment intervals with metformin. Five ovulatory normal women for a total of thirteen cycles served as control patients. All subjects collected daily cervical-vaginal fluid(CVF) samples with an aspirator, and CVF samples were characterized by a flow metric, die swell ratio (B), which measured CVF elasticity. Ovulatory cycles were indexed to the day of positive urine or serum LH (luteinizing hormone). CVF B levels from ovulatory normal women had a characteristic concave parabolic pattern of a minimum near the day of ovulation with higher values outside the periovulatory phase. In contrast, the five PCOS patients with or without metformin treatment had no periodicity of CVF B, and their CVF B levels were typically less compared to those in the early preovulatory and luteal phases of normal patients.
Grynnerup AG et al., 2012·Acta obstetricia et gynecologica Scandinavica
Anti-Müllerian hormone (AMH) plasma levels reflect the continuous non-cyclic growth of small follicles, thereby mirroring the size of the resting primordial follicle pool and thus acting as a useful marker of ovarian reserve. Anti-Müllerian hormone seems to be the best endocrine marker for assessing the age-related decline of the ovarian pool in healthy women; thus, it has a potential ability to predict future reproductive lifespan. The most established role for AMH measurements is before in vitro fertilization is initiated, because AMH can be predictive of the ovarian response, namely poor and hyper-responses. However, recent research has also highlighted the use of AMH in a variety of ovarian pathological conditions, including polycystic ovary syndrome, granulosa cell tumors and premature ovarian failure. A new commercial enzyme-linked immunosorbent assay for measuring AMH levels has been developed, making results from different studies more comparable. Nevertheless, widespread clinical application awaits an international standard for AMH, so that results using future assays can be reliably compared.
Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS), with the 67-85% of women with PCOS having serum concentrations of 25-hydroxy vitamin D (25OHD) <20 ng/ml. Vitamin D deficiency may exacerbate symptoms of PCOS, with observational studies showing lower 25OHD levels were associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity and elevated cardiovascular disease risk factors. There is some, but limited, evidence for beneficial effects of vitamin D supplementation on menstrual dysfunction and insulin resistance in women with PCOS. Vitamin D deficiency may play a role in exacerbating PCOS, and there may be a place for vitamin D supplementation in the management of this syndrome, but current evidence is limited and additional randomized controlled trials are required to confirm the potential benefits of vitamin D supplementation in this population.
Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by chronic anovulation and hyperandrogenism. Hormonal changes can affect hearing loss and inner ear functions. We evaluated hearing loss with audiometric tests in young patients with PCOS. Twenty-six women having PCOS and 25 normal individuals were enrolled in the study. Age ranges for PCOS and control groups were 20-35 years. Hormonal and biochemical values including LH, LH/FSH, E2, testosterone, fasting glucose and fasting insulin were calculated. Each subject was tested with low- (250-2000Hz) and high-frequency audiometry (4000-8000Hz). For each set of tests, mean values of air conduction at each frequency were measured for the PCOS and control groups and compared. No difference was observed in speech frequencies on audiologic tests between the groups, however high-frequency hearing loss were significantly higher (p<0.05) in PCOS patients than in control women. Also, hearing thresholds were normal range in all of frequencies in PCOS and control subjects. PCOS patients showed high levels of LH, LH/FSH, testosterone and fasting insulin. Our findings suggest that patients diagnosed with PCOS should be advised audiologic evaluation especially in the high frequency.
The female athlete triad (the triad) is an interrelationship of menstrual dysfunction, low energy availability (with or without an eating disorder), and decreased bone mineral density; it is relatively common among young women participating in sports. Diagnosis and treatment of this potentially serious condition is complicated and often requires an interdisciplinary team. Articles from 1981 to present found on PubMed were selected for review of major components of the female athlete triad as well as strategies for diagnosis and treatment of the conditions. The main goal in treatment of young female athletes with the triad is a natural return of menses as well as enhancement of bone mineral density. While no specific drug intervention has been shown to consistently improve bone mineral density in this patient population, maximizing energy availability and optimizing vitamin D and calcium intake are recommended. Treatment requires a multidisciplinary approach involving health care professionals as well as coaches and family members. Prevention of this condition is important to minimize complications of the female athlete triad.
Sacco S et al., 2012·The journal of headache and pain
Migraine is a predominantly female disorder. Menarche, menstruation, pregnancy, and menopause, and also the use of hormonal contraceptives and hormone replacement treatment may influence migraine occurrence. Migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and menopause. Those variations are mediated by fluctuation of estrogen levels through their influence on cellular excitability or cerebral vasculature. Moreover, administration of exogenous hormones may cause worsening of migraine as may expose migrainous women to an increased risk of vascular disease. In fact, migraine with aura represents a risk factor for stroke, cardiac disease, and vascular mortality. Studies have shown that administration of combined oral contraceptives to migraineurs may further increase the risk for ischemic stroke. Consequently, in women suffering from migraine with aura caution should be deserved when prescribing combined oral contraceptives.
Haller-Kikkatalo K et al., 2012·Clinical & developmental immunology
Female fertility can be affected by diseases or dysfunctions of reproductive tract, neuroendocrine system, and immune system. Reproductive autoimmune failure can be associated with overall activation of immune system or with immune system reactions specifically directed against ovarian antigens. Majority of the antiovarian autoantibodies are directed against β-subunit of follicle stimulating hormone (anti-FSH). This paper summarizes a current clinical classification of female infertility in the context of general activation of autoimmunity and antiovarian autoimmunity by describing serum anti-FSH. The presence of naturally occurring anti-FSH in healthy women will be discussed. In addition, the putative impairment of ovarian folliculogenesis in case of increased production of those antibodies in infertile women will be characterized.
To prospectively estimate the risk for earlier ovarian failure among women undergoing hysterectomy with ovarian preservation, as compared with women of similar age without hysterectomy. A prospective cohort study was conducted among women aged 30 to 47 years undergoing hysterectomy without bilateral oophorectomy (n=406) and women with intact uteri (n=465). Blood samples and questionnaire data were obtained at baseline and annually for up to 5 years. Hazard ratios (HR) for ovarian failure, defined as follicle-stimulating hormone levels 40 international units/L or higher, were calculated using Cox proportional hazards models. Ovarian failure occurred among 60 of the women with hysterectomy and 46 of the women in the control group. Women undergoing hysterectomy were at nearly a twofold increased risk for ovarian failure as compared with women with intact uteri (HR 1.92, 95% confidence interval [CI] 1.29-2.86). The proportional hazards model further estimated that 14.8% of women with hysterectomies experienced ovarian failure after 4 years of follow-up compared with 8.0% of the women in the control group. Risk for ovarian failure was greater for women who had a unilateral oophorectomy along with their hysterectomy (HR 2.93, 95% CI 1.57-5.49), but also it was significantly increased for women who retained both ovaries (HR 1.74, 95% CI 1.14-2.65). Increased risk of earlier ovarian failure is a possible consequence of premenopausal hysterectomy. Although it is unresolved whether it is the surgery itself or the underlying condition leading to hysterectomy that is the cause of earlier ovarian failure, physicians and patients should take into account this possible sequela when considering options for treatment of benign conditions of the uterus. II.
The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates. In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation. For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days -5 to -1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods. The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.
We hypothesized that oligomenorrhea (menstrual cyclicity ≥42 days), hyperandrogenism, low levels of sex hormone-binding globulin (SHBG), childhood insulin, and metabolic syndrome (MetS) at age 14 years would predict MetS and class III obesity (body mass index ≥40 kg/m(2)) at age 24 years. In this prospective study of schoolgirls, at age 14 years, the girls were categorized as regularly cycling (n = 375), oligomenorrheic (n = 18), or oligomenorrhea plus biochemical hyperandrogenism (polycystic ovary syndrome [PCOS]; n = 12), together designated PCOS. Significant explanatory variables for MetS at age 24 years included childhood insulin, MetS, and PCOS category (all positive) and SHBG (negative) at age 14 years. Using categorical data, top decile of childhood insulin, MetS at age 14, bottom decile of SHBG, and PCOS category were significant positive predictors for MetS at age 24. SHBG (negative), black race (positive), and oligomenorrhea (positive) were significant explanatory variables for class III obesity at age 24. Using categorical data, black race, MetS at age 14, bottom decile of SHBG, PCOS category, and top decile of childhood insulin were positive explanatory variables for class III obesity at age 24 years. Oligomenorrhea, PCOS (a subcohort of oligomenorrhea), hyperandrogenism, low SHBG, MetS, and childhood insulin at age 14 years may represent a critical, reversible pathway for the development of MetS and class III obesity in young adulthood.
Micu MC et al., 2011·Arthritis Care Res (Hoboken)·
Administration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women. Fourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease. In 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003). NSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases.
Kalyan S et al., 2011·Journal of Gynecologic Surgery·
The aim of this study was to provide a clinical reference for the acute postoperative changes to lipids and inflammation following premenopausal hysterectomy with bilateral oophorectomy and compare them to normal reference values.
The study design was a planned secondary analysis of data from a randomized double-blind trial comparing the effectiveness of two different hormone therapies for preventing post-oophorectomy bone loss and controlling vasomotor symptoms. These data were obtained on hospital discharge before randomization to treatment. Premenopausal women scheduled for a hysterectomy with bilateral oophorectomy for benign reasons were identified from preoperative lists and approached, prior to hospital discharge, to participate in this study. Postoperative data were compared with premenopausal reference intervals using Z scores. Thirty-three (33) women (mean age 45 ± 4.8 years) were studied an average of 7 days postsurgery. Hemoglobin, albumin, testosterone, and high-density lipoprotein values were decreased in comparison to the normal mean, having Z scores of −3.0, −2.5, −2.4, and −1.7, respectively. C-reactive protein levels were quite significantly elevated (Z score = 20.3). The high levels of inflammation and abnormal lipids postsurgical menopause are important considerations for physicians when planning subsequent treatment and care. (J GYNECOL SURG 27:9)
Thyroid and Metabolic Function · Insulin and Metabolism
Sakumoto T et al., 2010·Reproductive medicine and biology·
Open Access
Obesity, which disturbs lipid and glucose metabolism, is a recent medical concern. It threatens human health and also has adverse effects on reproductive functions by causing insulin resistance/hyperinsulinemia, especially in women with polycystic ovary syndrome (PCOS). For PCOS patients to prevent these adverse effects, it is important to take into account improving their lifestyles by exercise and proper diets. The relationship between insulin resistance/hyperinsulinemia and reproductive disorders should be understood as fully as possible in order to provide effective treatment. It is well known that insulin resistance and compensatory hyperinsulinemia can be triggered by obesity with visceral fat accumulation. Hyperinsulinemia affects granulosa cells in small follicles and theca cells. This condition induces early response to luteinizing hormones on granulosa cells of small follicles and causes premature differentiation of these cells, which eventually results in anovulation. For improvement of anovulation because of hyperinsulinemia, insulin-sensitizing agents (biguanide and thiazolidinedione derivatives) are useful. Hyperinsulinemia may adversely affect the endometrial functions and environment, and evoke implantation disturbance. Treatment with an insulin-sensitizing agent (metformin) improves the levels of glycodelin, insulin-like growth factor binding protein 1, and blood flow in spiral arteries during the peri-implantation period. It supports endometrial function, improves the endometrial environment, and facilitates embryo implantation. The rate of early pregnancy loss during the first trimester is 30-50% in women with PCOS, which is threefold higher than for normal women. Metformin treatment improves the levels of insulin, the homeostasis model assessment for insulin resistance, and plasminogen activator inhibitor activity, and decreases early pregnancy loss. It goes without saying that lifestyle change is fundamental for improving reproductive performance in addition to treatment with insulin-sensitizing agents.
There are many types of ovarian activity that occur in women. This review provides information on the relationship between the hormone values and the degree of biological response to the hormones including the frequency and degree of uterine bleeding. The continuous process is termed the 'Continuum' and is thus similar to other processes in the body. This review draws on information already published from monitoring ovarian activity by urinary oestrogen and pregnanediol measurements using timed 24-h specimens of urine. Much of the rationalization was derived from 5 to 6 year studies of girls progressing from childhood to adulthood, women progressing through menopause, and the return of fertility post-partum. During these times, all the reported types of ovarian activity were encountered. All cycle types can be understood in terms of steps in the normal maturation of fertility at the beginning of reproductive life, its return post-partum and its demise at menopause. Each step merges into the next and therefore the sequence is termed the 'Continuum'. Unpredictable movement from fertile to infertile types and back can occur at any time during reproductive life. Stress is a major causative factor. Hormonal definitions for each step, the relevance of the various cycle types in determining fertility and in the initiation of uterine bleeding and the roles of the pituitary hormones in causing them, are presented. The findings explain the erratic fertility of women and why ovulation is not always associated with fertility. They provide an understanding of the various types of ovarian activity and their relation to pituitary function, fertility and uterine bleeding.
Baptiste CG et al., 2010·The Journal of steroid biochemistry and molecular biology·
Open Access
Polycystic ovary syndrome (PCOS) is a very common endocrine disorder characterized by chronic anovulation, clinical and/or biochemical hyperandrogenism, and/or polycystic ovaries. But most experts consider that hyperandrogenism is the main characteristic of PCOS. Several theories propose different mechanisms to explain PCOS manifestations: (1) a primary enzymatic default in the ovarian and/or adrenal steroidogenesis; (2) an impairment in gonadotropin releasing hormone (GnRH) secretion that promotes luteal hormone (LH) secretion; or (3) alterations in insulin actions that lead to insulin resistance with compensatory hyperinsulinemia. However, in the past 20 years there has been growing evidence supporting that defects in insulin actions or in the insulin signalling pathways are central in the pathogenesis of the syndrome. Indeed, most women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. But some women with typical PCOS do not display insulin resistance, which supports the hypothesis of a genetic predisposition specific to PCOS that would be revealed by the development of insulin resistance and compensatory hyperinsulinemia in most, but not all, women with PCOS. However, these hypotheses are not yet appropriately confirmed, and more research is still needed to unravel the true pathogenesis underlying this syndrome. The present review thus aims at discussing new concepts and findings regarding insulin actions in PCOS women and how it is related to hyperandrogenemia.
Sellix MT et al., 2010·Trends in endocrinology and metabolism: TEM
Clock gene expression has been observed in tissues of the hypothalamic-pituitary-gonadal (HPG) axis. Whereas the contribution of hypothalamic oscillators to the timing of reproductive biology is well known, the role of peripheral oscillators like those in the ovary is less clear. Circadian clocks in the ovary might play a role in the timing of ovulation. Disruption of the clock in ovarian cells or desynchrony between ovarian clocks and circadian oscillators elsewhere in the body may contribute to the onset and progression of various reproductive pathologies. In this paper, we review evidence for clock function in the ovary across a number of species and offer a novel perspective into the role of this clock in normal ovarian physiology and in diseases that negatively affect fertility.
Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.
Aghajanova L et al., 2010·Seminars in reproductive medicine
Progesterone plays an important role in regulating multiple events in the uterus. It controls endometrial proliferation and differentiation, which are important for uterine function. Dysregulation of progesterone signaling leads to impaired physiological functions. Indeed, aberrant expression of progesterone-regulated genes in the endometrium has been implicated in several gynecologic disorders, including endometriosis, polycystic ovarian syndrome (PCOS), and endometrial hyperplasia. Although several investigators have analyzed eutopic endometrial expression of progesterone-target genes, the genesis and consequences of progesterone resistance remain unclear. We review evidence for progesterone resistance in endometrium of women with endometriosis, PCOS, and endometrial hyperplasia, and we identify possible mechanisms associated with reduced progesterone activity in endometrium of (some) women with these gynecologic disorders that have a significant impact on women's health and well-being.
This review will address the current understanding of the relationship between prolactin (PRL) and endometriosis-associated infertility. Although the exact mechanisms of action of hyperprolactinemia in patients with endometriosis-associated infertility have not been clearly established, this report reviews results from relevant studies in the literature. These include serum PRL levels in endometriosis-associated infertility, PRL receptors in ectopic endometriotic tissues, basal PRL levels after TSH and Danazol (isoxazolic derivative of the synthetic steroid 5alpha-ethinyl-testosterone) therapy, peritoneal fluid and nocturnal serum PRL levels in endometriosis, infertility, and luteal phase PRL concentrations in patients with endometriosis. Obstetricians & Gynecologists, Family Physicians. LEARNING After completion of this article, the reader should be able to explain the relationship between prolactinand endometriosis-associated infertility, relate endometriosis with infertility, and summarize two ways in which prolactin and endometriosis may be linked in the pathophysiology of infertility.
To summarize the role of melatonin in the physiology and pathophysiology of the ovary. Review of literature. University Health Science Center. RESULT(S): Melatonin plays an essential role in the pathogenesis of many reproductive processes. Human preovulatory follicular fluid (FF) contains higher concentrations of melatonin than does plasma, and melatonin receptors are present in ovarian granulosa cells (GC). Melatonin has been shown to have direct effects on ovarian function. Reactive oxygen species and apoptosis are involved in a number of reproductive events including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum (CL) formation. Melatonin and its metabolites are powerful antioxidants; the primitive and primary function of melatonin may be its actions as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. A large amount of scientific evidence supports a local role of melatonin in the human reproductive processes. The indole also has potential roles in the pathophysiology of endometriosis, polycystic ovary syndrome (PCOS), and premature ovarian failure (POF). CONCLUSION(S): We summarize the current understanding of melatonin's essential functions in the human ovary. Melatonin could become an important medication for improving ovarian function and oocyte quality, and open new opportunities for the management of several ovarian diseases.
Costantino D et al., 2009·Eur Rev Med Pharmacol Sci·
To investigate the effects of treatment with Myo-inositol (an insulin sensitizing drug), on circulating insulin, glucose tolerance, ovulation and serum androgens concentrations in women with the Polycystic Ovary Syndrome (PCOS). Forty-two women with PCOS were treated in a double-blind trial with Myo-inositol plus folic acid or folic acid alone as placebo. In the group treated with Myo-inositol the serum total testosterone decreased from 99.5 +/- 7 to 34.8 +/- 4.3 ng/dl (placebo group: from 116.8 +/- 15 to 109 +/- 7.5 ng/dl; P = 0.003), and serum free testosterone from 0.85 +/- 0.1 to 0.24 +/- 0.33 ng/dl (placebo group: from 0.89 +/- 0.12 to 0.85 +/- 0.13 ng/dl; P = 0.01). Plasma triglycerides decreased from 195 +/- 20 to 95 +/- 17 mg/dl (placebo group: from 166 +/- 21 to 148 +/- 19 mg/dl; P = 0.001). Systolic blood pressure decreased from 131 +/- 2 to 127 +/- 2 mmHg (placebo group: from 128 +/- 1 to 130 +/-1 mmHg; P = 0.002). Diastolic blood pressure decreased from 88 +/- 1 to 82 +/- 3 mmHg (placebo group: from 86 +/- 1 to 90 +/- 1 mmHg; P = 0.001). The area under the plasma insulin curve after oral administration of glucose decreased from 8.54 +/- 1.149 to 5.535 +/- 1.792 microU/ml/min (placebo group: from 8.903 +/- 1.276 to 9.1 +/- 1.162 microU/ml/min; P = 0.03). The index of composite whole body insulin sensitivity (ISI comp) increased from 2.80 +/- 0.35 to 5.05 +/- 0.59 mg(-2)/dl(-2) (placebo group: from 3.23 +/- 0.48 to 2.81 +/- 0.54 mg(-2)/dl(-2); P < 0.002). 16 out of 23 women of Myo-inositol group ovulated (4 out of 19 in placebo group). Treatment of PCOS patients with Myo-inositol provided a decreasing of circulating insulin and serum total testosterone as well as an improvement in metabolic factors.
Two types of cervical mucus are recognized, oestrogenic and gestagenic. These are constituted by different subtypes, and their characteristics change depending on variations in the hormonal levels and on the existence of several pathologies. Our aim was to identify the ultrastructure and crystallization characteristics of the cervical mucus in women suffering from polycystic ovary syndrome, and to compare these characteristics with those of normal control women. Cervical mucus samples were taken from 10 women, 4 control group women (with normal ovulatory menstrual cycles) and 6 suffering from polycystic ovary syndrome (2 with ovulatory and 4 with anovulatory cycles). This mucus was characterized according to its ultrastructure and crystallization. The type of mucus obtained was related to the levels of oestradiol and progesterone present when the samples were taken. As regards mucus ultrastructure, differences were found between the control women and those with polycystic ovary syndrome and anovulatory menstrual cycles. Such variations were evident in the type of mesh and the average diameter of the mucus pores. Mucus crystallization in control women showed the usual oestrogenic disposition: fern-like (L, P2), rectilinear (S) or a hexagonal structure (P6). On the other hand, in women with polycystic ovary syndrome, indefinite mucus crystallizations were found, as well as crystallization patches resembling oestrogenic and gestagenic-like mucus. This study shows that the ultrastructure and crystallization characteristics of the cervical mucus in polycystic ovary syndrome women are different from those of control women. The latter would be dependent on their levels of oestradiol and progesterone.
BACKGROUND Hormonal effects of soy and isoflavones have been investigated in numerous trials with equivocal findings. We aimed to systematically assess the effects of soy and isoflavones on circulating estrogen and other hormones in pre- and post-menopausal women. METHODS The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate. RESULTS Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by approximately 20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones ( approximately 14%, SMD, P = 0.07, 21 studies). CONCLUSIONS Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.
We aimed to evaluate the effect of epilepsy on the reproductive hormones levels among female patients, and to investigate the frequency of catamenial pattern of seizures. A total of 42 female patients with epilepsy and 21 healthy females (control group) were included. Subjects were at least 2 years postmenarche with regular cycles. Symptoms of premenstrual syndrome (PMS) were assessed using calendar of premenstrual experience scoring. Patients were evaluated for catamenial pattern of seizures. Levels of FSH, LH, estradiol (E), and progesterone (P) were assessed for all subjects in the three phases of the cycles. Pelvi-abdominal ultrasound was performed near time of ovulation, to follow up size of mature follicle. Symptoms of PMS were not different in patients and controls, or in patients with and those without catamenial tendency. In both perimenstrual (M) and midluteal phases, FSH and P levels were lower and E/P ratio higher in patients group. There was a catamenial pattern of seizures in 31% of patients (53.8% M C(1); 46.15% inadequate luteal phase C(3)pattern). Patients with C(3)pattern showed lower P levels in the midluteal phase compared to patients with noncatamenial pattern, to those with C(1)pattern or to controls. Patients with C(1)pattern had lower P levels than controls in the M phase. There was evident disruption in the reproductive hormones in female patients with epilepsy with lower FSH and P levels and higher E/P ratio. A total of 31% of patients showed catamenial pattern of seizures (C(1)and C(3)patterns) that was significantly related to P withdrawal.
In 1980, Espey proposed a famous hypothesis that mammalian ovulation is comparable to an inflammatory reaction and many researches have proved the validity of his hypothesis in the last three decades. For example, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)- alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and other inflammatory cytokines presence was proven in the preovulatory follicle. Since granulocyte is the major leukocyte and it plays a very important role during inflammation, the importance of granulocyte and its related cytokine, granulocyte colony-stimulating factor (G-CSF) in the mechanism of human ovulation is easily predictable. G-CSF is one of the hemopoietic cytokines and it has strong positive effects on granulocytes. G-CSF increases the number of granulocytes and it improves the function of granulocytes. In this review, the participation of leukocytes in the ovulation mechanism is demonstrated first. Second, the participation of G-CSF is shown in comparison with the above mentioned cytokines. Finally, since G-CSF has been used for more than 20 years as a medicine without severe side effects in the field of oncology, the clinical application of G-CSF for the treatment of an ovulation disorder, luteinized unruptured follicle (LUF), will be discussed.
In the light of similarities between premenstrual syndrome and toxaemia, and the fact that treatment of the former with progesterone not only relieved the symptoms (Greene and Dalton, 1953) but also prevented the development of edema, hypertension, and albumin
Golden NH et al., 2008·Annals of the New York Academy of Sciences
Menstrual irregularity is a common occurrence during adolescence, especially within the first 2-3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.
Oligomenorrhea and polycystic ovaries in women are one of the most important causes of the high incidence of ovulation failure. This is linked, perhaps, to insulin resistance and related metabolic features. A small number of reports show that myo-inositol improves ovarian function, but in these trials the quality of evidence supporting ovulation is suboptimal. Furthermore, few of them have been placebo-controlled. The aim of our study was to use a double-blind, placebo-controlled approach with detailed assessment of ovarian activity (two blood samples per week) to assess the validity of this therapeutic approach in this group of women. Of the 92 patients randomized, 47 received 400 mcg folic acid as placebo, and 45 received myo-inositol plus folic acid (4 g myo-inositol plus 400 mcg folic acid). The ovulation frequency assessed by the ratio of luteal phase weeks to observa-tion weeks was significantly (P < 0.01) higher in the treated group (25%) compared with the placebo (15%), and the time to first ovulation was significantly (P < 0.05) shorter [24.5 d; 95% confidence interval (CI), 18, 31; compared with 40.5 d; 95% CI, 27, 54]. The number of patients failing to ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo group, and the majority of ovulations were characterized by normal progesterone concentrations in both groups. The effect of myo-inositol on follicular maturation was rapid, because the E2 circulating concentration increased over the first week of treatment only in the myo-inositol group. A significant increase in circulating high-density lipoprotein was observed only in the myo-inositol-treated group. Metabolic risk factor benefits of myo-inositol treatment were not observed in the morbidly obese subgroup of patients (body mass index > 37). After 14-wk myo-inositol or placebo therapy, no change in fasting glucose concentrations, fasting insulin, or insulin responses to glucose challenge was recorded. There was an inverse relationship between body mass and treatment efficacy. In fact a significant weight loss (and leptin reduction) (P < 0.01) was recorded in the myo-inositol group, whereas the placebo group actually increased weight (P < 0.05). These data support a beneficial effect of myo-inositol in women with oligomenorrhea and polycystic ovaries in improving ovarian function.
Thyroid and Metabolic Function · Insulin and Metabolism
Polycystic ovary syndrome (PCOS) is non-uniformly associated with insulin resistance (IR). We examined IR in women with PCOS. Sixty-nine PCOS women were subjected to the insulin suppression test (IST) to determine their steady-state plasma glucose (SSPG) as a direct measure of insulin sensitivity. SSPG exhibited a multimodal distribution suggesting the existence of subpopulations. The heterogeneous distribution of plasma glucose at 180 min (P = 0.011), with three modes, suggested differences in the plasma glucose level trajectories during the IST. Hence, the population was separated into three groups: (i) (n = 33), subjects with SSPG < or = 152.5 mg/dl, corresponding to the first to fifth deciles; (ii) (n = 29), subjects in the interval 152.5 mg/dl < SSPG < or = 300 mg/dl; (iii) (n = 7), subjects with SSPG > 300 mg/dl, corresponding to the tenth decile. Plasma glucose distributions at 180 min showed differences in their mean values and ranges among groups (P < 0.0001). The trajectories of the groups differed significantly during the IST (P < 0.0001). insulin sensitivity in our patients exhibited a discontinuous distribution, implying that PCOS is a heterogeneous disorder possessing subpopulations regarding IR.
To compare clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for inducing ovulation in patients with polycystic ovary syndrome.
Prospective cross-over trial.
University teaching hospital and a private practice setting. Five hundred and seventy-three patients were treated with clomiphene citrate for one menstrual cycle among which 470 patients were treated with clomiphene citrate plus N-acetyl cysteine for another cycle. All women suffered from polycystic ovary syndrome. Patients had clomiphene citrate 50-mg tablets twice daily alone or with N-acetyl cysteine 1,200 mg/day orally for 5 days starting on day 3 of the menstrual cycle. Primary outcomes were number of mature follicles, serum E2, serum progesterone, and endometrial thickness. Secondary outcome was the occurrence of pregnancy. Ovulation rate improved significantly after the addition of N-acetyl cysteine (17.9% versus 52.1%). Although the number of mature follicles was more in the N-acetyl cysteine group (2.1+/-0.88 versus 3.2+/-0.93), the difference was not statistically significant. The mean E2 levels (pg/ml) at the time of human chorionic gonadotropine injection, serum progesterone levels (ng/ml) on days 21-23 of the cycle, and the endometrial thickness were significantly improved in the N-acetyl cysteine group. The overall pregnancy rate was 11.5% in the N-acetyl cysteine group. Insulin resistance occurred in 260 patients (55.4%). There was no significant difference between the insulin resistance group (n = 260) and non-insulin resistance group (n = 210) as regards ovulation rate, number of follicles, serum E2 (pg/ml), serum progesterone (ng/ml), endometrial thickness (mm), or pregnancy rate. N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.
To model the effectiveness that can be obtained if levonorgestrel-only emergency contraception (EC) acts only through disrupting ovulation, in relation to other effects that may occur before or after fertilization and accounting for delays in administration. We modeled follicular growth as a function of follicular size, using known day-specific probabilities of conception and known disruption of ovulation by levonorgestrel-only EC, to estimate the expected effectiveness of EC. Combined data from multiple clinical studies. PATIENT(S): Simulation models. INTERVENTION(S): Disruption of ovulation. MAIN OUTCOME MEASURE(S): Effectiveness in the form of proportion of pregnancies prevented. RESULT(S): With disruption of ovulation alone, the potential effectiveness of levonorgestrel EC ranged from 49% (no delay) to 8% (72-hour delay). With complete inhibition of fertilization before the day of ovulation, the potential effectiveness of levonorgestrel EC ranged from 90% (no delay) to 16% (72-hour delay). CONCLUSION(S): The gap between effectiveness of levonorgestrel EC estimated from clinical studies and what can be attributed to disruption of ovulation may be explained by overestimation of actual effectiveness and supplementary mechanisms of action, including postfertilization effects. Additional data with follicular ultrasound and precise measures of delay between intercourse and EC administration would yield greater insight into effectiveness and mechanisms of action.
Although widely used, the mechanisms of action of the levonorgestrel emergency contraceptive pill (LNG ECP) are still unclear. There are increasing data to indicate that LNG is particularly effective as an ECP by interrupting follicular development and ovulation. An important outstanding question is whether it has any effect on fertilization or implantation. Ninety-nine women participated; they were recruited at the time they presented with a request for emergency contraception. All women took LNG 1.5 mg in a single dose during the clinic consultation. A blood sample was taken immediately prior to ingestion of the ECP for estimation of serum LH, estradiol and progesterone levels to calculate the day of ovulation. The specimens were analyzed in a single batch. Based on these endocrine data, we estimated the timing of ovulation to be within a +/-24-h period with an accuracy of around 80%. Women were followed up 4-6 weeks later to ascertain pregnancy status. The effectiveness of ECP when taken before and after ovulation was determined. Three women became pregnant despite taking the ECP (pregnancy rate, 3.0%). All three women who became pregnant had unprotected intercourse between Days -1 and 0 and took the ECP on Day +2, based on endocrine data. Day 0 was taken as ovulation day. Among 17 women who had intercourse in the fertile period of the cycle and took the ECP after ovulation occurred (on Days +1 to +2), we could have expected three or four pregnancies; three were observed. Among 34 women who had intercourse on Days -5 to -2 of the fertile period and took ECP before or on the day of ovulation, four pregnancies could have been expected, but none were observed. We found major discrepancies between women's self-report of stage of the cycle and the dating calculation based on endocrine data. These data are supportive of the concept that the LNG ECP has little or no effect on postovulation events but is highly effective when taken before ovulation.
Amenorrhea is a diagnostic criterion for anorexia nervosa (AN), although menstrual cycles have been found to persist in some women with all the other features of AN. This study sought to determine factors that are associated with amenorrhea in 39 women with current primary spectrum AN. The use of exercise to control weight (odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.3-9.9; P = .02), low novelty seeking scores (OR = 0.7; 95% CI = 0.58-0.94; P = .02), and low systolic blood pressure (OR = 0.9; 95% CI = 0.84-0.99; P = .046) were predictors of amenorrhea independent of body mass index.
Nagle CA et al., 2005·General and comparative endocrinology
The aim of this work was to study, in the Cebus apella monkey, the developmental changes in the microanatomy of the utero-ovarian ligament (UOL) and whether their vascular and neural elements might be involved in the transfer of signals between the ovaries and uterus. Sections including uterus, UOL, and ovary obtained from two foetuses, two prepubertal, and four cycling monkeys, two of them treated with a neuron-axonal tracer, diamidino yellow (DY) into the corpus luteum (CL) and the remaining two into the endometrium, were analyzed for the expression of neurofilament protein (NFP) and tracer distribution. Eight regularly cycling females were used to investigate the transfer to the CL of pulses of prostaglandin F(2alpha) (PGF(2alpha)) (n=4) or its vehicle (n=4) given intra-uterus. A convoluted artery, in conjunction with various vein channels, passed over the UOL allowing for a direct communication between uterus and ovaries. The artery acquired prominence during adulthood, in a manner well suited with the ovarian status. Immunohistochemical analysis revealed that NFP expression by the oocyte and by the endometrial epithelial cells was a highly conserved feature during development, whereas the appearance of NFP fibers in the ovaries, UOL, and uterus was a late event in the ontogenesis, likely regulated by the hormonal environment. Neurons, as an obvious source for these NFP fibers, were not recognized at any developmental stage, although some neuron-like cells were observed within the CL. The pattern displayed by the tracer DY, further suggested a reciprocal axonal transport among endometrial cells and follicular and luteal cells of both ovaries and between the ovaries themselves. The functionality of the utero-ovarian connection was assessed after injecting PGF(2alpha) intra-uterus. A short exposition to PGF(2alpha) pulses was required for lowering ovarian and peripheral progesterone concentrations causing luteolysis, indicating that transport mechanism operating between uterus and ovary must be very efficient. The results suggest that the vessels and axons contained in the UOL of the Capuchin monkeys might be two combined key pathways underlying the reciprocal transfer of signals controlling utero-ovarian homeostasis.
The purpose of this review is to put into a useful clinical context the changing over time of basic ovarian-pituitary-hypothalamic relationships during perimenopause. "Perimenopause" means changes in ovarian hormones, feedback relationships, and clinical experiences beginning in women ages 35-50 with regular flow and ending 1 yr after the final menstrual flow. A key observation must be explained--estradiol levels are increased in perimenopause. Inhibin B levels are lower and activin may be higher in midlife, menstruating women. These changes probably cause higher follicular phase FSH levels--"endogenous ovarian hyperstimulation" results. The positive estradiol feedback on LH is also disturbed--midcycle LH peaks and mid-luteal slow-frequency, high-amplitude LH pulses are less frequent. In addition to higher levels, estradiol receptors may increase in tissues of symptomatic women. Despite hyperstimulation of follicles, progesterone levels and luteal phase lengths are paradoxically decreased--reasons probably include LH peak disruptions and estrogen-stimulated greater corticotrophin-mediated reproductive suppression. In summary, disturbed feedback relationships causing higher and unpredictable estrogen and lower progesterone levels occur throughout perimenopause, especially during regular cycles. Prospective, population-based research is needed to systematically relate these feedback hormonal changes to clinical characteristics and to allow a diagnosis of perimenopause in regularly cycling midlife women.
Ruiz-Luna AC et al., 2005·Reproductive biology and endocrinology : RB&E
Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility.
Wade GN et al., 2004·American journal of physiology. Regulatory, integrative and comparative physiology
Natural selection has linked the physiological controls of energy balance and fertility such that reproduction is deferred during lean times, particularly in female mammals. In this way, an energetically costly process is confined to periods when sufficient food is available to support pregnancy and lactation. Even in the face of abundance, nutritional infertility ensues if energy intake fails to keep pace with expenditure. A working hypothesis is proposed in which any activity or condition that limits the availability of oxidizable fuels (e.g., undereating, excessive energy expenditure, diabetes mellitus) can inhibit both gonadotropin-releasing hormone (GnRH)/luteinizing hormone secretion and female copulatory behaviors. Decreases in metabolic fuel availability appear to be detected by cells in the caudal hindbrain. Hindbrain neurons producing neuropeptide Y (NPY) and catecholamines (CA) then project to the forebrain where they contact GnRH neurons both directly and also indirectly via corticotropin-releasing hormone (CRH) neurons to inhibit GnRH secretion. In the case of estrous behavior, the best available evidence suggests that the inhibitory NPY/CA system acts primarily via CRH or urocortin projections to various forebrain loci that control sexual receptivity. Disruption of these signaling processes allows normal reproduction to proceed in the face of energetic deficits, indicating that the circuitry responds to energy deficits and that no signal is necessary to indicate that there is an adequate energy supply. While there is a large body of evidence to support this hypothesis, the data do not exclude nutritional inhibition of reproduction by other pathways and processes, and the full story will undoubtedly be more complex than this.
The rise in FSH (FSHr) that leads to the recruitment of a cohort of follicles during the menstrual cycle occurs during the luteal-follicular transition, however, it is unclear whether it consistently occurs on one particular day, or is subjected to reproductive ageing. We determined the FSHr in 836 complete menstrual cycles from 102 women with regular menses using an algorithm, and additionally compared the relative variation in FSH during the last 14 days of the cycle. Possible effects of reproductive ageing on the onset of FSHr were also investigated. The day of FSHr follows a normal distribution with a median value of -4 (relative to first day of menses), mean -4.1 and SD 2.1. Analysis of the relative changes in FSH during the last 14 days of the cycle revealed the first significant rise on day -4 (P=0.0033), coinciding with the first significant drop in estrogens (P=0.0002). No effect of chronological age, or initial FSH levels, on FSHr was found, however, there was an inverse relationship between total follicular phase length (from day of FSHr to LH peak) and initial FSH levels (P<0.0001). The initial FSH rise in the cycle occurs consistently 4 days before menses, is related to a drop in estrogen levels, and is not affected by reproductive ageing.
To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary (PCOS) patients. Controlled clinical study. PCOS patients in a clinical research environment. PATIENT(S): Twenty nonobese PCOS patients were enrolled after informed consent. INTERVENTION(S): All patients underwent hormonal evaluations and a pulsatility study (sampling every 10 minutes for 4 hours) before and at the sixth month of therapy (metformin, 500 mg, p.o. b.i.d.). Ultrasound examinations and Ferriman-Gallwey scoring were also performed. MAIN OUTCOME MEASURE(S): Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17-hydroxy-progesterone (17-OHP), and testosterone (T), glucose, insulin, and C-peptide concentrations. RESULT(S): After 6 months of metformin administration, the plasma LH, 17-OHP, A, and T levels and LH/FSH ratio were significantly reduced. Insulin sensitivity, expressed as the glucose-to-insulin ratio, was significantly improved under glucose load after 6 months of treatment. Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women. The ovarian volume and Ferriman-Gallwey scores also were significantly reduced. CONCLUSION(S): Metformin administration improves reproductive axis functioning in hyperandrogenic nonobese PCOS patients. By acting on the ovary and restoring normal ovarian activity, metformin positively modulates the reproductive axis (namely GnRH-LH episodic release).
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Hilgers presents a refined classification of follicular and luteal phase deficiencies grounded in the integration of CrMS mucus pattern characteristics, cycle-phase-targeted estradiol and progesterone profiles, ultrasound folliculometry, and endometrial histology, introducing terminology that links specific chart signatures to defined endocrine subtypes and treatment protocols. Follicular deficiencies -- marked by short or poor-quality mucus phases and suboptimal estradiol -- and luteal deficiencies -- marked by a post-Peak phase under nine days, premenstrual spotting, or blunted serial progesterone curves -- are treated with tailored ovulation induction, cooperative progesterone replacement, and correction of contributing systemic disorders including thyroid dysfunction, hyperprolactinemia, and insulin resistance.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Disruptions along the hypothalamic-pituitary-ovarian axis — including luteal phase deficiency, inadequate LH surges, and follicular maturation failure — are among the most common and underdiagnosed contributors to infertility and recurrent pregnancy loss. Targeted hormone supplementation guided by cycle-specific progesterone and estradiol assays, timed to CrMS biomarkers, restores functional ovulatory and luteal competence without suppressing the axis.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
The sonographic ovulation classification is validated against targeted hormone profiles -- estradiol, LH, and serial post-Peak progesterone (P+3 through P+11) -- drawn at CrMS Peak-anchored time points rather than fixed calendar days. Hormone patterns corresponding to each sonographic category (e.g., absent LH surge in anovulation, progesterone rise without follicle rupture in LUF) confirm that ultrasound morphology reliably reflects the underlying endocrine disorder, establishing the biochemical legitimacy of the classification for clinical diagnosis.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Premenstrual syndrome in NaProTECHNOLOGY is defined by a recurrent cluster of symptoms -- including irritability, breast tenderness, bloating, depression, and carbohydrate craving -- beginning at least four days before menses, and is associated with late-luteal deficiencies in progesterone, estrogen, and beta-endorphin identified through CrMS-anchored hormone profiling. Treatment with cycle-synchronized bioidentical progesterone, targeted HCG injections to stimulate endogenous corpus luteum function, and low-dose naltrexone to modulate opioid dynamics produces superior symptom resolution compared to SSRI therapy in Hilgers' comparative data, without suppressing ovulation.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Hilgers distinguishes isomolecular hormones -- molecules structurally identical to endogenous estradiol and progesterone -- from heteromolecular artimones, his term for synthetic analogues such as medroxyprogesterone acetate, norethindrone, and ethinyl estradiol, which differ in receptor binding, metabolic pathways, and systemic effects. NaProTECHNOLOGY restricts hormone therapy to isomolecular compounds administered in cycle-synchronized, physiologic doses because artimones suppress the hypothalamic-pituitary-ovarian axis, mask underlying pathology, and produce non-physiologic metabolite profiles incompatible with a restorative reproductive medicine approach.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
A CrMS-synchronized hormone sampling protocol is detailed in which progesterone, estradiol, and other reproductive hormones are drawn at cycle-phase-specific time points defined by the charted Peak Day rather than by fixed cycle day, producing a targeted hormone profile that accurately reflects luteal and follicular function. This Peak Day-referenced approach substantially improves the diagnostic sensitivity for luteal phase deficiency, follicular dysfunction, and other endocrine abnormalities that fixed-day sampling routinely misclassifies.
Thyroid and Metabolic Function · Thyroid Disorders
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Infertility is not merely a reproductive inconvenience but frequently signals systemic or hormonal pathology — including polycystic ovarian disease, endometriosis, thyroid dysfunction, and immune abnormalities — each carrying independent health risks beyond failure to conceive. Identifying and treating these underlying conditions reduces long-term morbidity and reframes infertility evaluation as a form of preventive medicine rather than a terminal bypass decision.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Cooperative progesterone and estrogen replacement therapy administers bioidentical hormones in precise synchrony with the woman's CrMS-identified Peak day -- beginning progesterone at P+2 or P+3 and continuing through the luteal phase -- to augment deficient corpus luteum output rather than override the cycle with suppressive dosing. Serial serum progesterone across post-Peak days guides dose titration, and the approach is applied to luteal phase deficiency, recurrent miscarriage, premenstrual syndrome, and postpartum depression while preserving ovulatory function and fertility.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Amenorrhea and anovulation represent a spectrum of hypothalamic, pituitary, ovarian, and end-organ etiologies that must be differentiated through systematic hormonal and anatomical evaluation before treatment is initiated. NaProTECHNOLOGY integrates CrMS mucus charting with targeted biochemical testing to identify the level of dysfunction and guide ovulation induction or hormonal restoration appropriate to the specific cause.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Ovarian dysfunction — encompassing luteal insufficiency, abnormal folliculogenesis, and anovulation — is treated in NaProTECHNOLOGY with cycle-timed interventions including HCG trigger, progesterone supplementation, clomiphene, and thyroid optimization, guided by prospective CrMS charting rather than protocol-driven stimulation. This approach normalizes endogenous hormonal patterns rather than overriding them, preserving uterine receptivity and reducing multiple gestation risk.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Normal estradiol and progesterone reference ranges in NaProTECHNOLOGY are derived from fertile, ovulatory cycles with confirmed CrMS Peak days and sonographic ovulation, with blood sampling timed to Peak-anchored days (pre-ovulatory P-days for estradiol, P+3 through P+11 for luteal hormones) rather than to calendar cycle days. These day-specific normative values allow detection of subtle deficiencies -- such as a blunted progesterone rise at P+5 or inadequate pre-ovulatory estradiol -- that are clinically actionable for diagnosing follicular and luteal phase disorders but are invisible to standard mid-luteal or phase-independent reference intervals.
Thyroid and Metabolic Function · Thyroid Disorders
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Both overt and subclinical thyroid dysfunction are recognized in NaProTECHNOLOGY as significant causes of cycle-level reproductive abnormalities -- including oligomenorrhea, anovulation, luteal phase deficiency, heavy bleeding, and recurrent early pregnancy loss -- detectable through CrMS charting before standard screening would prompt thyroid evaluation. The chapter advocates comprehensive thyroid assessment (TSH, free T4, free T3, and thyroid antibodies) with fertility-optimized reference thresholds in women presenting with cycle disorders or infertility, followed by reassessment of CrMS patterns and hormone profiles after thyroid correction to identify and treat any residual follicular or luteal phase defects.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Serial progesterone measurement timed to the luteal phase and early pregnancy using CrMS Peak Day-referenced protocols reveals luteal insufficiency and early placental progesterone inadequacy that are associated with miscarriage risk and preterm labor. Progesterone supplementation guided by these standardized assessments has been associated with reduced pregnancy loss in NaProTECHNOLOGY-managed pregnancies, and the chapter details the specific drawing protocols, reference ranges, and supplementation decision thresholds used in clinical practice.
To compare the effects of letrozole and clomiphene citrate in the rat in terms of number of ovarian follicles; endometrial thickness; and serum levels of E2, FSH, LH, and T. Controlled prospective study. University research laboratory. ANIMAL(S): Thirty sexually mature female Wistar-Albino rats that were 20 weeks of age. INTERVENTION(S): Letrozole, 5 mg/kg of body weight daily (10 rats); clomiphene citrate, 100 microg/kg daily (10 rats); or saline solution, 2 mL/d (10 rats). After 2 days, rats were euthanized and ovariectomized. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness, and serum levels of hormones. RESULT(S): Mean levels of FSH, LH, E2, and T; number of mature follicles; and ovary size differed among the groups, whereas the mean endometrial thickness did not differ. CONCLUSION(S): In rats, the effect of letrozole on follicular maturation is similar to that of clomiphene citrate.
The third-generation aromatase inhibitors were initially introduced to treat postmenopausal breast cancer. We now realize that many other potential indications for aromatase inhibitors exist, especially in the field of gynecology. Preliminary data were suggestive that aromatase inhibitors could be used to treat endometriosis and uterine leiomyomata and induce or augment ovulation.
Aromatase inhibitors promote ovulation, most likely by increasing endogenous FSH production owing to decreased estrogen biosynthesis in the ovary and extraovarian tissues, including the brain. Aromatase inhibitors differ from the estrogen antagonist clomiphene citrate in that they do not exert a direct unfavorable effect on endometrial growth and development during the menstrual cycle.
Healey et al. (1) report important findings on the effects of the addition of an aromatase inhibitor to gonadotropin injections for superovulation. A relatively large number of patients and a control group were studied, and several clinically useful outcomes including pregnancy rates were reported.
The addition of letrozole to an ovulation induction regimen using injectable gonadotropins in a mixed population of patients with infertility does not seem to offer any benefits over gonadotropin-only cycles, because the decreased gonadotropin dose (the only apparent benefit) was offset by increased complexity of the treatment. Further randomized clinical trials using a similar design and patient sample may not provide clinically useful data. On the other hand, optimization of this regimen (gonadotropin plus aromatase inhibitor) in poor responders may offer an alternative in this subset of women (2).
From the existing literature, it appears that use of an aromatase inhibitor alone to induce or augment ovulation will continue to be an exciting area of research future (3, 4). In particular, the dosing and timing of administration (late luteal versus early follicular) of an aromatase inhibitor for ovulation induction should be optimized. Defining the hormonal profiles of the women who will benefit the most from aromatase inhibition may further increase the success of treatment.
In summary, Healey et al. (1) should be congratulated for conducting this interesting work. Carefully designed randomized studies on the use of aromatase inhibitors for ovulation induction or augmentation are warranted.
To investigate the effects of letrozole in patients undergoing superovulation with gonadotropins and IUI. Retrospective analysis. Academic teaching hospital. PATIENT(S): Women younger than 40 years of age with patent fallopian tubes and infertility of more than 1 year in duration who were undergoing IUI and gonadotropin therapy. INTERVENTION(S): Gonadotropins alone administered from day 3 or a combination of letrozole, 5 mg/d on day 3 to 7, and gonadotropins starting on day 5 of the menstrual cycle. Ultrasonography was performed before initiation of treatment, on day 9 of menstrual cycle, and as required thereafter until the dominant follicle reached 18 mm in diameter. Ovulation was triggered with 10,000 IU of hCG, and IUI was performed 24 and 48 hours later. MAIN OUTCOME MEASURE(S): Gonadotropin requirements, endometrial thickness, number of follicles, and pregnancy rate. RESULT(S): All 205 IUI treatment cycles conducted from March 2001 to March 2002 were included. Gonadotropins alone were used in 145 cycles and combination therapy was used in 60 cycles. Patients cotreated with letrozole required fewer gonadotropin administrations (median difference, 300 IU [95% confidence interval (CI), 225-375 IU]), developed more follicles larger than 14 mm (median difference, 1 follicle [95% CI, 1-2 follicles), and had a thinner endometrium (median difference, 1 mm [95% CI, 0.4-1.6 mm]). The pregnancy rate did not differ between patients using gonadotropin alone and those using gonadotropin plus letrozole (20.9% vs. 21.6%). CONCLUSION(S): The addition of letrozole to gonadotropins decreases gonadotropin requirements, increases the number of pre-ovulatory follicles and decreases endometrial thickness, without a negative effect on pregnancy rates.
Although numerous studies have attempted to elucidate the implication of endometriosis for infertility, this matter still remains unexplained. Diverse clinical approaches based on assisted reproduction techniques have produced conflicting results on this issue. Nevertheless, impairment of implantation and pregnancy rates seems to affect women who suffer from endometriosis. Whether this effect is due to alteration of the oocyte/embryo or the endometrium still remains to be elucidated, although actual data allude to deficiencies in both. Infertility due to poor quality embryos derived from impaired oocytes obtained from malfunctioning ovaries have been described by some groups. Endometrial defects have been argued by others. Adding more confusion to this topic, the influence of peritoneal fluid in women with endometriosis and/or mixed causes also needs to be considered. The aim of this review is to describe the current situation in the endometriosis-related infertility literature.
To confirm that hCG levels in follicular fluid and serum would be comparable between i.m. and s.c. administration of purified hCG. In a prospective study, serum and follicular fluid levels of hCG after an i.m. or s.c. injection of 10,000 IU of hCG were evaluated 36 hours after injection, that is, at the time of oocyte retrieval. This study was carried out in a university-affiliated IVF program. PATIENT(S): Forty women undergoing oocyte retrieval were entered into the study at the time of egg retrieval, that is, 36 hours after hCG administration. INTERVENTION(S): S.c. or i.m. injection of hCG. MAIN OUTCOME MEASURE(S): Serum and follicular fluid concentrations of hCG were evaluated 36 hours after injection at the time of oocyte retrieval. RESULT(S): There was a significantly higher serum hCG level in the s.c. group (348.6 +/- 98 IU/L) vs. the i.m. group (259.0 +/- 115 IU/L) and a significantly higher follicular fluid hCG level in the s.c. vs. the i.m. group (233.5 +/- 85 vs. 143.4 +/- 134 IU/L). CONCLUSION(S): After purified hCG administration via the s.c. route, both serum and follicular fluid levels are greater compared with the i.m. route.
To evaluate the effects of laparoscopic ovarian wedge resection on hormonal and metabolic parameters of polycystic ovary syndrome (PCOS) and to compare profiles of women who achieved pregnancy with those who did not.
Prospective study.
University hospital. PATIENT(S): Thirty-three women with PCOS. INTERVENTION(S): Laparoscopic ovarian wedge resection using harmonic scalpel. MAIN OUTCOME MEASURE(S): Pregnancy; levels of testosterone, DHEAS, gonadotropins, sex hormone-binding globulin (SHBG), and glucose and insulin during 2-hour glucose tolerance test; lipid profile; body mass index; and waist-to-hip ratio. RESULT(S): Twenty-two women (67%) achieved clinical pregnancy within the mean of 4.9 months after surgery. Baseline parameters of women who became pregnant differed from those who did not: those who became pregnant were less obese, had lower levels of total cholesterol, low-density lipoprotein, and triglycerides; higher levels of SHBG; lower levels of fasting insulin; lower insulin area under the curve; and higher insulin sensitivity index. Subjects not pregnant by 12 weeks after surgery underwent repeat endocrine and metabolic evaluations. In these women, wedge resection was followed by declines in testosterone, LH, and insulin sensitivity index. Wedge resection had no significant effect on SHBG, DHEAS, or lipid profile. CONCLUSION(S): Laparoscopic wedge resections are associated with the highest pregnancy rates among less obese subjects with favorable lipid profiles and lower insulin. In this study, the postoperative decline of serum testosterone and LH is not attributable to improvement of insulin sensitivity.
To investigate the possibility of direct effects of metformin on ovarian steroidogenesis. Cultured ovarian cells. Academic research environment. PATIENT(S): Women undergoing bilateral salpingoophorectomy for benign gynecological disease. MAIN OUTCOME MEASURE(S): Estradiol and P were measured in granulosa cell (GC) conditioned medium and androstenedione (A) and P in theca conditioned medium. RESULT(S): The effect of addition of metformin alone to GCs was variable, but significant inhibition of both P and E2 was seen (range 0%-30%). Metformin dose-dependently inhibited gonadotrophin and insulin-stimulated P and E2 production (range 25%-50%). In theca, metformin inhibited A production (0%-40%) with no effect on P. In the presence of insulin, A was inhibited dose-dependently and P increased by a similar magnitude. CONCLUSION(S): These results demonstrate a direct effect of metformin on ovarian steroidogenesis. The inhibitory effects on androgen production in particular would be beneficial in polycystic ovary syndrome (PCOS).
To review the use of hCG and to describe the clinical benefit of recombinant hCG (r-hCG) based on the published results of prospective, randomized studies. Review of published articles. Tertiary infertility care center.None.None. Oocyte number and quality, luteal phase progesterone, pregnancy and OHSS rate, and local tolerability. The published data consistently show that single doses of 250 microg r-hCG and 5,000 IU urinary (u)-hCG produce similar clinical outcomes when used in infertility treatment cycles for timed intercourse, IUI, and IVF in terms of the number of oocytes retrieved, number of mature oocytes harvested, and fertilization and pregnancy rates attained. Single doses of 10,000 IU u-hCG also gave results comparable to single doses of 250 microg r-hCG. P levels in the midluteal phase were significantly higher with the use of r-hCG compared with u-hCG, and local injection site adverse effects were significantly less frequent, demonstrating the higher purity of the recombinant product. A single 500-microg dose of r-hCG led to a higher rate of ovarian hyperstimulation syndrome compared with a 250-microg dose, with no significant improvement in pregnancy rates.A single dose of 250 microg r-hCG was at least as effective as single doses of 5,000 or 10,000 IU u-hCG but offered the advantages associated with use of a recombinant product: local injection site adverse effects were significantly less frequent with r-hCG than with u-hCG.
The median age at menopause in Western populations of women is approximately 51 years. While very late (i.e., after 54 years) menopause is exceedingly uncommon, a sizeable minority of women experience cessation of ovarian function at or prior to age 45. By convention, menopause that occurs at ages 40-45 is considered "early" and occurs in about 5% of women. Premature ovarian failure (POF) is reserved for the approximately 1% of women who experience hypergonadotropic amenorrhea prior to age 40 years. POF represents the end stage of a variety of disorders that result in the loss of ovarian follicles. Depending upon the age at diagnosis, the probability of a genetic, autoimmune, or idiopathic cause will be more or less likely. Two functioning X chromosomes appear necessary for normal ovarian function. The most obvious genetic cause of POF is Turner Syndrome, in which a complete or near-complete loss of the second X chromosome occurs. Turner Syndrome typically results in the most severe and irreversible POF, often clinically evident prior to menarche. Typically, in Turner Syndrome, menopause precedes menarche, and there is no evidence of ovarian function. However, cases with multiple tissues diagnosed as 45, X have been reported to result in ovarian function and even pregnancy. It is likely that mitigating factors, perhaps autosomal, can modify this most severe and irreversible cause of ovarian failure. Lesser degrees of ovarian failure have also been attributed to partial X chromosome deletions and milder degrees of X chromosome mosaicism. Fragile X syndrome is another example of mild POF that can be linked to disorders of the X chromosome. Other genetic defects are believed to cause POF, yet their prevalence has been difficult to determine. The localization of the gene for the blepharophimosis/ptosis/POF Syndrome has been recently reported, yet this finding has not been seen commonly in POF. Other genetic syndromes including POF await elucidation. Many transgenic "knock-out" animals have been created with deficient ovarian function. Most interesting along these lines is the heterozygous FSH receptor knock-out, which exhibits a reduced follicle reserve and early ovarian depletion. Application of this knowledge and translation of these transgenic experiments into elucidation of clinical disease has been difficult, but represents an area of tremendous potential progress in the understanding of the pathogenesis of POF. Another approach to the genetics of POF has been to examine the genome of affected and unaffected individuals. The genetics appear to differ greatly depending upon the timing of the expression of the POF. For example, women with early menopause are more likely to possess the PVUII polymorphic allele for estrogen receptor alpha. Whether or not this polymorph is more common in women with earlier menopause, i.e., POF, is unclear. Pedigree data indicate that early menopause and premature menopause sort similarly within families. The only difference between women with true POF and those with early menopause may be in the timing of the expression of the syndrome, and not in the genetics. Population genetic approaches analyzing affected and unaffected individuals are underway in several research centers and represent another area of progress. Immune and other, idiopathic causes of POF await further clarification. It is clear that this is an area of great research potential. Understanding how ovaries fail may assist women with this disorder by facilitating the development of novel therapies. Additionally, such information will provide important clues about optimizing ovarian function in individuals without POF who are seeking extension of their reproductive life spans or fertility enhancement by other means.
In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS. Double-blind, randomized, placebo-controlled trial. Academic reproductive endocrinology clinic. PATIENT(S): Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC. INTERVENTION(S): Twenty-five women were randomized into two treatment groups. Subjects in Group I (n = 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n = 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months. MAIN OUTCOME MEASURE(S): The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens. RESULT(S): Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (P=.04, Fisher's exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 +/- 13.8 microU/mL to 17.3 +/- 7.8 microU/mL after rosiglitazone (P=.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 +/- 0.3 microg/dL to 1.0 +/- 0.3 microg/dL after rosiglitazone therapy (P=.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 +/- 6.3 mU/mL to 7.2 +/- 3.7 mU/mL (P=.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change. Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism and chronic anovulation. Although the etiology of PCOS is unknown, perturbations of gonadotropin secretion are one of the hallmarks of this disorder. In normal menstrual physiology, the monotropic rise of plasma follicle-stimulating hormone (FSH) during the luteal-follicular transition is critical for follicular development and subsequent ovulation. One of the mechanisms by which FSH is differentially synthesized involves the luteal slowing of gonadotropin-releasing hormone (GnRH) pulse frequency by ovarian steroids. In PCOS, plasma leutinizing hormone (LH) is commonly increased, FSH is typically in the lower follicular range, and LH (and by inference GnRH) pulse frequency is persistently rapid at approximately one LH pulse per hour. The etiology of the neuroendocrine abnormalities in PCOS remain unclear; however, recent studies have revealed decreased sensitivity of the GnRH pulse generator to inhibition by ovarian steroids, particularly progesterone. This abnormality is reversed by the androgen receptor antagonist flutamide, suggesting that elevated androgen levels may alter the sensitivity of the hypothalamic GnRH pulse generator to steroid inhibition and lead to enhanced LH secretion. As such, women with PCOS require higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in inadequate FSH synthesis and persistent LH stimulation of ovarian androgens. The decreased sensitivity of the GnRH pulse generator may help to explain the genesis of PCOS during puberty. In normal early puberty, sleep-entrained increases in LH stimulate ovarian steroids, which subsequently suppress LH frequency and amplitude during the subsequent day. In hyperandrogenemic girls destined to develop PCOS, this nocturnal increase in ovarian steroids may not be adequate to suppress the GnRH pulse generator, leading to a persistently rapid LH pulse frequency, impaired FSH production, and inadequate follicular development.
Yong PY et al., 2003·Human reproduction (Oxford, England)
Analyses of the follicular reserve and activity of the ovary are central to our understanding of the regulation of follicular development. We have carried out a prospective analysis of endocrine and biophysical assessments under three differing basal conditions: the early follicular and mid-luteal phases, and following GnRH analogue down-regulation. Hormonal analyses were carried out before and after a single dose of FSH on spontaneously ovulating women (n = 58). Ovarian volume and antral follicle count (AFC) were also determined. Inhibin B and estradiol concentrations were increased by FSH under all three conditions, and inhibin A in the follicular phase and after down-regulation. Basal hormone concentrations, except inhibin A and B after down-regulation, did not generally correlate with AFC. A close relationship between inhibin B and AFC was evident at all stages after FSH administration (r = 0.70-0.77). AFC and inhibin B after FSH stimulation were well correlated with the number of oocytes recovered after superovulation. Multivariate analysis demonstrated that inhibin B after FSH administration in the down-regulated state showed the closest correlation with oocyte number. In the more clinically useful early follicular and luteal phases, basal FSH was the most significant contributor to the number of oocytes, with a significant contribution from luteal phase AFC. These data extend our understanding of the relationships between follicular number, follicular functional activity, and the recruitable follicular population. Down-regulation and subsequent FSH stimulation was required to clearly demonstrate the close relationship between inhibin B and the ovarian reserve. Without such complex manipulation, early follicular phase FSH (supplemented by AFC in the relatively hypogonadotrophic luteal phase) remains of greater value in predicting the ovarian reserve than the currently known direct products of the ovary.
To investigate the effects of reduction of insulin resistance and hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH-stimulated ovarian aromatase activity. Prospective study. Academic health center, Siena, Italy. PATIENT(S): Twenty women 18 to 26 years of age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and hyperandrogenemia. INTERVENTION(S): Recombinant FSH was administered. The next day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of treatment, the pretreatment protocol was repeated. MAIN OUTCOME MEASURE(S): Plasma levels of estradiol (E(2)), androstenedione (A), and testosterone (T). The ratios of basal levels and areas under the curve (AUCs) of products and substrates were compared before and after metformin administration to detect differences in aromatase activity. RESULT(S): Metformin treatment was associated with significant reduction in basal free testosterone plasma levels, insulin plasma levels, and insulin response to oral glucose tolerance testing. Administration of FSH was followed by a significantly lesser E(2) response after metformin therapy than before this therapy. The ratios of AUC(E2) to AUC(A) and to AUC(T), indicative of aromatase activity in response to FSH, were significantly lower after metformin therapy than before. CONCLUSION(S): Metformin therapy in women with PCOS is associated with a reduction in aromatase activity in response to FSH. Insulin affects production of both androgen and estrogen. Insulin therefore plays a central role in regulating the activity of thecal and granulosa cells.
To prove that several days of low-dose hCG alone can be used to stimulate folliculogenesis, complete FSH-initiated follicle/oocyte maturation, and achieve pregnancy in assisted reproduction technology. Case report. Reproductive endocrinology center at an academic institution. PATIENT(S): A 35-year-old female patient and her partner with male-related infertility. INTERVENTION(S): After an 8-day priming with hMG (225 IU/d), we administered low-dose hCG (200 IU/d) alone for 5 days in one GnRH-agonist suppressed patient until proper follicle development was obtained and intracytoplasmic sperm injection was performed. MAIN OUTCOME MEASURE(S): Daily serum levels of LH, FSH, hCG, E(2), P, and T; measurements of follicle number and size; oocytes retrieved and fertilized; pregnancy. RESULT(S): Although FSH levels rapidly declined after hMG discontinuation, E(2) and large follicles increased during hCG-only administration. Several good quality oocytes were retrieved and fertilized by intracytoplasmic sperm injection; three embryos were transferred and a twin pregnancy ensued. CONCLUSION(S): Replacement of FSH with low-dose hCG for several days in the late ovulation induction stages of assisted reproduction technology resulted in: [1] continued growth of large ovarian follicles and E(2); [2] an optimal preovulatory follicle pattern consisting of many large and few medium and small follicles; and [3] reproductively competent oocytes and pregnancy.
Estrogen and prolactin may accelerate the progression of murine systemic lupus erythematosus (SLE). In humans, 85% of lupus patients are women, which also suggests the importance of hormonal factors in disease pathogenesis. The purpose of this study was to examine hormonal and reproductive risk factors for lupus among women. This population-based, case-control study included 240 female SLE patients diagnosed between January 1, 1995 and July 31, 1999 who fulfilled the American College of Rheumatology classification criteria. Female controls (n = 321) were identified through driver's license records. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) as measures of association, adjusting for age, state, race, and education. Analyses were limited to exposures before diagnosis. Breast-feeding was associated with a decreased risk of developing SLE (OR 0.6, 95% CI 0.4-0.9), with a statistically significant trend for number of babies breast-fed and total weeks of breast-feeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier in women with subsequent development of SLE compared with controls (P < 0.001). There was little association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs. We found little evidence that estrogenor prolactin-related exposures are associated with an increased risk of lupus. The reduced risk observed among women who had breast-fed one or more babies should be examined in other studies. Early natural menopause, rather than decreasing risk of SLE because of reduced estrogen exposure, may be a marker of susceptibility to development of SLE.
Bulun SE et al., 2002·Annals of the New York Academy of Sciences·
Aromatase activity is absent in normal endometrium. In contrast, aromatase is expressed aberrantly in endometriosis, which gives rise to strikingly high levels of aromatase activity in this tissue. Both aromatase expression and activity are stimulated by PGE2. This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis, that is, deficient 17beta-HSD type 2 expression, impairs the inactivation of estradiol to estrone. These molecular aberrations collectively favor accumulation of increasing quantities of estradiol and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis using an aromatase inhibitor.
To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI. Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH. Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto. PATIENT(S): Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles). INTERVENTION(S): Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were >/=2 cm followed by IUI. MAIN OUTCOME MEASURE(S): Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate. RESULT(S): Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%). CONCLUSION(S): In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.
To assess the possibility of a postfertilization effect in regard to the most common types of hormonal emergency contraception (EC) used in the US and to explore the ethical impact of this possibility. DATA A MEDLINE search (1966-November 2001) was done to identify all pertinent English-language journal articles. A review of reference sections of the major review articles was performed to identify additional articles. Search terms included emergency contraception, postcoital contraception, postfertilization effect, Yuzpe regimen, levonorgestrel, mechanism of action, Plan B. The 2 most common types of hormonal EC used in the US are the Yuzpe regimen (high-dose ethinyl estradiol with high-dose levonorgestrel) and Plan B (high-dose levonorgestrel alone). Although both methods sometimes stop ovulation, they may also act by reducing the probability of implantation, due to their adverse effect on the endometrium (a postfertilization effect). The available evidence for a postfertilization effect is moderately strong, whether hormonal EC is used in the preovulatory, ovulatory, or postovulatory phase of the menstrual cycle. Based on the present theoretical and empirical evidence, both the Yuzpe regimen and Plan B likely act at times by causing a postfertilization effect, regardless of when in the menstrual cycle they are used. These findings have potential implications in such areas as informed consent, emergency department protocols, and conscience clauses.
Intensive FSH stimulation is a key tool of assisted reproduction technology but can cause severe complications through the development of an excessive number of small ovarian follicles. We tested the hypothesis that, in the late stages of ovulation induction, LH activity in the form of low-dose human CG (hCG) can stimulate and selectively modulate ovarian follicle function and growth, independently of FSH administration. Four groups of GnRH agonist-suppressed normoovulatory women (10 each group) received recombinant human FSH (r-hFSH) (150 IU/d) for 7 d followed by: group A, r-hFSH 150 IU/d alone; group B, r-hFSH 50 IU/d and hCG 50 IU/d; group C, r-hFSH 25 IU/d and hCG 100 IU/d; group D, hCG 200 IU/d alone. Despite several days of lowered or absent r-hFSH administration, 70% of hCG-treated patients successfully completed treatment. In these subjects, preovulatory E2 levels and large (>14 mm diameter) ovarian follicle development were not reduced; conversely, the number of small (<10 mm diameter) ovarian follicles was significantly decreased in groups B-D vs. group A. Low-dose hCG administration did not cause follicle luteinization. We conclude that, following FSH priming, LH activity administration can: 1) stimulate folliculogenesis for several days, in spite of rapidly declining FSH levels; and 2) hasten small follicle demise. Therefore, LH activity administration could be used to design radically novel ovulation induction regimens that, by partly or completely replacing mid-/late follicular phase FSH administration, may reduce costs and improve safety of assisted reproduction technology.
Perimenopause, a complex physiological transition for midlife women, begins with changes in experiences many years before cycles become irregular, oestradiol levels decrease or follicle-stimulating hormone levels increase. Erratic and average higher oestradiol levels as well as shorter luteal phase lengths and lower progesterone levels occur during perimenopause. These ovarian changes may be causally related to lower inhibin production but the dynamic prospective inter-relationships within women are not well documented. This review will first define perimenopause and then explore the limited published data on ovulatory characteristics in perimenopause. In addition, it will report preliminary prospective observational data on menstrual cycles and ovulation in initially ovulatory women followed through the perimenopause. Prospective data suggest that ovulation disturbances begin early in perimenopause and increase with irregular cycles. Combined with higher oestradiol levels they may cause menorrhagia. It is not yet known whether disturbances of ovulation relate to bone loss in perimenopausal, as in premenopausal, women. It is also not known whether progesterone therapy can effectively counteract the end organ (breast, endometrial, brain) effects of higher/erratic oestradiol levels and effectively treat perimenopausal vasomotor and other symptoms.
This study examined changes in the luteal vasculature throughout the menstrual cycle and during simulated pregnancy with human chorionic gonadotrophin (HCG) in the human. Endothelial cell and pericyte area were assessed by quantitative immunocytochemistry for CD34 and alpha-smooth muscle actin respectively, taking into consideration the dynamics of lutein cell hypertrophy and atrophy throughout the cycle and after HCG treatment. Endothelial cell proliferation was detected by Ki-67/CD34 dual staining and a proliferation index was obtained. The molecular regulation of angiogenesis was studied by examining changes in vascular endothelial growth factor (VEGF) immunostaining. The early luteal phase is associated with intense angiogenesis, as indicated by high endothelial cell proliferation, and by the mid-luteal phase a mature vasculature was apparent, as shown by maximal endothelial cell and pericyte areas. During the late luteal phase, decreased endothelial proliferation, endothelial cell and pericyte area indicated vascular regression. HCG treatment induced a second burst of total and endothelial cell proliferation and a concomitant increase in endothelial cell and pericyte areas. VEGF protein was expressed throughout the luteal phase and a significant increase was found after HCG treatment. Luteal rescue with HCG is associated with a second wave of angiogenesis and vascular stabilization.
Kaider AS et al., 2001·Early Pregnancy (Cherry Hill)·
The role of luteal phase estrogen in pregnancy outcome has been a matter of considerable debate. In order to evaluate the effectiveness of estrogen supplementation in gonadotropin releasing hormone agonist (GnRHa)/human menopausal gonadotropin (hMG)-stimulated cycles associated with low luteal estrogen concentration, a study was performed comparing the ongoing pregnancy rates in cycles with serum concentrations of estradiol (E2) <100 pg/ml 11 days post embryo transfer (p-ET), treated with luteal phase progesterone (P4) vs. E2 and P4 supplementation. Among 1106 serum samples studied, 951 were from women receiving GnRHa and follicle stimulating hormone (FSH) prior to oocyte retrieval and P4 (50 mg-100 mg IM daily) as luteal phase supplementation beginning day 11 after retrieval. The remaining 155 were from women receiving both E2 (2 mg-6 mg estrace orally each day) and P4 during the luteal phase. Significantly greater frequencies of preclinical losses were observed among women with human chorionic gonadotropin (hCG) concentrations>5 mIU/ml and concurrent E2 concentrations <100 pg/ml compared with E2 >100 pg/ml (p<0.00001). Among the 128 women who had hCG concentrations >5 mIU/ml and E2 concentrations <100 pg/ml, 102 received P4 only during the luteal phase and 26 were treated with estrace 2 mg-6 mg daily, as well as P4 during the luteal phase. The frequency of preclinical pregnancy losses among the 102 women with hCG >5 mIU/ml and E2 <100 pg/ml who did not receive luteal E2 supplementation was 72%, compared with 50% who received luteal E2 supplementation (p=0.04) The increase in preclinical pregnancy loss rates among women not receiving luteal E2 resulted in a decrease in ongoing pregnancy rate (8%), compared to those receiving luteal E2 supplementation (31%) (p=0.002). Our results indicated that a subset of women losing pregnancies preclinically after GnRHa and FSH stimulation due to low luteal phase serum E2 level may benefit from luteal estrogen supplementation. More sensitive and specific markers are needed to identify prospectively women in this risk group.
Gleicher N et al., 2001·Early Pregnancy (Cherry Hill)·
Innumerable studies have attempted to demonstrate that hormonal support of the luteal phase during ovulation induction cycles improves pregnancy rates. None has, however, so far been able to confirm the validity of such treatment conclusively, possibly because most studies only utilized progesterone substitution. Since luteal phase endometrium also requires estradiol support, this study attempted to investigate whether hormone substitution with progesterone and estradiol would be more successful in improving pregnancy rates. Amongst approximately 7500 consecutive ovulation induction cycles were identified prospectively which were characterized by a precipitous drop of luteal phase serum estradiol levels by more than 50% over a 48 hour period within 10 days from hCG administration. Those cycles were prospectively randomized to oral micronized estradiol substitution (Group I) or not (Group II), while both groups received routine progesterone substitution of the luteal phase. Cycles were then evaluated in regards to the occurrence of chemical, ectopic and clinical pregnancies. One hundred sixty-three Group I cycles resulted in 34 pregnancies (20.9%), which compared favorably to 21 pregnancies in 167 Group II patients (12.6%) (x2[1] = 4.06; p < 0.04). The advantage for Group I cycles (29/95 pregnancies, 31%) vs. Group II cycles (16/105, 15%) became even more pronounced when only women up to age 35 years were evaluated. Estradiol substitution maintained a significant advantage until age 38 (x2 [1] = 6.87; p < 0.009). While gravidity did not affect pregnancy success, estradiol substitution in Group I benefited nulliparous (23% pregnancy rate) over multiparous women (12% pregnancy rate) (x2 [2] = 6.86; p< 0.03). This association was, however, age-dependent. A combined estradiol and progesterone substitution of the luteal phase of ovulation induction cycles increases the overall pregnancy rate. Since estradiol substitution was initiated in this study only once a precipitous drop in serum estradiol levels had already taken place, an even larger improvement in pregnancy rates could conceivably be possible if earlier estradiol substitution of the luteal phase is initiated. A further expansion of investigations of similar protocols for routine ovulation induction and in vitro fertilization (IVF) cycles may be indicated, especially in women below age 38 years and in nulliparous females.
Thyroid and Metabolic Function · Insulin and Metabolism
To determine the metabolic and reproductive effectiveness of rosiglitazone in polycystic ovary syndrome (PCOS). Case report. Academic clinical practice and General Clinical Research Center. PATIENT(S): A 25-year-old woman with PCOS. INTERVENTION(S): Rosiglitazone maleate, 4 mg daily for 5 months until conception. MAIN OUTCOME MEASURE(S): Insulin sensitivity by steady-state plasma glucose technique; serum androgens, progesterone, and hCG; and pelvic ultrasound images. RESULT(S): Rosiglitazone treatment for 5 months improved insulin sensitivity, lowered serum free testosterone, and resulted in spontaneous ovulation and conception. CONCLUSION(S): Rosiglitazone is a promising insulin sensitizer for treatment of PCOS. Clinical trials are warranted.
Women have twice the incidence of major depression compared with men. They are prone to develop episodes of depression during times of reproductive hormonal change at puberty, with use of oral contraceptives, during the premenstrual phase of the menstrual cycle, postpartum and during the perimenopause (see review: ). describes the variety of disturbances in biological rhythms observed in mood disorders. In this report, we describe the chronobiological disturbances observed in female-specific mood disorders, namely, premenstrual dysphoric disorder, pregnancy and postpartum depression and menopause. We hypothesize that changing reproductive hormones, by affecting the synchrony or coherence between components of the circadian system, may alter amplitude or phase (timing) relationships and thereby contribute to the development of mood disorders in predisposed individuals.
To examine the direct effect of metformin on thecal cell androgen production. Basic science research laboratory, University of Texas Southwestern, Dallas, Texas. INTERVENTION(S): Human ovarian theca-like tumor cells were treated with various concentrations of metformin in the presence and absence of forskolin for 48 hours. MAIN OUTCOME MEASURE(S): Media were collected, and radioimmunoassay (RIA) for progesterone, 17 alpha-hydroxyprogesterone (17OHP), androstenedione, and testosterone was performed. The effect of metformin on the expression of various enzymes involved in theca cell steroidogenesis was examined. RESULT(S): Metformin (50 microM and 200 microM) significantly inhibited androstenedione production from both forskolin-stimulated and unstimulated theca cells. Testosterone production was also significantly inhibited in forskolin-treated cells in the presence of 200 microM of metformin-treated compared with forskolin-only-treated cells. Western blot analysis revealed that metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3beta-hydroxysteroid dehydrogenase (3 beta HSD) or cholesterol side-chain cleavage (CYP11A1) protein expression. Northern analysis revealed a significant decrease in the expression of CYP17 mRNA in forskolin-stimulated cells treated with metformin (200 microM) compared with forskolin-only-treated cells, however, there was no significant change in steroidogenic acute regulatory protein mRNA expression. CONCLUSION(S): Our results suggest that metformin may have a direct effect on thecal cells' androgen production.
The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 pg i.v.). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 microg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% post-treatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5+/-1.76 mm pre-treatment vs 21.6+/-2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7+/-288.5 pmol/l pre-treatment vs 986.4+/-382.1 pmol/l post-treatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.
Progestogens, which include the natural hormone, progesterone, and synthetic steroid derivatives, are used to treat a variety of reproductive disorders. Since synthetic progestogens are often associated with undesirable side effects, improved formulations and modes of administration of progesterone have been sought. In order to find an optimal therapeutic agent, different progesterone formulations and routes of administration have been studied. This paper explains several methods of measuring progesterone levels and summarizes clinical data on the pharmacokinetic profiles of natural progesterone administered by the oral, intramuscular, vaginal, intranasal, percutaneous, sublingual and rectal routes.
Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.
Human chorionic gonadotropin (hCG) is widely used as a surrogate to luteinizing hormone (LH) to trigger ovulation in controlled ovarian hyperstimulation (COH). Yet this molecule may exert direct effects on the endometrium. These effects, not mediated by ovarian hormones, are probably a consequence of stimulation of endometrial hCG/LH receptors. Because the half-life of hCG differs markedly from that of LH, possible pharmacological effects of hCG on the endometrium could alter endometrial receptivity in COH. Arguments supporting a clinical action of gonadotropins, and hCG in particular, on the endometrium abound. Notably, evidence has been reported of decidualization of stromal cells of the human endometrium in vitro as a result of exposure to gonadotropins, including hCG. The present article discusses, from a clinical standpoint, the main basis supporting the hypothesis that hCG administration as commonly used in infertility treatments may exert direct effects in vivo on endometrial histology and partake in endometrial transformations of the luteal phase. Preliminary results suggest that endometrial effects of hCG exist in vivo and should be taken into account when assessing the endometrial effects of hormones.
Progesterone, supplied in a variety of formulations, is commonly used in assisted reproduction. However, even the commonly accepted uses of progesterone in fertility care are believed to be largely empirical, as are the current available treatment options. While a critical balance of estrogen and progesterone is necessary for successful embryo implantation, achieving that balance is subject to differences in prescribing practice. In evaluating recommendations for the use of progesterone, discussion of its role in assisted-reproduction procedures must distinguish between known therapeutic benefits and empirical benefits.
To investigate whether uterine contractility at the time of embryo transfer (ET) can be reduced by early onset of luteal support with progesterone administered vaginally. Prospective analysis. Assisted reproduction unit. PATIENT(S): Eighty-four women undergoing 84 GnRH-a and FSH/hCG cycles for IVF-ET were studied. INTERVENTION(S): Vaginal progesterone was randomly started on the day of oocyte retrieval (group A, n = 43) or on the evening of ET (group B, n = 41). On the day of hCG administration and just before ET, 2-minute sagittal uterine scans were obtained by ultrasound and digitized with an image analysis system for assessing uterine contraction frequency. MAIN OUTCOME MEASURE(S): Uterine contraction frequency. RESULT(S): Whereas uterine contraction frequency was similar in both groups on the day of hCG (4.6 +/- 0.3 and 4.5 +/- 0.3 contractions per minute, respectively), only women in group A showed decreased uterine contraction frequency on the day of ET (2.8 +/- 0.2 vs. 4.2 +/- 0.3 contractions per minute). CONCLUSION(S): Vaginal progesterone administration starting on the day of oocyte retrieval induced a decrease in uterine contraction frequency on the day of ET as compared with preovulatory values. Uterine relaxation before ET is likely to improve IVF-ET outcome by avoiding the displacement of embryos from the uterine cavity.
To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility. Prospective randomized trial. Infertility clinic in a university teaching hospital. PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction. INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9. MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities. RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group. CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.
Kalro BN et al., 2001·Obstet Gynecol Clin North Am·
Although central and peripheral factors have been implicated in the neuromodulation of GnRH in PCOS, there are no definitive or conclusive data to establish a primary causal role for any one factor. Because increased GnRH pulse frequency is at least a contributor to the secretion of excess LH and insufficient FSH that are the proximate cause of chronic anovulation in PCOS, strategies to slow the GnRH pulse generator are likely to promote ovulation in women with PCOS. Several pharmacologic agents, such as dopamine agonists and antagonists, have been tried, but the lack of consistent effects in women with PCOS limits their clinical utility. Current treatment strategies include the use of the combined oral contraceptive pills, antiandrogens or androgen receptor blockers, and insulin sensitizers. Oral contraceptive preparations are effective in suppressing ovarian hyperandrogenemia, regulating menstrual cycles, and reducing the risk of endometrial hyperplasia. Androgen blockade and antiandrogens provide symptomatic relief from androgen-induced acne and hirsutism and have been reported to restore ovulation in women with PCOS. Whether this effect is mediated peripherally or centrally remains to be clarified. The most recent class of pharmacologic agents to gain popularity are the "insulin modifiers." With increasing evidence that insulin resistance constitutes a key metabolic element, it seems logical that improving insulin sensitivity and glucose disposal might wholly, or partially, reverse certain features of PCOS, including anovulation. To date, insulin modifiers have proved most promising in improving the clinical features and promoting fertility, but whether this effect is centrally mediated is yet to be elucidated.
To compare subcutaneous (SC) and intramuscular (IM) hCG administration and their association with body mass index (BMI) in women undergoing IVF-ET using hMG and ICSI. Prospective, randomized controlled trial. Private infertility clinic. PATIENT(S): Twenty-one ovulatory women, 29-39 years, were enrolled. Treatment of one patient who failed to respond to hMG was canceled. INTERVENTION(S): A standard IVF-ET treatment plan using an initial dose of 300 U of hMG was followed. Patients were randomly assigned to receive 10,000 IU hCG, either IM in the gluteal region or SC in the lower abdomen. Exactly 12 hours later, serum for hCG determination was obtained. All oocytes were fertilized using ICSI technology. MAIN OUTCOME MEASURE(S): Human chorionic gonadotropin levels 12 hours after injection, BMI, and oocyte maturity. RESULT(S): No significant differences in hCG levels were found, with mean levels of 225 +/- 24 mIU/mL for SC injection versus 213 +/- 26 mIU/mL for IM injection. No differences were observed in the percentage of mature oocytes. A significant negative correlation was found between BMI and hCG levels in all patients, regardless of route of administration. CONCLUSION(S): The highest levels of hCG were measured in women with the lowest BMI. Patients' body size, rather than route of hCG delivery, appears to determine circulating levels of hCG.
To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate (CC) treatment was unsuccessful. Prospective trial in infertility patients treated with CC. Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences, University of Toronto. PATIENT(S): Twelve patients with anovulatory polycystic ovary syndrome (PCOS) and 10 patients with ovulatory infertility, all of whom had previously received CC with an inadequate outcome (no ovulation and/or endometrial thickness of < or =0.5 cm). INTERVENTION(S): The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3-7 after menses. MAIN OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and pregnancy rates. RESULT(S): With CC treatment in patients with PCOS, ovulation occurred in 8 of 18 cycles (44.4%), and all ovulatory cycles for the women included in this study had endometrial thickness of < or =0.5 cm. In 10 ovulatory patients, 15 CC cycles resulted in a mean number of 2.5 mature follicles, but all cycles had endometrial thickness of < or =0.5 cm on the day of hCG administration. With letrozole treatment in the same patients with PCOS, ovulation occurred in 9 of 12 cycles (75%) and pregnancy was achieved in 3 patients (25%). In the 10 patients with ovulatory infertility, letrozole treatment resulted in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm. Pregnancy was achieved in 1 patient (10%). CONCLUSION(S): Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility. Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction.
To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. Randomized, double-blind, placebo-controlled trial. Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.
To determine the rate of clinically evident polycystic ovary syndrome (PCOS) among first-degree female relatives within families with a proband affected by PCOS. Clinical and biochemical evaluation of the mothers and sisters of 93 patients with PCOS. The diagnosis of PCOS was established by: [1] a history of oligomenorrhea, [2] clinical evidence (i.e., hirsutism) or biochemical evidence (i.e., elevated total or free T) of hyperandrogenism, and [3] the exclusion of related disorders. Tertiary care university. PATIENT(S): Patients with PCOS and their mothers and sisters. INTERVENTION(S): Interview, physical examination, and hormonal testing on blood samples were performed for all subjects. MAIN OUTCOME MEASURE(S): The presence of hirsutism and hyperandrogenemia was determined in the mothers and sisters of the patients with PCOS. RESULT(S): Of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) and 16 (32%) were affected with PCOS, respectively. A higher rate of PCOS was observed when only premenopausal women not taking hormones (i.e., untreated) were considered (i.e., 35% of mothers and 40% of sisters), consistent with amelioration of symptoms with hormonal therapy or aging. These rates of PCOS are significantly higher than that observed in our general population (approximately 4%) and suggest the involvement of a major genetic component in the disorder. CONCLUSION(S): The rates of PCOS in mothers and sisters of patients with PCOS were 24% and 32%, respectively, although the risk was higher when considering untreated premenopausal women only.
Ovarian hormonal function is under hypothalamo-hypophysis control during the genital life of women. Local hormonal production induces follicular stimulation and maturation. Two main types of functional disorder can be observed: unilocular cyst, related to an ovulation mechanism, and polycystic ovaries. The former is a follicular cyst related to the absence of LH stimulation, or a luteal cyst, which may be anechoic or display a heterogeneous content (pseudo-septa, pseudo-solid but avascular mass). The latter includes the polycystic ovarian syndrome, which is characterized by an increased ovarian area ( 6cm(2)), stroma and follicles number, the multifollicular ovaries, which are related to functional hypothalamic anovulation and characterized by a normal ovarian size with increased follicles number, and macropolycystic ovaries which are observed in case of previous pelvic infection disease or surgery. Functional disorders may be observed during pregnancy: luteoma, luteal cyst and hyperreactio luteinalis. Finally, ovarian insufficiency may occur too early.
Thyroid and Metabolic Function · Thyroid Disorders
To review the menstrual function and fertility in thyroid disease, mainly in hyperthyroidism and hypothyroidism. Also to register the consequences of (131)I therapy, which is used widely in the treatment of Graves' disease and thyroid cancer, on subsequent pregnancies and on fertility in these patients. A MEDLINE computer search was used to identify relevant studies. The type of menstrual disturbances and the status of fertility were recorded from all the studies found. Also, the fertility and genetic hazard of female patients with Graves' disease and thyroid cancer who were treated with (131)I were registered. RESULT(S): Both hyperthyroidism and hypothyroidism may result in menstrual disturbances. Menstrual abnormalities are less common now than in previous series. In a recent study, we found that only 21.5% of 214 thyrotoxic patients had some type of menstrual disturbance, compared to 50 to 60% in some older series. The most common manifestations are hypomenorrhea and oligomenorrhea. According to the results of endometrial biopsies, most thyrotoxic women remain ovulatory. Moreover, the genetic hazard incident to radioiodine therapy in Graves' disease and thyroid carcinoma is very small; exposure to (131)I does not cause reduced fecundity, and the risk of loss of fertility is not a contraindication for its use in these patients. mIn hypothyroidism, the frequency of menstrual irregularities has very recently been reported to be 23.4% among 171 hypothyroid patients studied. This is much less than that reported in previous studies, which showed that 50 to 70% of hypothyroid female patients had menstrual abnormalities. The most common manifestation is oligomenorrhea. Severe hypothyroidism is commonly associated with failure of ovulation. Ovulation and conception can occur in mild hypothyroidism. These pregnancies are, however, often associated with abortions, stillbirths, or prematurity. The latter may be of greater clinical importance in infertile women with unexplained infertility. CONCLUSION(S): These new data, mainly concerning menstrual abnormalities in hyperthyroidism and hypothyroidism, are inconsistent with what is generally believed and written in the classic thyroid textbooks and indicate that such opinions should be revised.
A large part of infertility treatment involves the use of exogenous gonadotropins. The last decade has seen a progressive switch from human menopausal gonadotropin (hMG), the original gonadotropin product, to progressively more costly products, primarily or exclusively containing follicle-stimulating hormone (FSH). Though obviously at least in part driven by marketing efforts of pharmaceutical companies, this switch has received relatively little scrutiny despite its obvious cost implications. We therefore investigated whether a switch back to a generic or less costly hMG-driven ovulation induction protocol would affect patient outcome after ovulation induction and, by implications, with other assisted reproductive technologies. We prospectively studied clinical pregnancy rates in a large number of consecutive ovulation induction cycles in a well-defined patient population (group 1) which, after October of 1997, had been switched from a predominantly FSH to an hMG-driven protocol, based on an institutional formulary change. Until a transition period (between July and September 1997), this patient population had been on a primarily FSH-driven protocol (between July 1996 and June 1997). In parallel, we evaluated a second patient population (group 2), which was managed by the same physicians outside of formulary requirements and remained almost exclusively on principally FSH-driven ovulation induction cycles. FSHand hMG-driven ovulation induction protocols did not differ in pregnancy outcome during the prospective study period. Group 1 patients, however, demonstrated a significant increase in pregnancy rates after the switch from FSH to hMG stimulation had taken place (P = 0.02), while group 2 patients demonstrated no change in pregnancy rate during the same time period. Generic hMG products do not adversely affect pregnancy rates in comparison to more costly FSH products in routine ovulation induction cycles and should be considered an appropriate alternative to more expensive FSH products.
To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus. Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility. During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs. NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility.
Progesterone is the natural progestagen produced by the corpus luteum during the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits the efficacy of once-daily administration and also results in unphysiologically high levels of progesterone metabolites, particularly those reduced at the 5-a position. These metabolites can cause dizziness and drowsiness to the point of preventing the operation of a motor vehicle. Synthetic progestins, such as medroxyprogesterone acetate and norethindrone acetate (NETA), have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 mg/day during the mid-luteal phase. To avoid this problem, synthetic progestins such as NETA have been administered transdermally. These compounds, though, just like synthetic estrogens administered non-orally, retain undesirable hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route available for administering progesterone. Early experience was gained with vaginal suppositories, which lack manufacturing controls. Recently, a new progesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characteristics of its polycarbophil-based gel, which conveys controlled and sustained-released properties. Investigations have shown that because of local direct vagina-to-uterus transport, which results in a preferential uterine uptake of progesterone, this formulation given in conjunction with physiological amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphysiologic. Studies in infertility show that vaginal progesterone in this form allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewer side effects occur when used for hormone replacement than typically encountered with progestins and oral progesterone. Uses in patients with infertility and hypoestrogenism and secondary amenorrhea are reviewed.
Thyroid and Metabolic Function · Insulin and Metabolism
Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. In the 22 women given D-chiro-inositol, the mean (+/-SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417+/-11,572 to 5158+/-6714 microU per milliliter per minute (81+/-69 to 31+/-40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1+/-0.8 to 0.5+/-0.5 ng per deciliter (38+/-7 to 17+/-3 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women's diastolic and systolic blood pressure decreased by 4 mm Hg (P<0.001 and P=0.05, respectively, for the comparisons with the changes in the placebo group), and their plasma triglyceride concentrations decreased from 184+/-88 to 110+/-61 mg per deciliter (2.1+/-0.2 to 1.2+/-0.1 mmol per liter) (P=0.002 for the comparison with the change in the placebo group). None of these variables changed appreciably in the placebo group. Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001). D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.
To investigate whether the timing of administration of clomiphene citrate (CC) affects hormone levels, follicular recruitment, reproductive end organs, and pregnancy rates. Prospective, randomized, double-blind trial. Academic center. PATIENT(S): Twenty-three patients with unexplained infertility. INTERVENTION(S): Twenty-three patients with unexplained infertility underwent 45 cycles of CC and IUI. For each cycle, patients were randomized either to receive 100 mg of CC on days 1-5 and placebo on days 5-9 (study group), or placebo on days 1-5 and CC on days 5-9 (control group). MAIN OUTCOME MEASURE(S): The difference in uterine artery PI, number of follicles, endometrial thickness, and pregnancy rates. RESULT(S): Gonadotropins and E2 levels, as well as uterine artery pulsatility index, were significantly higher in the study group on day 5. In addition, in the study group, a longer time interval existed between finishing CC and IUI (8 versus 6 days; MD = 2 days; 95% CI = 1-3) and the pregnancy rate was higher than in the control group (6 versus 0; OR = 15.1; 95% CI = 1.1-72.4). CONCLUSION(S): Clomiphene citrate commenced on day 1 of the menstrual cycle, rather than day 5, results in more rapid follicular growth, a longer CC-free period before IUI, and higher pregnancy rates. Although methodologically sound, our results should be taken with some degree of caution because they are based on a relatively small number of patients.
Koivunen R et al., 1999·Acta Obstet Gynecol Scand·
To study the prevalence of polycystic ovaries (PCO) in women of reproductive age. A total of 189 healthy volunteers aged 20-45 years were examined. The subjects were divided into two groups according to age: < or =35 and > or =36 years. Transvaginal ultrasonography was performed and blood samples were collected on cycle day 1-6. The prevalence of PCO in the entire study population was 14.2% (27/189). In the age group of < or =35 years the prevalence was 21.6% (19/88) and in the age group of > or =36 years 7.8% (8/101). Compared to women with normal ovaries, those with PCO had significantly higher serum testosterone (T) concentrations. Women with PCO tended to have lower serum FSH concentrations and higher LH/FSH ratios than controls. Women with PCO had significantly more irregular cycles (44% vs. 19%, p=0.001) and problems in conceiving (25.9% vs. 9.2%, p=0.01) than women with normal ovaries. The findings demonstrate that the prevalence of PCO in healthy women varies with age, being more common among women aged < or =35 years than in those aged > or =36 years. Although the hormonal parameters and clinical findings among women with PCO mimicked those of PCOS, it remains unclear if these women will later develop full-blown syndrome.
To determine the prevalence of polycystic ovary syndrome (PCOS) among hyperandrogenic women who report normal menses. Prospective observational study. Academic practice in reproductive endocrinology. PATIENT(S): Fifty-eight consecutively seen new patients with hyperandrogenism who reported normal menses. INTERVENTION(S): Ovulatory status was assessed with timed serum progesterone measurements. The following tests also were carried out: vaginal ultrasound examination; measurement of the ovarian response of 17-hydroxyprogesterone (17-OHP) after the administration of leuprolide acetate, 1 mg SC; and determination of fasting serum LH, FSH, E2, 17-OHP, insulin, and androgen levels. MAIN OUTCOME MEASURE(S): Determination of ovulatory status, polycystic appearance of ovaries, and increased response of 17-OHP to leuprolide acetate. RESULT(S): Twelve (20.7%) of the hyperandrogenic women were anovulatory and met the usual criteria for the diagnosis of PCOS. The ovulatory patients had lower serum total and unbound testosterone levels. Thirty-one (53.4%) of the ovulatory women had polycystic ovaries on ultrasound examination and/or an increased 17-OHP response to leuprolide acetate, suggesting the diagnosis of PCOS despite the presence of ovulation. Considering both the anovulatory and ovulatory patients, 74% of the hyperandrogenic women studied could have PCOS. CONCLUSION(S): The data suggest that most (74%) hyperandrogenic women who report normal menses have evidence for the diagnosis of PCOS.
To investigate the involvement of opioid tone, obesity, and hyperinsulinemia in GH secretion in women with polycystic ovary syndrome (PCOS). Controlled clinical study. Catholic University of Sacred Heart School of Medicine in Rome, Italy. PATIENT(S): Twenty-two patients with PCOS and 14 healthy, normally ovulating volunteers, matched for age and body mass index. INTERVENTION(S): Patients underwent a GH-releasing hormone (GHRH) test and an oral glucose tolerance test before and after 4-5 weeks of treatment with 50 mg/d of naltrexone. MAIN OUTCOME MEASURE(S): Serum concentrations of GH, insulin, glucose, steroids, and gonadotropins, as well as the GH area under the curve (AUC-GH) and the insulin area under the curve (AUC-I), were measured before and after naltrexone treatment. RESULT(S): In patients with PCOS, the administration of naltrexone increased the GH response to the GHRH test without interfering with the insulin response to the oral glucose tolerance test. However, the GH response to the GHRH test was improved significantly only in lean patients with PCOS, whereas obese patients with PCOS did not show any improvement in GH secretion. In obese control subjects, the treatment reduced plasma basal insulin concentrations and increased the AUC-GH, whereas in lean control subjects, the treatment reduced the GHRH-induced response. In normoinsulinemic patients with PCOS, the GH response to the GHRH test increased significantly after treatment, whereas the AUC-I was not affected. In hyperinsulinemic patients with PCOS, treatment with naltrexone significantly reduced the AUC-I, whereas the AUC-GH increased only in lean hyperinsulinemic patients with PCOS. CONCLUSION(S): Naltrexone treatment improves GHRH-induced GH secretion in patients with PCOS. However, this GH response is heterogeneously represented in relation to both obesity and hyperinsulinism.
To investigate the relationship between the ovarian stromal area and clinical hormonal characteristics in women with polycystic ovary syndrome (PCOS). Twenty-eight women with PCOS (group 1) and 26 healthy women (group 2) participated in this study. For measuring the ovarian stromal area, transvaginal ultrasonography was performed on all women during the early follicular phase of the menstrual cycle. Venous blood was sampled from the women to determine serum follicle stimulating hormone, luteinizing hormone (LH), estradiol, androstenedione, free testosterone (FT), total testosterone (TT), 17 alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate, and fasting insulin and glucose levels. Two-tailed t and Pearson correlation tests were used for statistical analysis. Women with PCOS were heavier, and their serum FT, TT and LH levels were significantly higher than in the normals (P < .001, P < .012 and P < .001, respectively). The ovarian stromal area measured by transvaginal ultrasonography was also significantly larger than in the normals (P < .001). Only basal serum insulin levels seemed to correlate positively with the ovarian stromal area in women with PCOS (r = .43 P = .09). Although transvaginal ultrasonography has played an important role in the evaluation of women with PCOS, we could not demonstrate a relationship between the ovarian stromal area and hormonal characteristics of PCOS. Therefore, transvaginal ultrasonography and hormonal parameters must be used as complementary diagnostic methods in women with PCOS.
A case-control study was conducted to determine whether menstrual and gynecologic abnormalities precede the onset of chronic fatigue syndrome (CFS) in women with this disorder to a greater extent than that observed among healthy controls. We identified 150 women who met the 1988 Centers for Disease Control criteria for CFS from the Brigham and Women's Hospital Cooperative CFS Research Center. A comparison group of 149 women being seen for nongynecologic conditions were selected from the waiting area of the Brigham and Women's Hospital Internal Medicine outpatient department. Women with and without CFS completed self-administered questionnaires on menstrual, reproductive, and medical history. Women with CFS reported increased gynecologic complications and a lower incidence of premenstrual symptomatology. After adjustment for age, a somewhat greater number of cases compared with controls self-reported irregular cycles, periods of amenorrhea, and sporadic bleeding between menstrual periods. Factors suggestive of abnormal ovarian function--such as a history of polycystic ovarian syndrome, hirsutism, and ovarian cysts--were reported more often in CFS cases compared with controls. Frequent anovulatory cycles due to ovarian hyperandrogenism (PCOS) or hyperprolactinemia may increase risk for CFS through loss of the potential immunomodulatory effects of progesterone in the presence of continued estrogen production. We hypothesize that frequent anovulatory cycles due to PCOS and/or hyperprolactinemia may explain the increased reporting of gynecologic complications and the lower reported premenstrual symptomatology observed in women with CFS.
Thyroid and Metabolic Function · Insulin and Metabolism
Ciampelli M et al., 1998·Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
In recent years the metabolic implications of polycystic ovary syndrome (PCOS) have received a great deal of attention; in fact 50% of women with PCOS are obese and a similar percentage of subjects was found to show exaggerated insulin secretion and reduced insulin-stimulated glucose uptake. The presence of these features in women with PCOS has profound clinical implications in terms of morbidity due to diabetes mellitus, dyslipidemia, hypertension and cardiovascular disease. Moreover, hyperinsulinemia has recently been proposed as a possible independent risk factor for endometrial and breast cancer. In the light of these considerations, the importance of metabolic screening in patients with PCOS in order to improve their quality of life cannot be underestimated. In this review we analyze all the clinical pathologies in which hyperinsulinemia of PCOS could be involved. Furthermore, in order to clarify the possible mechanisms leading to the insulin disorders of the syndrome, we review the available data about the insulin receptor abnormalities, as well as those concerning the insulin resistance and the exaggerated insulin secretion. Finally, we examine the main therapeutic strategies to ameliorate the insulinemic status of PCOS patients in order to potentially be able to prevent the long-term consequences of this syndrome.
Brisken C et al., 1998·Proc Natl Acad Sci U S A·
Open Access
Recently generated progesterone receptor (PR)-negative (PR-/-) mice provide an excellent model for dissecting the role of progesterone in the development of the mammary gland during puberty and pregnancy. However, the full extent of the mammary gland defect in these mice caused by the absence of the PR cannot be assessed, because PR-/- mice do not exhibit estrous cycles and fail to become pregnant. To circumvent this difficulty, we have transplanted PR-/- breasts into wild-type mice, and we have demonstrated that the development of the mammary gland in the absence of the PR is arrested at the stage of the simple ductal system found in the young virgin mouse. Mammary transplants lacking the PR in the stromal compartment give rise to normal alveolar growth, whereas transplants containing PR-/- epithelium conserve the abnormal phenotype. Chimeric epithelia in which PR-/- cells are in close vicinity to PR wild-type cells go through complete alveolar development to which the PR-/- cells contribute. Together, these results indicate that progesterone acts by a paracrine mechanism on a subset of mammary epithelial cells to allow for alveolar growth and that expression of the PR is not required in all the cells of the mammary epithelium in order for alveolar development to proceed normally.
Functional disorders of the gastrointestinal tract comprise a common but ill-defined group of diseases; they primarily afflict women. Although predominantly involving nerve and muscle, the cellular and molecular bases of the pathogenesis of these functional disorders are unknown. Clinical studies indicate that some result from neural dysfunction within the enteric nervous system, others may be due to muscular problems, and the causes of still others remain unknown. Laboratory studies have shown that ovarian products such as progesterone, luteinizing hormone, human chorionic gonadotropin, and relaxin (but not estrogen), are neural antagonists of gastrointestinal motility. The production and secretion of these ovarian substances are controlled by gonadotropin-releasing hormone (GnRH) released from the hypothalamus; they probably act on gamma-aminobutyric acid receptors and alter chloride influx into the cell. GnRH analogs are effective drugs that downmodulate the hypothalamic-pituitary-gonadal axis and inhibit the secretion of gonadal products involved in such hormone-dependent diseases as endometriosis and prostate cancer. Acting on the GnRH receptors (seven transmembrane domain receptors) on myenteric neurons, GnRH analogs are also effective neural modulators in such disorders as functional bowel disease. These analogs are a promising new group of compounds that may be used to treat difficult gastrointestinal problems.
To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). Prospective study. The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.
It is now accepted that gelatinase B (92 kd type IV collagenase) is involved in blastocyst implantation and trophoblast invasion. However, little is known about the regulation of this enzyme at the fetomaternal interface. Progesterone has been demonstrated to inhibit gelatinase B secretion from endometrial cells, myometrium, and cervical fibroblasts. Interestingly, the promotor of gelatinase B contains a progesterone-responsive element that may explain transcriptional activation of this metalloproteinase by progesterone. It may be hypothesized that progesterone secreted from trophoblast cells, representing the fetal part of the fetomaternal interface, may have a role in the regulation of gelatinase secretion and blastocyst implantation. To this end, use was made of first-trimester trophoblast cells obtained from first-trimester pregnancy terminations. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients. Metalloproteinase activity was measured by zymography, and the expression of the gelatinase B messenger ribonucleic acid was determined by the solution hybridization/ribonuclease protection assay. Primary cell cultures of trophoblasts from first trimesters of pregnancy constitutively elaborated two species of type IV collagenases (gelatinase A and B) as assessed on a gelatin matrix. Treatment with progesterone decreased the accumulation of a gelatinase B species in a dose-dependent fashion. Administration of a progesterone receptor antagonist onapristone (ZK-98.299) neutralized the progesterone inhibitory effect on the gelatinase B in a dose-dependent fashion, thus supporting the presumption that the progesterone effect is receptor mediated. Progesterone significantly attenuated the expression of gelatinase B by trophoblast cells, an effect that was neutralized by ZK-98.299. These observations provide strong indirect support for the participation of progesterone in the regulation of gelatinase B in trophoblast cells. It may be an important regulator of gelatinase production at the fetomaternal interface.
To verify the occurrence of preferential distribution of vaginally administered progesterone to the uterus compared with extrapelvic regions in vivo and in humans. Prospective clinical study. University medical school. PATIENT(S): Twenty postmenopausal women undergoing transabdominal hysterectomy for benign pathologies. INTERVENTION(S): Forty-five minutes before surgery, the women received a single vaginal administration of an oil-based micronized progesterone (100 mg) solution currently available on the market for IM use. During the operation, parallel blood samples were drawn from the uterine and radial arteries. MAIN OUTCOME MEASURE(S): Plasma levels of progesterone were measured by RIA. RESULT(S): Mean (+/- SD) plasma levels of progesterone were significantly higher in the uterine artery than in the radial artery (9.75 +/- 3.21 vs. 5.12 +/- 2.06 ng/mL, respectively). CONCLUSION(S): Vaginal administration allows a preferential distribution of progesterone to the uterus, which confirms the existence of the so-called "first uterine pass effect."
Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of polycystic ovarian disease (PCOD). On the other hand, being generally admitted that opioids may play a role in glycoregulation and that opioid tone is altered in PCOD, an involvement of the opioids in determining the hyperinsulinemia of PCOD patients could be suggested. The aim of this study was to evaluate the effect of a chronic opioid blockade on insulin metabolism and peripheral insulin sensitivity in PCOD hyperinsulinemic patients. Twenty-three women with PCOD were studied. An oral glucose tolerance test (OGTT) and a clamp study were performed at baseline (during the follicular phase) and after 6 weeks of naltrexone administration (50 mg/d orally). Based on the insulinemic response to the OGTT, 16 women were classified as hyperinsulinemic and seven as normoinsulinemic. Naltrexone treatment significantly reduced fasting (P < .05) and area under the curve (AUC) (P < .02) plasma insulin levels only in the hyperinsulinemic group. Moreover, hyperinsulinemic patients showed similar C-peptide incremental areas after naltrexone treatment, whereas in the same patients the fractional hepatic insulin extraction calculated from the incremental areas of insulin and C-peptide was found to be increased after chronic opioid blockade by naltrexone. For peripheral insulin sensitivity, the hyperinsulinemic group showed significantly lower (P < .01) total-body glucose utilization (M) compared with the normoinsulinemic group. No change in the M value was found after treatment in both groups. These data suggest that the insulin sensitivity and hyperinsulinemia after an OGTT are two distinct deranged features of the insulin disorder of PCOD patients.
The symptoms of women with premenstrual syndrome improve in response to suppression of ovarian function, although these women have no evidence of ovarian dysfunction. We undertook a study to determine the role of estrogen and progesterone in this syndrome. We first studied the effect of ovarian suppression with leuprolide, an agonist analogue of gonadotropin-releasing hormone, or placebo on symptoms in 20 women with the premenstrual syndrome. Ten women whose symptoms improved during leuprolide treatment were given estradiol and progesterone in a double-blind, crossover design, each for four weeks, during continued leuprolide administration. Women without premenstrual syndrome (normal women) participated in a similar protocol. Outcomes were assessed on the basis of daily self-reports by the patients and biweekly rater-administered symptom-rating scales. The 10 women with premenstrual syndrome who were given leuprolide had a significant decrease in symptoms as compared with base-line values and with values for the 10 women who were given placebo. The 10 women with premenstrual syndrome who were given leuprolide plus estradiol or progesterone had a significant recurrence of symptoms, but no changes in mood occurred in 15 normal women who received the same regimen or in 5 women with premenstrual syndrome who were given placebo hormone during continued leuprolide administration. In women with premenstrual syndrome, the occurrence of symptoms represents an abnormal response to normal hormonal changes.
To assess the effect of insulin-lowering treatment on menstrual cyclicity in polycystic ovary syndrome (PCOS). Forty oligoamenorrheic women with PCOS were recruited in a prospective clinical study to receive metformin for a minimum period of 6 months. Twenty-two women completed the study. Serum LH, FSH, free testosterone, and glucose and insulin response to oral glucose load were measured both before and after 8 weeks of metformin treatment. Menstrual cyclicity and serum progesterone levels at the midluteal phase were assessed at the 30th week of metformin treatment. Twenty-one of 22 women had restoration of menstrual cyclicity (95.7%). Four of these women (19%) became pregnant within the 6th and 7th months of treatment. All four of the pregnant women delivered, and the infants were healthy. Thirteen of 15 women who had regular menses demonstrated a serum progesterone level within the ovulatory range (3.1-28 ng/mL). Fasting (P < .001) and the integrated insulin response to the glucose load decreased (P < .001) after 8 weeks of metformin treatment. This was accompanied by significant decreases in serum LH (P < .001) and free testosterone (P < .001) levels and LH/FSH ratio (P < .001). There was a small but significant reduction in body mass index after 8 weeks of metformin treatment (P < .001). A 6-month course of metformin may improve menstrual cyclicity and fertility in women with the PCOS. Insulin-sensitizing agents provide a rational approach to the treatment of the metabolic and endocrine abnormalities in PCOS women.
To examine the endometrial effects of three different doses of progesterone administered vaginally. Forty women 25-41 years old deprived of ovarian function received estradiol (E2) for 28 days. From days 15 to 27, a new mucus-like vaginal gel of progesterone was administered every other day, randomly, dosed at 45 mg (group A, n = 14), 90 mg (group B, n = 13), or 180 mg (group C, n = 13). Plasma gonadotropins, estrone, E2, and progesterone were measured. An endometrial biopsy was performed on day 20 (n = 20) or 24 (n = 20) for endometrial dating and for estrogen and progesterone receptor determinations. Plasma estrogen levels were in the menstrual cycle range. Mean progesterone levels were lower in group A (2.4 +/- 0.2 ng/mL) than in group B (3.6 +/- 0.2 ng/mL) or C (3.4 +/- 0.4 ng/mL) (P < .005). Plasma FSH and LH decreased significantly during progesterone treatment. In all groups, we observed secretory transformation in the glands (day 20) and stroma (day 24) and the distribution of estrogen and progesterone receptors seen in normal menstrual cycles. Transvaginal administration of progesterone induced normal secretory transformation of the endometrium despite low plasma levels, suggesting a direct transit into the uterus or "first uterine pass effect."
Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive.
Thyroid and Metabolic Function · Insulin and Metabolism
To evaluate the complications and outcome of pregnancy in women with polycystic ovary disease (PCOD). The course and outcome of 47 singleton pregnancies in women with well-documented PCOD were compared with those in 100 healthy controls. Women with PCOD had a significantly higher body mass index as compared to the control group (P < .05); however, the proportion of lean versus obese subjects in the two groups was similar. The incidence of an abnormal glucose challenge test, gestational diabetes mellitus and pregnancy-induced hypertension was significantly increased in pregnant women with PCOD (P < .05). When lean PCOD subjects were compared with lean control subjects, the difference in the incidence of the above complications was still significant (P < .05). The incidence of pregnancy complications was similar when obese PCOD subjects were compared with obese controls. Women with PCOD were at increased risk of gestational diabetes and pregnancy-induced hypertension, and this risk appeared to be independent of body mass index.
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproductive age women characterized in its broadest definition by the presence of oligoamenorrhea and hyperandrogenism and the absence of other disorders. Defects of gonadotropin secretion, including an elevated LH level, elevated LH to FSH ratio, and an increased frequency and amplitude of LH pulsations have been described, but the prevalence of these defects in a large, unbiased population of PCOS patients has not been determined. Sixty-one women with PCOS defined by oligomenorrhea and hyperandrogenism and 24 normal women in the early follicular phase had LH samples obtained every 10 min for 8-12 h. Pool LH levels from the frequent sampling studies were within the normal range in the 9 PCOS patients (14.8%) who were studied within 21 days after a documented spontaneous ovulation. Excluding these post-ovulatory patients, 75.0% of the PCOS patients had an elevated pool LH level (above the 95th percentile of the normal controls), and 94% had an elevated LH to FSH ratio. In the anovulatory PCOS patients, pool LH correlated positively with 17-OH progesterone (R = 0.30, P = 0.03), but not with estradiol, estrone, testosterone, androstenedione, or DHEA-S. Pool LH and LH to FSH ratio correlated positively with LH pulse frequency (R = 0.40, P = 0.004 for pool LH, and R = 0.39; P = 0.005 for LH/FSH). There was also a strong negative correlation between pool LH and body mass index (BMI) (R = -0.59, P < 10(-5)). The relationship between BMI and LH secretion in the PCOS patients appeared to be strongest with body fatness, as pool LH was correlated inversely with percent body fat, whether measured by skinfolds (R = -0.61, P < 10(-5)), bioimpedance (R = -0.55, P < 10(-4)), or dual energy x-ray absorptiometry (DEXA) (R = -0.70, P = 0.001; n = 18 for DEXA only). By DEXA, the only body region that was highly correlated with pool LH was the trunk (R = -0.71, P = 0.001). The relationship between body fatness and LH secretion occurred via a decrease in LH pulse amplitude (R = -0.63, P < 10(-5) for BMI; R = -0.58, P < 10(-4) for bioimpedance; and R = -0.64, P = 0.004 for whole body DEXA), with no significant change in pulse frequency with increasing obesity (R = -0.17, P = 0.23 for BMI). 1) the prevalence of gonadotropin abnormalities is very high in women with PCOS selected on purely clinical grounds, but is modified by recent spontaneous ovulation; 2) the positive relationship between LH pulse frequency and both pool LH and LH to FSH ratio supports the hypothesis that a rapid frequency of GnRH secretion may play a key etiologic role in the gonadotropin defect in PCOS patients; 3) pool LH and LH pulse amplitude are inversely related to body mass index and percent body fat in a continuous fashion; and 4) the occurrence of a continuous spectrum of gonadotropin abnormalities varying with body fat suggests that nonobese and obese patients with PCOS do not represent distinct pathophysiologic subsets of this disorder.
The objective was to verify the hypothesis of a 'first uterine pass effect' or direct preferential vagina-to-uterus transport, suggested by the evidence of higher than expected uterine tissue concentrations after vaginal administration of progesterone; we used a human ex-vivo uterine perfusion model. A mixture of tritiated (3H) and unlabelled progesterone was applied to the cuff of vaginal tissue remaining attached to the cervix after hysterectomy. At the end of the perfusion period (up to 12 h), 3H and 14C radioactivity was measured in samples of uterine tissue. Tritiated water and [14C]dextran were tested to determine the extent of non-specific vagina-to-uterus transport (leaks). Finally, sections of uterine tissue exposed only to [3H]progesterone were prepared for autoradiography. By 4-5 h after application progesterone had diffused to the entire uterus and had reached a steady state; 4 h after application, progesterone concentrations reached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrial tissue respectively. Endometrial extraction of progesterone was higher when the experiment was performed on uteri obtained during the luteal phase (280 +/- 156 ng/100 mg of endometrial tissue) than those removed during the proliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg of endometrial tissue). These data demonstrate that a 'first uterine pass effect' occurs when drugs are delivered vaginally, thereby providing an explanation for the unexpectedly high uterine concentrations relative to the low serum concentration observed after vaginal administration. Hence, the vaginal route permits targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.
We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta2-adrenoceptors (beta2-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta2-AR regulation seen in healthy women, in that there is no luteal phase rise in beta2-AR. It has been postulated that abnormal cyclical regulation of beta2-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta2-AR regulation in female asthmatics during the follicular phase, when endogenous hormone levels are normally low. Seven nonsmoking female subjects with mild asthma, with a mean (SEM) age of 26 (2) years and FEV1 of 94.7% (6.4) of predicted, completed this randomized, double-blind, crossover study. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol (ethinyloestradiol), 50 microg, or medroxyprogesterone, 10 mg. Lymphocyte beta2-AR parameters were evaluated at baseline (T0), 24 h (T24), and 72 h (T72) after ingestion. Baseline levels of progesterone and estradiol were comparable on both cycles. Receptor binding density (log Bmax; fmol/10(6) cells) decreased significantly after progesterone but not after estrogen at T24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T24 vs T0 with progesterone. Comparing Bmax for progesterone with estrogen at T24 amounted to a 1.25-fold significant difference (95% CI, 1.00 to 1.56). This was associated with a trend (p=0.06) toward a lower cyclic-adenosine monophosphate (AMP) response to isoproterenol hydrochloride (isoprenaline) 10(-4) M (Emax) at T24 vs T0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given during the follicular phase, decreased beta2-AR density and cyclic-AMP response in female asthmatics, in contrast to the previously observed up-regulating effect of progesterone seen in healthy women. This paradoxical effect of progesterone in female asthmatics suggests an abnormal regulation of beta2-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.
To evaluate effectiveness and safety of a regimen of extended clomiphene citrate (CC) and prednisone for patients who fail treatment with CC alone. Retrospective observational analysis. University-based tertiary infertility center. PATIENT(S): Twenty-four anovulatory patients who failed to ovulate after CC 150 mg administered for 5 days. INTERVENTION(S): Treatment consisted of CC given on cycle days 3 through 9 (extended) at a starting dose of 100 to 150 mg/d. Additionally, patients were given prednisone 5 mg orally each night throughout the cycle. MAIN OUTCOME MEASURE(S): Ovulation was confirmed by luteal serum P. Pregnancy was confirmed by rising hCG levels and transvaginal ultrasound. RESULT(S): A total of 60 cycles were available for review. Forty-four of these cycles were ovulatory (73%) and 11 patients (46%) conceived on this therapy. Logistic (two-parameter) pregnancy occurrence over time (cycles) revealed a maximum pregnancy probability of 0.66 and a cycle fecundity of 0.36. No complications of therapy were noted. CONCLUSION(S): Clomiphene citrate-resistant anovulatory patients have high rates of ovulation and pregnancy after treatment with extended CC and prednisone. This therapy offers a potential reduction in cost and risk and should be considered in this group of patients before gonadotropin stimulation or surgery.
Progesterone is a known immunosupressant in humans and may be important in treatment regimens for women with immunological and endocrinological reproductive failure. The molecular mechanism of progesterone-mediated immunosuppression remains controversial. We used the reverse transcriptase polymerase chain reaction (RT-PCR) technique to detect progesterone receptor RNA in human peripheral blood mononuclear cells (PBMCs). No expression could be documented in PBMCs from men or women representing various reproductive states. We also used the glucocorticoid receptor antagonist RU 43044 to address the hypothesis that progesterone exerts immunomodulatory effects via interactions with the glucocorticoid receptor. Both hydrocortisone (10(-6) and 10(-7) M) and progesterone (10(-5), 10(-6) and 10(-7) M) inhibited phytohaemagglutinin-induced lymphocyte proliferation in a dose-dependent fashion. RU 43044 (10(-5) M) significantly reversed the immunosuppressive effect od hydrocortisone but not that of progesterone. These studies indicate that human PBMCs do not express the classical progesterone receptor. Our results further suggest that progesterone does not mediate its immunomodulatory effects via interaction with the glucocorticoid receptor. Interaction with other members of the steroid and thyroid hormone receptor superfamily, local conversion to other steroid substances or non-classical receptor-mediated mechanisms may be involved.
Klein NA et al., 1996·The Journal of clinical endocrinology and metabolism
Women experience a decline in fertility that precedes the menopause by several years. Previous studies have demonstrated a monotropic rise in FSH associated with reproductive aging: however, the mechanism of this rise and its role in the aging process are poorly understood. The purpose of this study was to characterize ovarian follicular development and ovarian hormone secretion in older reproductive age women. Sixteen women, aged 40-45 yr, with regular ovulatory cycles were studied. The control group consisted of 12 ovulatory women, aged 20-25 yr. Serum obtained by daily blood sampling was analyzed for FSH, LH, estradiol (E), progesterone, and inhibin (Monash polyclonal assay). Follicle growth and ovulation were documented by transvaginal ultrasound. Older women had significantly higher levels of FSH throughout the menstrual cycle. E, progesterone, LH, and inhibin levels did not differ between the two age groups when compared relative to the day of the LH surge. Ultrasound revealed normal growth, size, and collapse of a dominant follicle in all subjects. Older women had significantly shorter follicular phase length associated with an early acute rise in follicular phase E, reflecting accelerated development of a dominant follicle. We conclude that older reproductive age women have accelerated development of a dominant follicle in the presence of the monotropic FSH rise. This is manifested as a shortened follicular phase and elevated follicular phase E. The fact that ovarian steroid and inhibin secretion were similar to those in the younger women suggests that elevated FSH in women of advanced reproductive age may represent a primary neuroendocrine change associated with reproductive aging.
The relationship between symptoms of premenstrual syndrome (PMS) and serum levels of pregnenolone (Pe), pregnenolone sulfate (PS), 5 alpha-pregnane-3,20-dione (5 alpha-DHP), 3 alpha-hydroxy-5 alpha- pregnan-20-one (5 alpha-THP), LH, 17 beta-estradiol (E2), and progesterone (P) was investigated during 2 consecutive menstrual cycles in 12 patients using daily measurements. Corresponding hormones were also measured during 1 cycle in 8 control women. Pe, PS, 5 alpha-DHP, and 5 alpha-THP showed a significant cyclicity within menstrual cycles and a high rate of correlation with P variation in both PMS patients and controls. No significant difference was found between PMS patients and controls in average serum concentrations of Pe, PS, 5 alpha-DHP, 5 alpha-THP, and LH during the luteal phase, whereas a significantly higher level of E2 and a lower level of P were observed in PMS patients. The variation in symptom scores was compared with that in hormone levels within each woman. The symptom peak showed a delay of 3-4 days after the serum P, Pe, 5 alpha-DHP, and 5 alpha-THP peaks. However, the plasma PS peak appeared on the same day or only 1 day before the symptom peak in PMS patients. When comparing the 2 cycles studied, more negative symptoms occurred in cycles with higher luteal phase E2, Pe, and PS concentrations, whereas higher luteal phase 5 alpha-DHP and 5 alpha-THP concentrations were associated with improved symptom ratings in PMS patients. These results suggest that the mentioned steroids are related to the severity of distressing symptoms in PMS patients.
The pulsatile release pattern of LH during the entire menstrual cycle is well defined; however, the response of corpora lutea to these LH pulses in patients suffering from corpus luteum insufficiencies (CLI) is largely unknown. Patients suffering from CLI were selected from infertile patients on the basis of low progesterone (P < 25 nmol/L) in a blood sample withdrawn during a monitoring cycle. During the next cycle, nine blood samples were collected during the follicular and luteal phase and follicular development was assessed by vaginal sonography. Of 109 patients who had a CLI in the monitoring cycle, 55 had a CLI again, and 38 women agreed to undergo assessment of pulsatile hormone secretion. These women again had P < 25 nmol/L at days 6 and 7 of the luteal phase and blood samples were withdrawn through antecubital vein catheters from 0900-1700 h at 10-min intervals on days 7, 8, or 9 following ovulation. From 38 patients with such defined CLI, 16 (42%) had no LH episode and significantly lower basal LH levels in comparison with 14 control subjects. Thirteen (34%) of the patients had normal appearing LH episodes despite too low P and E2 concentrations, but their CL did not react to the LH episodes. The remaining 9 patients (24%) had normal LH episodes; their CL reacted to these episodes, but their basal P levels were too low. In all blood samples LH was not only determined using an immunoassay but also by the mouse Leydig cell testosterone production bioassay. It could be established that no CLI exists, which is due to the release of bioinactive LH. It is anticipated that the differentiation of three different types of CLI, one of hypothalamic and two of ovarian origin, may allow the development of differential diagnostic and therapeutic tools in the future.
To characterize women with idiopathic premature ovarian failure (POF) by their ovarian ultrasonographic appearances to establish the prevalence of follicular activity and relationship to autoimmunity, estrogen status, and historical background. Retrospective analysis of clinical, endocrine, autoimmune, ultrasonographic, and bone densitometry parameters. Reproductive Endrocrinology Clinics of The Middlesex Hospital, London, United Kingdom. Data from 135 women with idiopathic POF were analyzed. A reference group of 18 women with normal ovarian function, studied in their follicular phase, was used for comparison of endocrine and ultrasound data. A reference group of 57 women with normal ovarian function was used for comparison of bone densitometry measurements. Serum E2 concentrations, autoantibody screen, ultrasonographic measures of ovarian volume, uterine cross-sectional area and endometrial thickness and dual roentgenogram bone mineral densitometry of the lumbar spine. The detection of ovaries by ultrasound (in 76%) and follicular activity (in 60% of patients) was associated with higher bone mineral density compared with women in whom ovaries could not be identified. Of 13 patients presenting with primary amenorrhea, ultrasonography identified ovaries in 62% and follicles in 38% whereas 38% had positive autoimmunity. Evidence of autoimmunity was found in 31% of patients overall and these were indistinguishable from the nonautoimmune remainder in every respect. Ovarian follicular activity, previously considered to be rare, as in the "resistant ovary syndrome," is found in the majority of women with POF using pelvic ultrasonography. Patients presenting with primary amenorrhea have a similar degree of ovarian function, determined by ultrasound, and autoimmunity as those presenting with secondary amenorrhea. The role of autoimmunity in the pathogenesis of POF is not distinguished from nonautoimmune ovarian damage by the measurements made in this study.
To assess the efficacy of IVP-ET in infertile women with the polycystic ovary syndrome (PCOS) and to provide a comprehensive review of contemporary therapeutic options and their complications as reflected in the current literature. Pertinent studies in medical literature identified through computerized bibliographic search and via manual review of relevant scientific publications. In vitro fertilization and ET is an effective therapy for PCOS patients who are refractory to ovulation induction in vivo or who have coexisting infertility factors. The use of GnRH agonist (GnRH-a) is associated with significant reductions in the incidence of pregnancy loss and may improve fertilization and cleavage rates. In the PCOS patient, the use of purified FSH preparations does not appear to improve pregnancy rates nor other clinical parameters when compared with hMG. Severe ovarian hyperstimulation syndrome (OHSS) is an important consideration when PCOS patients undergo superovulation protocols. Strategies for OHSS prevention include the use of intravenous albumin immediately after oocyte retrieval, triggering of ovulation with a GnRH-a, or withholding menotropin therapy for several days before hCG administration. Cryopreservation of all embryos for future transfer in an artificial cycle has also proven to be an effective alternative in PCOS patients at high risk for severe OHSS. Pregnancy rates for PCOS patients undergoing IVF-ET are comparable with those for women with tubal factor infertility. Therefore, IVF-ET should be offered to patients with PCOS who are refractory to conventional infertility modalities.
Recent data indicate that an altered opioid tone could be involved in the LH hypersecretion and metabolic alterations seen in polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the presence of a common mechanism of action of opioids on altered insulin and gonadotropin release in patients suffering from PCOS. Twenty-eight women affected by PCOS and 8 normal ovulatory women were studied; an oral glucose tolerance test (OGTT) and GnRH tests were performed during the follicular phase before and after 6 weeks of naltrexone treatment (50 mg/day, orally). Plasma levels of sex hormone-binding globulin and steroids were assayed in the basal samples, whereas FSH and LH were analyzed during the GnRH stimulus. Insulin and glucose were assayed by the OGTT. Based on the insulinemic response to OGTT, 17 women were classified as hyperinsulinemic and 11 as normoinsulinemic. No difference in glucose and hormone plasma concentrations was observed before and after naltrexone treatment in both groups. Only basal sex hormone-binding globulin values were higher in normoinsulinemic compared to hyperinsulinemic subjects. Administration of the opioid antagonist significantly reduced the insulin response to OGTT only in the hyperinsulinemic group. No difference were found in the LH increment after the GnRH stimulus in both group of patients before treatment; on the contrary, naltrexone administration reduced the LH response to GnRH in hyperinsulinemic women but failed to be effective in normoinsulinemic subjects. Only 5 patients showed no concordance of drug-induced changes in insulin and LH secretion. In control subjects, naltrexone failed to have any effect on insulin or LH secretion. These data support the involvement of endogenous opioids in the regulation of insulin and LH secretion in a specific group of PCOS patients exhibiting an exaggerated insulin response to OGTT.
Rossi AM et al., 1995·Eur J Obstet Gynecol Reprod Biol·
The outcome of 103 pregnancies in 64 women with constant hyperprolactinemia was evaluated. Seventy-eight pregnancies had been induced with bromocriptine and 25 occurred without any treatment. In all, 66% of the pregnancies ended in delivery, 17% in miscarriage, 10% in tubal pregnancy and 7% in induced abortion. The pregnancy of women with untreated hyperprolactinemia was more frequently ectopic when compared to those in women treated by bromocriptine. Obstetric complications as well as signs of tumoral enlargement during pregnancy were rare in hyperprolactinemic women treated or untreated with bromocriptine. Untreated hyperprolactinemia as a risk factor in tubal pregnancy is proposed.
To explore the pulsatile-release characteristics of LH and P in women with premenstrual syndrome (PMS) compared with age-matched phase-matched controls. Prospective, repeated measures, two-group study. Human volunteers in an academic research environment. Six women with rigorously defined prospectively determined PMS; six age-matched phase-matched controls. Frequency, amplitude, concentration, and coincident pulsatile release characteristics of LH and P at three symptom-related points of the luteal phase. No significant between-group differences in frequency, amplitude, or concentration were found. In pooled data, significant coincident pulsing between LH and P was demonstrated. The length of time between LH and P pulses systematically increased across the luteal phase, a finding not previously reported. In the PMS group only, significant coincident pulsing occurred at an unexpected zero time lag on the symptom-onset sampling day. A progressively increasing coupling interval may reflect the gradual decline of the corpus luteum. Presence of a zero time lag between LH and P at symptom onset in women with PMS may indicate an aberrance in corpus luteum response to LH stimulation.
Vaginal progesterone suppositories are an accepted treatment for infertility attributed to luteal phase defects. Although oral micronized progesterone may be preferable to suppositories for many patients, there are no studies on its use for patients with luteal phase defects. This study evaluated the efficacy of oral micronized progesterone for the treatment of luteal phase defects. Seven women with luteal phase defects previously corrected by vaginal suppositories were administered oral micronized progesterone (200 mg by mouth three times a day). Endometrial biopsies were performed to evaluate treatment efficacy. Questionnaires were used to assess side effects, including sedation. On oral micronized progesterone, all patients had in-phase endometrial biopsies. Despite complaints of drowsiness, the majority of patients preferred the oral formulation over the vaginal route of administration. We conclude that oral micronized progesterone is efficacious in the treatment of luteal phase defects.
To correlate luteal estradiol (E2) levels with pregnancy outcome, 36 consecutive conceptions resulting from gamete intrafallopian transfer in gonadotropin releasing hormone agonist/human menopausal gonadotropin (GnRH-a/hMG) cycles were analyzed. GnRH-a was initiated during the preceding luteal phase. HMG was adjusted individually. Human chorionic gonadotropin (hCG), 5,000 IU, was administered when E2 was > 500 pg/mL and the leading follicle > 17 mm (day 0). The luteal phase was supported by (1) hCG, 1,500 IU in three doses from day 5 and (2) progesterone (P) from day 7. E2 and P levels were analyzed in three groups of normally progressing pregnancy (NPP), abortion (AB) and preclinical abortion (PAB). No significant differences in mean E2 levels were seen between the groups from day 0 through day 5 after hCG. Midluteal E2 levels were significantly different between the groups (P < .05). Late luteal E2 values were significantly higher for NPP than for either AB or PAB (P < .05). There were no significant differences in luteal P values between the NPP, AB and PAB groups. Decreased luteal E2 appears to be associated with early pregnancy wastage; this may be due to inadequate endometrial support.
To examine the role of steroid hormone receptor compartmentalization in infertile women with "in-phase" or "out-of-phase" endometrium. Nonrandomized prospective clinical study. A university clinic. Twenty-nine infertile patients without evidence of endometriosis, tubal factor, male factor, galactorrhea, or hyperandrogenism were enrolled. Sixteen patients had in-phase endometrium and a P level > or = 10 ng/mL (conversion factor to SI unit, 3.18) (group A). Four patients had out-of-phase endometrium and a P level > 10 ng/mL (group B). Four patients had in-phase endometrium and a P level < 10 ng/mL (group C), and five patients had out-of-phase endometrium and a P level < 10 ng/mL (group D). Each patient underwent determination of serum P and endometrial sampling on postovulatory days 6 to 9 based on serum LH measurement. Dating according to endometrial histology and biochemical assessment of estrogen receptor (ER) and P receptor (PR) were performed on each sample. The level of cytosol ER was significantly lower in out-of-phase endometrium regardless of serum P level. There were no significant differences in the levels of cytosol PR and nuclear ER and PR among groups. In a long-term follow-up study, 6 of 29 patients became pregnant. The cytosol ER:PR ratio in these patients was found to fit a single straight regression line (y = 0.34x - 2.2). Out-of-phase endometrium probably depends on inadequate cytosol ER. An appropriate cytosol ER:PR ratio may be important to become pregnant.
We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.
The purpose of this study was to examine the effects of menstrual cycle phase on four selected indices of athletic performance: aerobic capacity, anaerobic capacity, isokinetic strength, and high intensity endurance. Sixteen eumenorrheic women (VO2max > or = 50 ml.kg-1.min-1) were tested during the early follicular (F) and midluteal (L) phases of the menstrual cycle. Cycle phases were confirmed by serum estradiol and progesterone assays. No significant differences were observed between F and L tests in weight, percent body fat, sum of skinfolds, hemoglobin concentration, hematocrit, maximum heart rate, maximum minute ventilation, maximum respiratory exchange ratio, anaerobic performance, endurance time to fatigue (at 90% of VO2max), or isokinetic strength of knee flexion and extension. Both absolute and relative VO2max, however, were slightly lower in L than in F (F = 3.19 +/- 0.09.min-1, L = 3.13 +/- 0.08.min-1, P = 0.04; and F = 53.7 +/- 0.9 ml.kg-1.min-1, L = 52.8 +/- 0.8 ml.kg-1.min-1, P = 0.06). These results suggest that the cyclic increases in endogenous female steroid hormones of an ovulatory menstrual cycle may have a slight, deleterious influence on aerobic capacity, with potential implications for individual athletes. Nevertheless, the cycle phase did not impact significantly on the majority of the other performance tests and cardiorespiratory variables measured in this study.
The present study extends a previous report of lower plasma ACTH levels in women with premenstrual syndrome (PMS) compared with asymptomatic controls. Plasma levels of estradiol and progesterone were measured daily in 10 women with confirmed PMS and 8 asymptomatic women. Daily symptom reports were maintained during the same menstrual cycle. Both estradiol and progesterone levels were consistently, but not significantly, higher throughout the cycle in PMS subjects compared with controls. From the follicular to the early luteal phase, estradiol levels were significantly higher in a previously defined PMS subgroup 2 with more severe symptoms throughout the cycle compared with both the less severe PMS subgroup 1 and controls. Progesterone levels were significantly and positively correlated with PMS symptoms along the entire menstrual cycle, preceding the symptoms by 5-7 days. These preliminary results provide support for the hypothesis that the presence of progesterone at early luteal phase levels is required for PMS symptoms to occur.
To determine whether luteal phase defect (LPD) may be an etiologic factor in ectopic pregnancy (EP). All patients who were seen over a 6-year period with the chief complaint of infertility underwent an extensive infertility workup and were followed prospectively. The diagnoses of the causes of infertility were assigned retrospectively. Two hospital-based tertiary care reproductive endocrine-infertility units. A total of 1,077 infertility patients were evaluated. Of the 633 who became pregnant, the infertility had been due to LPD in 51 and to anovulation in 210. All the infertility patients who became pregnant were followed to determine whether they miscarried, developed an EP, or had a viable birth. The incidence of EP and miscarriage in the patients whose infertility was found to be due to LPD were compared with a control group in whom the infertility was due to anovulation. The EP rate in the patients with LPD was significantly higher than in a control group whose infertility was due to anovulation (6 of 51 pregnancies versus 6 of 210 pregnancies, respectively). The spontaneous abortion rate in LPD cases also was highly significantly greater than in the control group (19 of 51 pregnancies versus 12 of 210 pregnancies, respectively). The EP and spontaneous abortion rates also were higher in patients with LPD who were untreated than in those who were treated. This study suggests that there is a significantly increased incidence of tubal EP in patients with LPD and that when patients with LPD become pregnant early ultrasound should be performed to rule out EP. The study also indicated that spontaneous abortion occurs in a significantly high percentage of LPD cases.
This chapter has presented a somewhat complex view of the gonadotrope population, indicating that it consists of independent subsets. There may be regulatory cells that influence development and other ancillary processes needed for normal reproduction. For example, normal differentiation of PRL cells requires a functioning population of gonadotropes (Kendall et al., 1991). In addition, gonadotropes appear to be autoregulatory; subsets may produce inhibin or activin (in rats) and follistatin. Production of GnRH itself may serve as another regulatory tool. The gonadotrope population appears to be quite dynamic and convertible in the female rat. Cytological and cytochemical changes with the stage of the cycle are obvious. Increases in the numbers of immunoreactive gonadotropes parallel increases in GnRH target cells and culminate in peak expression of LH and FSH beta subunit mRNAs. The immunoreactive gonadotropes are greatly reduced after the surge activity, as though the cells had disappeared from the population. However, gonadotropes can still be detected by their content of gonadotropin mRNAs. This finding has led to the hypothesis that the gonadotropes recycle themselves. However, do they go through a resting phase? Is there a normal cycle of cell death and turnover? These are basic questions that must be answered in order to understand how the population is organized and renewed. Finally, we have returned to one of our original problems. Whereas it is clear that nonparallel release can be brought about by granules or cells with only one gonadotropin, the exact mechanisms that sort the gonadotropin molecules or turn off bihormonal expression are not known. A combination of autoregulatory events involving follistatin, activin, inhibin, and possibly steroids may play a role in modulating expression by a given subset. Delays in maturation may also prevent secretion of FSH and, hence, effect the delayed rise seen during late proestrus. The nonsecretory FSH cells seen in the studies by Lloyd and Childs (1988a) may be delayed maturers, requiring additional receptor types or changes in the calcium flux pattern to secrete their product. We also have a new question to address. What is the significance of the presence of GH in proestrous gonadotropes? Is GH a regulatory hormone, bound to receptors inside gonadotropes, or do subsets of somatotropes augment the population, producing a cocktail of GH and gonadotropins to aid ovulation? Either hypothesis is intriguing. Co-storage of GH and gonadotropins would be an efficient way of providing the hormones needed by the ovary. However, further work with in situ hybridization is needed to detect GH mRNA in such cells.(ABSTRACT TRUNCATED AT 400 WORDS)
To determine pharmacokinetic and endometrial effects of vaginally delivered micronized P. Functionally agonadal estrogen-replacement recipients received either micronized P administered vaginally or bi-daily IM injections of P. Hourly blood samples were obtained, from baseline to 6 hours after the initial dose of P and again on simulated cycle day 21 when transvaginal ultrasound (US) measurements and tissue samples of the endometrium were performed. Blood and tissue samples were assayed for P. Endometrial histology, estrogen receptor (ER) and P receptor (PR) contents were evaluated. University of Southern California School of Medicine, Los Angeles, California. Twenty functionally agonadal and four normally ovulating women. Delivery differences were assessed by [1] endometrial P concentrations; [2] USs; [3] histologic datings; [4] ER and PR contents, and [5] serum P levels. Endometrial P concentrations were higher with vaginally administered P than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum P after IM administration (11.50 +/- 2.60 versus 1.40 +/- 0.40 versus 0.30 +/- 0.10 ng/mg protein [36.56 +/- 8.27 versus 4.45 +/- 1.27 versus 0.95 +/- 0.32 nmol/L], respectively). After 7 days of P, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses. Vaginal micronized P enhances P delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.
To determine the ability of luteal phase length determined by basal body temperature (BBT) pattern and a midluteal serum progesterone level to predict the result of an endometrial biopsy in a subsequent cycle. We performed a retrospective analysis of 141 women with a history of infertility who were being evaluated for luteal function. The luteal phase length determined from a BBT chart of one menstrual cycle was compared to a single midluteal serum progesterone level from a second menstrual cycle. These findings were compared to a luteal phase endometrial biopsy performed in a third menstrual cycle. Subjects were divided into four groups depending upon luteal phase length (normal 11 or more days) and serum progesterone level (normal at least 10 ng/mL). The four groups were designated "normal," "short luteal phase," "low progesterone," and "abnormal," depending upon the results of the two tests. The frequency of in- and out-of-phase endometrial biopsy results in the four groups was compared. There was no difference in the occurrence of an in- or out-of-phase endometrial biopsy when the four groups were compared. Neither luteal phase length nor a single midluteal serum progesterone level was predictive of subsequent in-phase or out-of-phase endometrial biopsy.
To examine whether luteal E2 is obligatory for obtaining an adequately developed endometrium. Survey of women with premature ovarian failure (POF) in a prospective, controlled, randomized study. In vitro fertilization unit in a tertiary care university medical center. Fourteen amenorrheic women with POF, candidates for oocyte donation, were divided into two distinct groups with seven women in each subgroup. Endometrial priming with a fixed dose of oral micronized E2, 4 mg/d for 14 days, was similarly performed in the study and the control groups. Progesterone replacement during the luteal phase was also identical in the two groups and was accomplished by IM P in oil, 50 mg/d for another 14 days. Only the control group continued to have the same E2 regimen during the luteal phase. Follicular phase mean E2 levels as well as luteal phase mean P levels were similar in both groups. However, luteal E2 levels differed significantly between the study and the control groups (21 +/- 5 and 692 +/- 199 pg/mL, respectively; conversion factor to SI units, 3.671). Nevertheless, histologic evaluation of endometrial biopsies on days 21 and 26 were similar for both groups. Endometrial gland dating, using light microscopy in the study and the control groups, on day 21, was 19.1 +/- 0.8 and 18.4 +/- 0.5, respectively, and on day 26, 25.4 +/- 0.8 and 25.9 +/- 0.5, respectively. Dating of the stroma in the two biopsies was also similar in both groups. Moreover, transmission electron microscopy performed in two patients of the study group showed typical characteristics of a secretory endometrium. Luteal E2 depletion in the human does not seem to adversely affect the morphological developmental capacity of the endometrium. Our results suggest that E2 secretion by the corpus luteum in the human does not appear to be obligatory for the development of a normal secretory endometrium. The actual receptivity of the endometrium after such preparation needs to be evaluated.
To determine whether the use of luteal phase support improves pregnancy rate (PR) in infertility. A meta-analysis of randomized trials of luteal phase support. Search of the National Library of Medicine MEDLINE data base from 1971 using the words luteal, pregnancy, human, and comparative. Bibliography of relevant articles, reviews, and abstracts of scientific meetings were hand searched. All randomized controlled trials of luteal phase support in infertility were included. Luteal phase support for recurrent abortion and nonrandomized trials were excluded. The common odds ratio was calculated for each intervention using the Mantel-Haentzel test. Homogeneity of treatment effect was evaluated using the Breslow-Day test. Pregnancy per cycle, rate of spontaneous abortion, and ovarian hyperstimulation syndrome rate. Eighteen trials met the above criteria. Human chorionic gonadotropin improved PRs in IVF when GnRH agonist (GnRH-a) was used (n = 151) and was superior to P (n = 352). Its benefit in all IVF cycles, however, was not established because of significant heterogeneity of treatment effect. Progesterone improved the PR in all IVF cycles (n = 457). No significant reduction in spontaneous abortion was noted with luteal support (n = 200). Ovarian hyperstimulation syndrome occurred in 5% of patients with hCG. Combination of data from trials of luteal support with other infertility therapies was not possible because of the differences in patient populations. The meta-analysis supports the routine use of hCG in IVF cycles using a GnRH-a. Progesterone was also beneficial for luteal phase support in IVF. For other infertility therapy, however, further research is needed to evaluate the role of luteal phase support.
To establish age-stratified reference values for salivary luteal P levels. One hundred thirty-six regularly menstruating women (18 to 48 years of age), screened for weight, exercise, and steroid medication use, collected daily saliva samples for one complete menstrual cycle. Luteal P levels were measured by 3H-RIA, and data were aligned by day of next menstrual onset. Means (+/- 1 SD range) and percentiles, calculated using both untransformed and log transformed data, were calculated for each luteal day and for indices of luteal P production. Reference values for salivary daily luteal P levels and indices of luteal P are presented for three age groups (18 to 24 years, 25 to 39 years, and 40 to 48 years). The age-stratified reference values presented here can be used, without collateral clinical procedures, to assess salivary luteal P levels. Salivary monitoring is ideally suited for research and long-term clinical observation, but the characteristics of salivary P data may limit the usefulness of these values for individual diagnosis.
Lignans are a group of phytochemicals shown to have weakly estrogenic and antiestrogenic properties. Two specific lignans, enterodiol and enterolactone, are absorbed after formation in the intestinal tract from plant precursors particularly abundant in fiber-rich food and are excreted in the urine. We evaluated the effect of the ingestion of flax seed powder, known to produce high concentrations of urinary lignans, on the menstrual cycle in 18 normally cycling women, using a balanced randomized cross-over design. Each subject consumed her usual omnivorous, low fiber (control) diet for 3 cycles and her usual diet supplemented with flax seed for another 3 cycles. The second and third flax cycles were compared to the second and third control cycles. Three anovulatory cycles occurred during the 36 control cycles, compared to none during the 36 flax seed cycles. Compared to the ovulatory control cycles, the ovulatory flax cycles were consistently associated with longer luteal phase (LP) lengths (mean +/- SEM, 12.6 +/- 0.4 vs. 11.4 +/- 0.4 days; P = 0.002). There were no significant differences between flax and control cycles for concentrations of either estradiol or estrone during the early follicular phase, midfollicular phase, or LP. Although flax seed ingestion had no significant effect on LP progesterone concentrations, the LP progesterone/estradiol ratios were significantly higher during the flax cycles. Midfollicular phase testosterone concentrations were slightly higher during flax cycles. Flax seed ingestion had no effect on early follicular phase concentrations of DHEA-S, PRL, or sex hormone-binding globulin. Our data suggest a significant specific role for lignans in the relationship between diet and sex steroid action, and possibly between diet and the risk of breast and other hormonally dependent cancers.
To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. Prospective, randomized, open label crossover protocol with 7 days between dosages. Academic institution. Fifteen normal postmenopausal women. All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. Serum P concentrations were measured in all groups. Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.
To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). Tertiary University Institution, Hôpital A. Béclère. PATIENTS, Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.
Induction of ovulation is indicated for anovulatory and amenorrheic women as well as for women who have an inadequate luteal phase. It is also indicated as a strategy for recruiting multiple follicles for women with unexplained infertility and those who are undergoing assisted reproductive technologies. The use of various agents and detection of ovulation are described. This includes a discussion of clomiphene citrate, bromocriptine, human menopausal gonadotropins, urinary follicle stimulating hormone and pulsatile gonadotropin releasing hormone therapy. Regimens, success rates and potential complications of each form of therapy are reviewed. Also discussed is the use of combination therapy and partial ovarian destruction.
Serum progesterone (P) levels were determined at the time of routine prenatal registration (227 patients) or upon presentation for evaluation of vaginal bleeding and/or abdominopelvic cramping/pain (135 patients). P associated with a normal intrauterine gestation was 24.63 +/- 4.19 (SD) ng/mL as compared with 6.29 +/- 2.43 ng/mL and 6.02 +/- 2.39 ng/mL for spontaneous abortions and ectopic gestations, respectively. Further, P differed between asymptomatic (11.92 +/- 9.61 ng/mL) and symptomatic patients (4.81 +/- 3.92 ng/mL) who were subsequently shown to have an abnormal gestation. By establishing a P cutoff point of < or = 14.2 ng/mL and < or = 10.5 ng/mL in asymptomatic and symptomatic patients, respectively, 100% screening sensitivity was reached, and therefore no abnormal gestations would escape detection in our study population. P was either in the normal or abnormal range as early as four weeks' estimated gestational age and persisted as such through the luteal-to-placental shift and up to the time of pregnancy loss or 12 weeks' estimated gestational age. Although there was no significant correlation between P and chorionic gonadotropin levels and pregnancy outcome, the binding constant for native chorionic gonadotropin was 15-52 times lower in 12 of 41 cases of spontaneous abortion but not ectopic gestation, suggesting a possible molecular basis for suboptimal P production. P is therefore an excellent adjunctive marker for prediction of early pregnancy outcome, and in some cases qualitative abnormalities in chorionic gonadotropin may dictate its production.
Ovarian laparoscopic resection was applied to 23 sterile patients affected with polycystic ovarian disease (PCOD) resistant to different pharmacological treatments, in order to induce ovulation. After resection, 56% of the patients had spontaneous ovulatory cycles and 13 pregnancies arose. Ten of the pregnancies were spontaneous and three followed treatment with clomiphene. Hormone changes were assessed in 15 patients, including five with spontaneous menstruation but without ovulation and five with persistent amenorrhoea for 3 months after resection. A significant decrease in both androstenedione and testosterone levels occurred in all patients. These decreases were not related to the clinical results of resection. Luteinizing hormone (LH) did not vary greatly in any group after resection. Mean values and mean pulsatility of follicle stimulating hormone (FSH) increased significantly only in pregnant patients or those with spontaneous ovulatory cycles. The results of gonadotrophin-releasing hormone (GnRH) assays did not change after resection. The mechanisms involved in the resumption of cyclic function of the hypophyseal-ovarian axis after resection are discussed briefly.
The null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment. Twenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects. Serum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days. The human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.
A physically active and athletic lifestyle is not only a healthy but a fulfilling choice for women. Although there is extensive literature on 'athletic amenorrhoea' which implies that exercise causes loss of the menstrual cycle, there is inadequate scientific evidence for a causal relationship. The reproductive system adapts to environmental, nutritional, emotional and physical stressors or 'threats' by downward adjustment towards the premenarcheal pattern. The hormonal milieu of this adaptation is low gonadal steroid and high glucocorticoid levels which synergistically increase the risk for a negative bone balance. Athletic women may become amenorrhoeic if reproductive immaturity, emotional stress and undernutrition coexist with increasing exercise loads. Treatment for athletic women with menstrual cycle changes requires that hypothalamic stressors be identified and decreased. In addition, as progesterone deficiency (from disorders of ovulation, whether flow is regular or absent) is the most prevalent menstrual cycle change, treatment with medroxyprogesterone on days 16 to 25 of their cycle will not only provide regular flow (if estrogen levels are sufficient) but will also promote increased bone density.
To determine if repetitive administration of hCG causes decreased pregnancy wastage rates in patients who are at a high risk of luteal inadequacy. Ovulation induction using human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defects that may cause increased pregnancy wastage. An increased risk of abortion exists also in pregnancies in patients with previous repeated miscarriage, women older than 37 years, and various causes of infertility such as hyperprolactinemia. Because the presumed common denominator to the increased rate of pregnancy wastage in all these cases is luteal dysfunction, repetitive hCG administration, 2,500 U two times weekly, was carried out between the 4th and 8th week of gestation in 249 cases of ovulation induction and/or previous abortions, whereas 198 gestations served as controls (no hCG administration). In the hCG treatment group, 43 ended in miscarriage (17.3%) versus 97 abortions in the control group (49%, P less than 0.01). In 160 cases of hMG/hCG generated gestations, 94 received hCG and 66 did not. The pregnancy wastage rates were 21.3% and 42.4%, respectively (P less than 0.05). In 144 cases of CC/hCG-induced pregnancies, 95 received hCG and 49 served as controls. The respective abortion rates were 15.8% and 44.8% (P less than 0.01). The remaining 143 spontaneous conceptions occurred in infertile patients with previous repeated abortions. In 60 of these conceptions, hCG was administered during the first 4 weeks of gestation and 83 cases served as control. The pregnancy wastage rates were 13.3% versus 56.6%, respectively (P less than 0.001). Repetitive administration of hCG during the early gestation in cases that are at high risk of luteal inadequacy may significantly decrease the pregnancy wastage rate.
Our purpose was to determine whether infertile patients who have endometriosis show luteal phase defects. The luteal function in 24 infertile patients who had endometriosis was compared with the luteal function in 20 patients who had unexplained infertility and did not have endometriosis (control). In both groups serum luteinizing hormone, follicle-stimulating hormone, progesterone, and estradiol were assayed every day throughout the menstrual cycle. Endometrial biopsy specimens were obtained from eight patients of the endometriosis group for histologic dating of the endometrium. No significant differences in progesterone levels were observed between these two groups during the mid and late luteal phase. Seven of the eight patients who underwent histologic dating showed a luteal phase pattern, whereas only one patient was out of phase. Infertile patients who have endometriosis do not always have luteal phase defects.
The premenstrual syndrome (PMS) has been proposed to result from excessive exposure to and/or withdrawal of brain opioid activity during the luteal phase. Because hypothalamic opioids are believed to modulate GnRH secretion, in part under the influence of ovarian steroids, we performed longitudinal studies of gonadotropin and ovarian steroid secretion across ovulatory, symptomatic cycles of 17 PMS patients and 8 normal volunteers. Pulsatile LH secretion was measured every 10 min for 8 hr at times when central opioid activity was expected to be low (early follicular phase), high (mid-luteal phase; ML), and declining (late luteal phase). In both subject groups, a cycle-phase effect was observed for LH pulse frequency (p = < 0.001) and amplitude (p = 0.002), and for the transverse mean concentrations of LH (p = 0.05), FSH (p < = 0.001), estradiol (E2) (p = < 0.001) and progesterone (P) (p = < 0.001). ML P secretion in PMS patients was pulsatile, and mean concentrations (over 30-60 min) were similar to those of normal controls. The changes in pulsatile LH secretion across the cycle were not different in the PMS patients compared to the normal women, though mean FSH in the ML phase was higher in the PMS group (p = < 0.05). The similar changes in luteal LH pulse frequency fail to provide evidence that GnRH secretion is impaired, thus challenging the view that the neuroregulation of the menstrual cycle in women with PMS is markedly altered.
It has become apparent in recent years that regulation of the ovulatory cycle cannot be accomplished solely through the mediation of the two pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Within the last decade, discoveries of additional regulatory mechanisms involved in the neuroendocrine control of the events of the ovulatory cycle have provided new insight into the control of this complex biological phenomenon (127). Among the most interesting of these discoveries are …
Blood samples were obtained during early follicular, periovulatory, and luteal phases in four women with out-of-phase endometrial biopsy specimens and four normal controls. In the study cycle, follicular development was evaluated and a late luteal phase endometrial biopsy was performed in each subject. Area under the luteal phase progesterone curve positively correlated with degree of maturity of the endometrial biopsy. Peak serum estradiol, maximum follicular diameter, and both immunoactivity and bioactivity of the preovulatory luteinizing hormone and follicle-stimulating hormone surges were similar in the luteal phase defect cycles as compared with normal cycles. Likewise luteinizing hormone bioactivity in the luteal phase of the luteal phase defect cycles was similar to that of normals. These data show that the immunoactivity and bioactivity of periovulatory and luteal phase gonadotropins may be normal in luteal phase defect cycles.
Cyclofenil is a triphenylethylene derivative, similar in structure to clomiphene citrate, which is used to induce ovulation in anovulatory women. The effects of cyclofenil on a group of 10 normal cyclic and 10 oligomenorrhoeic subjects were examined in a double blind controlled cross-over study. Both groups of women were administered either cyclofenil or, following a washout cycle, a placebo in two treatment cycles. Urinary oestrone and pregnanediol excretion were measured daily and ultrasound scans performed to assess follicular development. Frequent sampling of blood was performed on day 6 to study luteinizing hormone (LH) and follicle stimulating hormone (FSH) pulsatile release. Cervical mucus changes and sperm-cervical mucus interaction were studied after identification of the LH peak. There were no significant differences between cyclofenil and placebo cycles in the following: ovulation rates, daily urinary oestrone and pregnanediol excretion, the number or size of developing follicles, LH pulsatility (parameters studied: number of peaks, pulse interval, pulse amplitude, pulse area and mean nadir LH), mean FSH level on day 6, cervical mucus and sperm-cervical mucus interaction. In view of our inability to demonstrate an effect on any parameter of endocrine function in normal and oligomenorrhoeic women, these results throw doubt on the therapeutic value of cyclofenil in its present dosage and formulation.
To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.
In order to clarify the relationship between endometrial histology and progesterone (P4), plasma P4 and estradiol levels in the luteal phase were measured in 126 cases of unexplained infertility. Endometrial biopsies were performed in the midluteal period of menstrual cycles. Forty-three of the 126 cases showed retarded endometrium. Of these 43 cases, 23 exhibited three different types of abnormal P4 secretion. Type A showed low P4 levels throughout the luteal period. Type B showed low P4 levels only in the early luteal period. Type C showed normal P4 levels in the early luteal period followed by a prompt decline. These findings indicated that P4 determination during the early, mid- and late luteal phases is necessary to assess P4 secretion. However, 20 of the 43 cases had normal P4 levels through the entire luteal phase, demonstrating an insufficient response of the endometrium to P4. Consequently, histological examination of the endometrium is required to investigate the luteal phase defect.
A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of LUF syndrome were identified: mature follicle LUF, in which release of an ovum was not demonstrated after a follicle attained maturity (serum estradiol reached 200 pg/mL while serum progesterone remained less than 2.5 ng/mL), versus premature luteinization LUF, where the serum progesterone increased above 2.5 ng/mL before follicular maturation was attained. The use of either hCG alone or hCG in combination with hMG in a single injection at the time of follicular maturation successfully corrected mature follicle LUF in 21 of 46 patients (46%), whereas ovulation-inducing drugs plus hCG or hCG and hMG corrected LUF in 24 of 25 patients (96%). Clomiphene citrate proved inferior to hMG in that it corrected LUF in 3 of 25 patients (12%) versus 12 of 22 patients (95%) who had undergone hMG therapy. Thus, hMG-hCG therapy is the most efficacious for mature follicle LUF, but because release can occur spontaneously on occasion by an appropriately timed single gonadotropin injection, one could offer the less costly options first. For premature luteinization, speeding up follicular maturation with gonadotropin therapy is effective. Upon failure of this technique, the more costly endogenous gonadotropin suppression followed by hMG can be employed.
We report an interesting case of above-normal serum estradiol concentration of unknown origin. A 30-year-old white woman was seen for infertility problems. Hormonal evaluation revealed the following results. Postovulatory progesterone concentrations and profile (a plot of hormone concentration vs time of cycle) were within the normal range for our laboratory (Table 1). However, the post-ovulatory estradiol concentrations were extremely high, although the curve appeared normal in profile (Table 1).
An improved delivery method to achieve sustained physiological P levels would be useful. Based on this single-dose pharmacokinetic study, micronized P prepared in a nonliquefying vaginal cream holds promise as a convenient method to achieve this goal with a single daily application.
In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.
The bioavailability and the clinical usefulness of the P administered by nasal spray were investigated. Ten healthy menopausal women received an IN spray administration (4 doses of an oleic P solution 20 mg/mL, corresponding to nearly 11.2 mg of P) and the circulating P levels were calculated. Sixty minutes after administration, the maximum concentration (CMax, 3.75 +/- 0.214 ng/mL) was reached. High P levels (greater than 2 ng/mL) lasted until 360 minutes, and the AUC 0 to 720 was 1,481.6 +/- 343 ng.h/mL. Progesterone administration by spray formulation has proven to be effective in reaching therapeutic levels and to be acceptable to patients and, probably, clinically safe.
Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment. Fifteen women from a private practice setting volunteered to be studied during each of two nonconception, gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG), hCG was administered either as a single dose of 10,000 IU (single dose) or in two divided doses of 5,000 IU given 1 week apart (split dose). Early, midluteal, and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured, and their median values and intraquartile ranges (IQR) compared using nonparametric analysis. Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1,146.0 pg/mL (the IQR ranged from 633 to 1,650, IQR = 1,017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460, IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129, IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7, IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17, IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12, IQR = 2) for the single-dose regimen. In hMG-stimulated cycles, a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.
Rabbit uterine cervical fibroblasts produced a large amount of matrix metalloproteinases (MMPs) such as collagenase (MMP-1) and stromelysin (MMP-3) and a small relatively amount of tissue inhibitor of metalloproteinases (TIMP). When cells were treated with progesterone or oestradiol-17 beta, both steroids concurrently decreased the level of procollagenase and prostromelysin in the culture media and the steady-state levels of the respective mRNAs. On the other hand, the level of TIMP in the culture media and the steady-state level of its mRNA were simultaneously increased by these steroids. Similarly, the suppression of production of MMPs and the augmentation of TIMP production by both steroids were observed with interleukin 1 (IL-1)-treated cells, but the action of progesterone was more effective than that of oestradiol-17 beta in the IL-1-untreated and -treated cells. These results suggest that collagenolysis in uterine cervical fibroblasts is negatively regulated by steroid hormones via the acceleration of TIMP production and the suppression of synthesis of MMPs at the pretranslational level.
Women with luteal phase deficiency have been shown to have an increased frequency of luteinizing hormone pulses in the early follicular phase of the menstrual cycle. Because progesterone is known to modulate luteinizing hormone secretion, it has been hypothesized that the decreased progesterone secretion in a previous luteal phase deficiency cycle could lead to the abnormal luteinizing hormone secretory pattern in the ensuing early follicular phase. With the possibility that the higher luteinizing hormone pulse frequency might lead to another deficient luteal phase, it becomes conceivable that luteal phase deficiency could be self-perpetuating. To test this hypothesis, luteal phase deficiency was induced in six normal women by decreasing luteinizing hormone support of the corpus luteum with a gonadotropin-releasing hormone antagonist Nal-Glu, administered twice daily beginning in the midluteal phase after a control cycle. During the antagonist-treated luteal phase, each subject met the predetermined criteria for induced luteal phase deficiency: a 33% or greater decrease in integrated progesterone from the control cycle and an integrated progesterone level less than 100 ng/ml per day. Luteinizing hormone secretion patterns were determined by frequent blood sampling performed every 10 minutes for 12 hours in the early follicular phase of the control cycle and the cycle after antagonist administration. Daily luteal progesterone levels were measured in the control, treatment, and posttreatment cycles. Each volunteer served as her own control. Standard parameters were compared between the control and posttreatment pulse studies in the early follicular phase: (1) luteinizing hormone pulse frequency was 9.5 +/- 1.0 vs 10.0 +/- 0.9 pulses/12 hours, control vs posttreatment, respectively, p = 0.5; (2) luteinizing hormone pulse amplitude was 11.0 +/- 1.3 vs 12.0 +/- 2.2 ng/ml, p = 0.6; and (3) luteinizing hormone mean level was 19.4 +/- 2.3 vs 22.2 +/- 3.3 ng/ml, p = 0.1. Corpus luteum function was also compared between the control and posttreatment cycles. Luteal phase length was 13.7 +/- 0.6 vs 12.7 +/- 0.6 days, p = 0.08. Integrated progesterone values were 136.9 +/- 12.9 vs 130.5 +/- 11.3 ng/ml per day, p = 0.5. Therefore no discernible abnormalities in early follicular luteinizing hormone secretions or corpus luteum secretion of progesterone occurred after an induced luteal phase deficiency cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
Doxycycline and other antibiotics have been implicated in oral contraceptive (OC) failure, but information is sparse and studies of a doxycycline-OC interaction are nonexistent. Because an interaction between doxycycline and OCs, especially those containing low-dose estrogen, could result in an unplanned and unwanted pregnancy, a controlled clinical trial of the effects of doxycycline on OC hormone concentrations was performed. Twenty-four women aged 18-35 years were recruited as volunteers from among the patients seen in a University-based family planning clinic. While they were on a steady dose of the OC Ortho-Novum 1/35, serum concentrations of ethinyl estradiol, norethindrone, and endogenous progesterone were measured on days 18, 19, and 20 of the menstrual cycle (control phase). These measurements were repeated on days 18, 19, and 20 of the following menstrual cycle while the patient was taking doxycycline, 100 mg twice daily (treatment phase). No statistically significant differences in serum levels of ethinyl estradiol, norethindrone, or endogenous progesterone were seen between the control and treatment phases. However, there was large inter-patient and intra-patient variability in ethinyl estradiol and norethindrone levels. No elevations of endogenous progesterone occurred to suggest ovulation during antibiotic administration in either phase. It is not known what effects longer or earlier administration of doxycycline during the OC cycle would have on serum hormone concentrations or ovulation. Pregnancies attributed to failure of OCs because of tetracycline use could in fact be due to other causes or could represent a true interaction that only manifests itself in a small proportion of women at risk.
Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomiphene, constitute rational and effective adjuncts to therapy.
Canalization of cervical mucus from 31 patients at the obstetric/gynecologic clinic at the Universita Cattolica del S. Cuore in Rome, Italy has studied to determine the biochemical basis of canalization and its dependence on estrogen, to study the action on the canalization of hormones used to induce ovulation, and to correlate fern pattern and canalization. Cervical mucus was collected daily and applied to a glass slide, covered with an object cover, and allowed to dry. The typical arrangement of the dendritic crystals and the presence of channels among them were confirmed. Depending on the phase of the ovulatory cycle, the crystals differed in direction and in number. The number of channels consistently increased as estradiol levels increased during the proliferative phase. This happened in both natural and induced ovulatory cycles. The cervical mucus of patients with primary amenorrhea canalized when treated with estrogens. The channels ran parallel to each other. Yet, during the secretory phase, the number of channels fell rapidly and the channels were lined up in a crisscross fashion. This suggested that sperm penetration is dependent on the orientation of mucus crystals. Indeed in vitro studies showed that spermatozoa enter the periovulatory mucus in tightly packed files as if the mucus allowed only passage in this linear formation. The biophysical characteristics of canalization paralleled those of ferning. Moreover, like ferning, the presence of essential salts and proteins induced canalization. It is concluded that canalization can be used to accurately measure estradiol levels and thus to detect ovulation.
Fifteen infertile women with inadequate luteal phase, histologically documented in at least two separate cycles, and normal midluteal plasma levels of progesterone (greater than or equal to 10 ng/mL), estradiol (70 to 300 pg/mL), and prolactin (less than 20 ng/mL) received "pure" follicle-stimulating hormone (pFSH), 150 IU intramuscularly, for 4 days (days 1 to 4 of the cycle). The endometrial defect was corrected in 7 of the 15 (46.7%) patients during the first treated cycle. Hormonal levels were similar in control and treatment cycles. Two of 5 patients with no additional infertility factors except luteal phase deficiency (LPD) became pregnant and carried to term singleton pregnancies. In 5 additional infertile patients with normal luteal function as assessed by endometrial histological study (2 cycles) and hormone measurements (first study cycle), a third biopsy was performed in a consecutive cycle under pFSH administration. In no case was the normal secretory pattern impaired. It is concluded that (1) some forms of LPD may be successfully treated by early follicular pFSH therapy and (2) pFSH does not alter the normal endometrial secretory pattern.
beta-Endorphin has a role in the regulation of the normal menstrual cycle and possibly in the onset of puberty. We have reviewed the evidence pointing to an alteration in this neuropeptide that may contribute to the pathogenesis of various reproductive dysfunctions. Elevated or high levels of beta-endorphin have been associated with exercise-associated amenorrhea, stress-associated amenorrhea, and polycystic ovarian syndrome. Depressed or low levels of beta-endorphin have been associated with PMS and menopause. Alterations in the levels of beta-endorphin may change the pulsatile release of GnRH via noradrenergic and/or dopaminergic pathways. We have primarily focused on beta-endorphin as representative of the endogenous opioid peptides, but other opioid peptides may also contribute to the pathogenesis of various types of reproductive dysfunction. Perhaps it will become possible to characterize and hone our understanding of the function of beta-endorphin and the other substances composing the endogenous opioid peptides. A better understanding of their role in physiological as well as pathophysiological processes may allow for the development of rational approaches to the treatment of specific disorders pertaining to reproduction. Many questions remain unanswered. Among the most relevant are: what is the precise mechanism of action by which beta-endorphin exerts its influence on pulsatile GnRH release? Is there a functional relationship between CNS and peripheral (serum) levels of beta-endorphin? Are the detected changes in beta-endorphin levels merely associated, or are they a cause of a particular disorder? Since it took almost 40 years between the time prostaglandins were first discovered and eventual realization of their clinical application, it may take some time before the beta-endorphin story is complete.
The notion of an oscillator or signal generator in the central nervous system that controls the rhythmic release of GnRH and, thereby, the pulsatile secretion of the gonadotropic hormones, originated in the finding of strikingly abrupt and rhythmic fluctuations in the concentration of LH in the plasma of ovariectomized monkeys. These oscillations had a period of about one hour when blood samples were obtained at 10 to 20 minute intervals.I
These surprising observations were presaged by reports of seemingly random, major fluctuations in plasma gonadotropin concentrations in gonadectomized monkeys" and rats as well as in women.' In these earlier studies, the sampling intervals employed were never less than one hour and unable, therefore, to reveal the orderly, rhythmic events that occur with frequencies of one event per hour or more.
In the original study describing pulsatile LH secretion in ovariectomized monkeys the possibility was considered that the circhoral discharges of LH may be initiated by autoregulatory mechanisms involving long or short feedback loops, but the more likely view that these discharges were due to intermittent signals from the central nervous system unrelated to circulating LH levels that resulted in putative increments in GnRH release was favored. Nevertheless, the possible role of autoregulatory mechanisms in the control of pulsatile LH secretion was repeatedly considered,6 but finally laid to rest in the relatively recent past.7Conversely, the view that each pulse of LH released from the pituitary gland is the consequence of a bolus of GnRH secreted into the pituitary portal system has been unequivocally upheld by the demonstration of synchronous increments of GnRH assessed in the pituitary portal circulation and of LH measured in samples of peripheral blood obtained simultaneously.s, 9 In any case, the phenomenon of pulsatile gonadotropic hormone secretion was rapidly extended to most vertebrate species studied in this regard, including our own, and forms the basis of an increasingly voluminous, rapidly expanding literature.
There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.
THE response of the uterus to estrogen is a complexphenomenon involving numerous biochemical events (1). The most dramatic outcome of estrogenization of the immature uterus is the proliferation of various cell types. It is customary to divide the response of the uterus to estrogen into two major temporal phases. In the early phase, within the first 4 h after estrogen administration, there is an increase in uterine wet weight (2), glucose metabolism (3), histamine depletion (4), and RNA polymerase activity (5). One of the early events that is likely to be important in the proliferative response of the uterus to estrogen is activation of protooncogenes which encode nuclear regulatory proteins (6–8) and the enhanced expression of growth factors and their receptors (9) and cAMP-independent protein kinase (10). The intermediate and late phase (4–48 h after estrogen) responses include increases in protein and RNA synthesis and an increase in uterine dry weight and DNA content (11, 12).
In order to delineate factors contributing to variation in hormone levels, progesterone and prolactin (PRL) levels from 28 normal women, obtained daily during one menstrual cycle and every 20 minutes during a midluteal 24-hour admission in a subgroup of five subjects, provided a data base for analysis of these variables. Pulsatile analysis of the 24-hour data was conducted using an adaptive-threshold algorithm, and normal reference ranges were generated from randomly selected daily hormone values. Our data verify that inherent variation can significantly alter single random serum levels of reproductive hormones. These variations included menstrual cycle day, circadian influence, pulsatile secretion, assay error, and biologic heterogeneity. Besides the expected day-to-day change in progesterone levels during the luteal phase, seven of ten women exhibited a significant circadian variation in progesterone; however, the time of day of the peak level was not consistent among women. Prolactin levels did not demonstrate any clinically relevant change over the menstrual cycle, but did have a consistent circadian pattern (nocturnal rise) over the 24-hour study period. Pulsatile variation occurred in both progesterone and PRL levels during the 24-hour admission. Five different reference ranges were generated from randomly selected single daily values from the 28 normal menstrual cycles. Although the mean levels calculated for each reference range were similar, the reference ranges demonstrated considerable variation due to the random sampling. In the five progesterone reference ranges, the lower limit of the range varied from 2.7-6.1 ng/mL, whereas the upper limit varied from 24.2-42.1 ng/mL.(ABSTRACT TRUNCATED AT 250 WORDS)
In 20 fertile women one menstrual cycle was monitored by ovarian ultrasonography, laparoscopy, and estimation of 17 beta-estradiol (E2) and progesterone levels in serum and peritoneal fluid (PF). Three groups were studied, performing the laparoscopy within 1, 3, and 5 days after ovulation. The results indicate that the opening in the corpus luteum remains at least during the first 1.5 postovulatory days. The process of the closure starts thereafter and has been accomplished 4 to 5 days after ovulation. Progesterone and E2 levels in PF follow a similar pattern, showing high levels in the first, decreasing levels in the second, and low levels in the last laparoscopy groups. Therefore the significance of inspection of the ovaries and hormone level estimation in PF depend on the timing of the laparoscopy in relation to the moment of ovulation, especially in the first 5 postovulatory days.
It has been reported that the pregnancy rate after in vitro fertilization (IVF) after pituitary desensitization with luteinizing hormone-releasing hormone agonist (LH-RH-a) is twice as low if the luteal phase is not supported. We therefore tested the respective advantages of luteal support using human chorionic gonadotropin (hCG, 1,500 IU three times) and progesterone (P, micronized, oral administration, 400 mg/d) after 171 embryo transfers (ET) in which the cycle was stimulated with the LH-RH-a triptoreline. The type of luteal phase support was randomly selected except when the estradiol level exceeded 2,700 pg/mL. The clinical pregnancy rate and the ongoing pregnancy rate were significantly higher using hCG (after the transfer of 3 embryos, 45% and 43% with hCG versus 23% and 17% with P). The same results were noted for the embryo implantation rate per ET (19% of embryos are viable after 6 months of pregnancy after hCG versus 7.5% after P). Adequate luteal support, therefore, significantly improves the results of IVF when LH-RH-a are used. The poor results obtained with P in this study might be related to its poor bioavailability after oral administration.
To examine the differential regulation of glycoprotein hormone secretion from the gonadotrope by GnRH, the Nal-Glu GnRH antagonist was administered to euthyroid women in the early follicular phase (days 1-5) of the menstrual cycle, and the results compared to previous studies with the Nal-Arg GnRH antagonist. After a 4-h period of baseline sampling at a frequency of every 10 min, a single sc dose of the GnRH antagonist was administered to each subject. Frequent sampling continued for 8 h, followed by hourly sampling for a further 16 h. LH, FSH, and free alpha-subunit were measured serially in assays with high specificity. There was a 90% concordance of LH and free alpha-subunit pulses during the baseline sampling period. Pulsatile secretion of LH and free alpha-subunit was immediately abolished at the highest dose of the Nal-Glu antagonist for at least 8 h. The maximum percent suppression of LH after administration of the Nal-Glu GnRH antagonist was 70 +/- 4%, 80 +/- 4%, and 83 +/- 1% at doses of 15, 50, and 150 micrograms/kg, respectively, compared to 51 +/- 10%, 70 +/- 5%, and 69 +/- 5% at doses of 50, 150, and 500 micrograms/kg Nal-Arg antagonist. Decreases in FSH were 28 +/- 2%, 32 +/- 7%, and 39 +/- 2%, with increasing doses of the Nal-Glu antagonist compared with 25 +/- 6%, 17 +/- 6%, and 28 +/- 4% reductions at increasing doses of the Nal-Arg antagonist. Free alpha-subunit decreased 22 +/- 4%, 23 +/- 4%, and 28 +/- 3% at increasing doses of the Nal-Glu antagonist and 12 +/- 4%, 27 +/- 4%, and 30 +/- 7% with increasing doses of the Nal-Arg antagonist. For the Nal-Glu antagonist, suppression of LH was greater than that of FSH and free alpha-subunit at all doses (P less than 0.001), while FSH suppression was greater than that of free alpha-subunit at the highest dose only (P less than 0.05). For the Nal-Arg antagonist, LH suppression was greater than that of FSH or free alpha-subunit at all doses (P greater than 0.01), and FSH suppression exceeded that of free alpha-subunit at the 50 micrograms/kg dose. Suppression of LH was greater with the Nal-Glu antagonist than with the Nal-Arg antagonist at doses of 50 and 150 micrograms/kg (P less than 0.05), and FSH suppression was greater with the Nal-Glu antagonist at 150 micrograms/kg (P less than 0.01), while the degrees of maximum suppression were similar for the two different GnRH antagonists for free alpha-subunit.(ABSTRACT TRUNCATED AT 400 WORDS)
Nine obese and ten non-obese women with polycystic ovarian disease (PCO), and seven obese and eight non-obese normal women, had an oral glucose tolerance test (OGTT) before and after treatment with GnRH agonist (buserelin 400 micrograms/day s.c. for 8 weeks) in order to investigate the effect of ovarian suppression on their insulinaemic secretion. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol (E2), androstenedione (A), testosterone (T), DHEAS, cortisol and insulin (I) were measured at time 0 of OGTT; in all samples of OGTT, E2, T, A and I were also assayed. PCO patients showed higher basal androgen levels than control patients. All subjects showed a normal glycaemic response to OGTT. The mean fasting and areas under the curve (ISA) of plasma I were significantly greater in the obese PCO women than in non-obese PCO, the normal obese and non-obese women. All PCO patients showed significantly higher fasting I and ISA values in respect to all control patients. Hyperinsulinaemic responses were 89% in PCO obese, 30% in non-obese PCO and 29% in obese control patients. After buserelin treatment, these values did not change significantly in respect to pretreatment in all groups, in spite of a significant decrease of androgen secretion. During OGTT, no variations of steroid plasma concentrations were seen in both normal or hyperinsulinaemic PCO patients. The data of this study show that hyperandrogenism, hyperinsulinism and obesity were associated with different modalities in PCO patients and that a marked decrease of androgen secretion did not restore a normal insulinaemic response to OGTT, suggesting that hyperandrogenism does not produce hyperinsulinism.
Serum gonadotropin, prolactin, estradiol, sex hormone binding globulin (SHBG) and androgen levels were measured before, 5 days and 6 weeks following ovarian wedge resection in 9 patients with polycystic ovary syndrome. Elevated levels of LH, androstenedione, testosterone and dehydroepiandrosterone-sulphate (DHEA-S) were found before surgery. There was a marked decrease in androstenedione and DHEA-S levels 5 days following wedge resection, but a rebound effect could be observed 6 weeks later. Serum gonadotropin, prolactin, testosterone and SHBG concentrations were practically unaffected by surgery. At 6-12 months follow up patients showed regular, mainly ovulatory cycles, but pregnancy occurred only in two cases.
Ovarian function was evaluated over a minimum of 3 consecutive menstrual cycles from each of 41 women with unexplained infertility. Follicular development and ovulation were monitored using real time ultrasonography and luteal function was evaluated by daily salivary progesterone measurement. In 129 spontaneous cycles, normal single ovulations were detected in 121 (93.8%). Luteal phase insufficiency was identified in 21 (17.4%) of these 121 cycles and this was a recurrent phenomenon in the cycles of 5 of the 41 women (12.2%). A successful pregnancy was seen only in association with consistently normal salivary progesterone profiles or where the empirical use of clomiphene citrate therapy had corrected previously diagnosed luteal phase insufficiency. Basal body temperature records or mid-luteal serum progesterone measurements were less satisfactory indices of luteal function than a salivary progesterone profile.
Luteal phase defect (LPD) accounts for a significant proportion of reproductive disorders, however its etiology is still debated. A prospective study was performed on 37 ovulatory women to determine whether LPD can occur in cycles characterized by completely normal folliculogenesis. Criteria for normal folliculogenesis included: a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presence of a dominant follicle that disappeared, an increase of serum progesterone, and normal serum levels of prolactin, testosterone, dehydroepiandrosterone sulfate, follicle-stimulating hormone, and LH. Thirty of 37 women fulfilled the above mentioned strict criteria and underwent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographic parameters of folliculogenesis and ovulation. Women with delayed endometrial development demonstrated slightly longer follicular phases (17.0 +/- 1.1 versus 14.5 +/- 0.3 days). Perfectly normal follicular and periovulatory events may be followed by deficient luteal phases.
The recurrent deficiency of progesterone (P) secretion by the corpus luteum has been associated with infertility and habitual abortion and given the clinical diagnosis of luteal phase deficiency (LPD). There is evidence that both follicular and luteal phase abnormalities can result in LPD cycles. In this study we have examined reproductive hormone levels and preovulatory follicular size in women with LPD (n = 10). For the purposes of this study, LPD was determined by an endometrial biopsy in the studied cycle that was more than 2 days out of phase. These biopsies were performed in women with infertility or habitual abortion who exhibited an out of phase biopsy in a prior cycle. The control group consisted of 28 normal women. Daily serum levels of the following hormones were determined in each subject: LH and FSH [immuno- and bioactive (LH-immuno and LH-bio)], P, estradiol (E2), and inhibin. The LPD women exhibited significant decreases in integrated luteal phase levels of inhibin [10,615 +/- 898 vs. 13,560 +/- 662 (U/L).days; P less than 0.02] and E2 [5,015 +/- 275 vs. 6,435 +/- 393 (pmol/L).days (1366 vs. 1753 (pg/mL).days); P less than 0.05] in addition to the expected decrease in P [280 +/- 23 vs. 420 +/- 23 (nmol/L).days (88 vs. 132 (ng/mL).days); P less than 0.01]. On days 6-11 after the LH surge (day 0), there was a significant (P less than 0.05) decrease in mean LH-bio levels in LPD compared with those in normal women (146 +/- 26 vs. 212 +/- 24 micrograms/L). The midcycle LH surge was deficient in LPD when both LH-immuno [482 +/- 30 vs. 672 +/- 43 (micrograms/L).days; P less than 0.01] and LH-bio [1711 +/- 179 vs. 2248 +/- 226 (micrograms/L).days; P less than 0.05] levels were compared with normal values. When comparing the follicular phase in LPD with that in normal women, similar follicle size, peak and integrated E2 levels, and mean LH and FSH (immuno and bio) levels were found. The only follicular phase abnormality noted in this study was decreased mean levels of serum inhibin in the early and midfollicular phases (221 +/- 19 vs. 308 +/- 25 U/L; P less than 0.01). In this group of women with LPD, low levels of inhibin in the follicular phase were consistent with the concept of a defect in function of the preovulatory follicle, possibly as a result of previously described defects in gonadotropin secretion in this condition.(ABSTRACT TRUNCATED AT 400 WORDS)
Twenty-four women with luteal phase defects who were ovulatory on clomiphene therapy with or without human chorionic gonadotropin (hCG) at midcycle for three to eight cycles yet failed to produce a live birth were treated with a short course of menotropin (hMG-S), one to two ampules for five days in the early follicular phase followed or not followed by hCG at midcycle for three to eight cycles. The luteal phase defect was diagnosed with repeat endometrial biopsies with a lag time of three or more days prior to clomiphene therapy. A complete infertility workup revealed only eight patients (33%) with a purely endocrine factor (luteal phase defect). The rest (16 patients, or 67%) had one or two additional infertility factors. Two abortions occurred in this group during clomiphene therapy, while five pregnancies (four live births and one spontaneous abortion) occurred during hMG-S therapy. The ovulation rates were similar for hMG-S (89%) and clomiphene (91%) therapy, but the frequency of a normal ovulatory cycle was significantly greater (P = .026) for hMG-S therapy (71%) than for clomiphene therapy (57%). The midluteal mean serum progesterone level was lower and the mean luteal length shorter in the cycles with less than 130 ng/mL/d of total integrated luteal progesterone. The postcoital test results showed better cervical mucus, with increased mucus volume and better fluidity and spinnbarkeit, in hMG-S cycles than in clomiphene cycles. It appears that hMG-S treatment can improve ovarian function and achieve successful pregnancy in patients with luteal phase defects who fail to produce a live birth during clomiphene treatment.
The oral route of progesterone administration has long been considered impractical because of poor absorption and short biologic half-life. Recent reports suggest that micronization of progesterone enhances absorption and increases serum and tissue levels of progesterone. This study checks serum progesterone levels before and 0.5, 1, 2, 3, 4, and 6 hours after oral administration of 200 mg of progesterone in seven subjects. Progesterone was plain milled, micronized, plain milled in oil, micronized in oil, or micronized in enteric-coated capsules. All patients exhibited a significant increase in serum progesterone levels after oral progesterone administration. Mean peak progesterone levels (30.3 +/- 7.0 ng/ml) (p less than 0.005) were achieved with micronized progesterone in oil at 2.0 +/- 0.3 (p less than 0.05) hours after administration. Four types of oral progesterone had equivalent mean peak elevations and mean times to peak: plain milled, 9.6 +/- 2.5 ng/ml at 4.0 +/- 0.5 hours; micronized 13.2 +/- 2.4 ng/ml at 3.2 +/- 0.4 hours; plain milled in oil, 11.3 +/- 3.0 ng/ml at 4.0 +/- 0.5 hours; and micronized in enteric-coated capsules, 11.2 +/- 3.0 ng/ml at 4.1 +/- 0.7 hours. Contrary to traditional teaching, these data show that significant serum progesterone levels can be achieved by oral administration. Absorption can be significantly improved by the physical characteristics of the progesterone and the vehicle used with oral administration.
Inadequate production of progesterone by the corpus luteum results in luteal phase deficiency, which is a frequent cause of recurrent spontaneous abortion. The diagnosis is made by assessment of endometrial biopsy specimens. Measurement of serum progesterone offers a less invasive alternative, but its utility as a diagnostic test is limited since there is no agreement on the level that will accurately differentiate between normal and luteal phase deficiency cycles. The purpose of this study was to determine whether there was an optimal time in the menstrual cycle when serum progesterone measurement could improve the diagnostic accuracy of the test. The results demonstrate that this time period is day 25 to day 26 and not the midluteal phase as has previously been suggested. The discriminatory level was found to be 21 nmol/L and provided a test with sensitivity of 81% and specificity of 73%.
Luteal phase deficiency (LPD) is a reproductive disorder associated with infertility and spontaneous abortion. This study was undertaken to determine whether LPD might be related to an abnormal pattern of gonadotropin secretion. We tested this hypothesis by evaluating the pattern of pulsatile LH secretion in both the follicular and luteal phases of the menstrual cycle in normal women (n = 21) and women with LPD (n = 20), which was diagnosed on the basis of two out of phase endometrial biopsies. In addition, we sought to determine whether changes in progesterone (P) pulse patterns could account for the decrease in average serum P levels in women with LPD. To this end, we examined the pulse patterns of P and compared these patterns between normal women and those with LPD. Frequent blood sampling was performed in both groups to determine their respective hormone secretion patterns. In the follicular phase, blood samples were obtained every 10 min for 12 h; in the luteal phase the samples were obtained every 10 min for 12 h; in the luteal LH, FSH, and P were assayed in each sample. Pulse detection was performed by an adaptive threshold method of pulse analysis. The LH pulse frequency was significantly higher in the women with LPD than in the normal women in the early follicular phase [P less than 0.05; LPD, 12.8 +/- 1.4 (+/- SE); normal, 8.2 +/- 0.7 pulses/12 h]. LH pulse frequency was similar in the early and late follicular phases in the women with LPD, whereas it was higher in the late follicular phase in normal women. Mean serum FSH levels were not different between groups in both the early and late follicular phases. In the luteal phase the P pulse amplitude and mean serum P level were significantly lower in the LPD group than in the normal women (P less than 0.01). We conclude that 1) a too rapid LH pulse pattern in the early follicular phase may lead to inadequate LH support of the corpus luteum and become manifest as LPD; 2) the mechanism for inadequate P secretion in LPD is decreased P pulse amplitude; 3) the finding of similar serum FSH levels in the two groups in both the early and late follicular phases did not support compromised folliculogenesis as an etiological factor for LPD.
One hundred fifty-six women with cycle disorders presenting as absence or infrequency of ovulation and with luteal phase deficiency (group II, according to the World Health Organization classification) received clomiphene citrate (CC) for ovulation induction. The administered dosage ranged from 50 to 250 mg/d. The follicular development in terms of numbers of small (less than 8 mm), intermediate (9 to 15 mm), and large (greater than 15 mm) follicles and their distribution in either one or both ovaries on the day of assumed ovulation was related to the dosage of CC. A statistically significant increase was found in the total number of follicles in relation to the dosage of CC (P less than 0.003). In view of the development of the mature follicles, the gradual increase in CC daily dosage was thought to be associated with additional mature follicles before ovulation. However, this increased follicular recruitment was not regarded as statistically significant. Treatment with low doses of CC resulted in follicular development in only one ovary, whereas increased follicular recruitment after high CC dosage was found in association with follicular development in both ovaries.
Borenstein R et al., 1989·Aust N Z J Obstet Gynaecol·
Fourteen pregnancies were achieved with tamoxifen therapy in 12 women who failed to conceive with clomiphene citrate. There were no side-effects and fewer treatment cycles were required than with clomiphene citrate treatment. Ovulation and cervical score with tamoxifen therapy were significantly higher (p less than 0.005).
We tested the hypothesis that disturbed follicular development and disturbed luteal progesterone (P4) secretion are associated with reduced gonadotropin secretion in the early follicular phase by measuring pulsatile LH and FSH secretion at that time in 53 normally menstruating women. Three groups of women were identified on the basis of serum sex steroid concentrations (measured daily throughout the cycle) and luteal phase length. Group A (n = 27) had normal ovarian hormone secretion with peak serum estradiol (E2) concentrations of 440 pmol/L or more, peak serum P4 concentrations of 19 nmol/L or more, and luteal phase length of 9 days or more. Group B (n = 16) had normal peak serum E2 values, but peak serum P4 values less than 19 nmol/L and/or luteal phase length less than 9 days. Group C (n = 10) had peak serum E2 values below 440 pmol/L. Risk factors for the disturbances found in groups B and C were exercise and/or intermittent dieting. Compared to group A, both groups B and C had reduced mean serum LH concentrations (3.1 +/- 1.5 vs. 2.3 +/- 1.4 and 2.0 +/- 1.0 IU/L; P less than 0.05) and reduced LH pulse frequencies (5.2 +/- 2.1 vs. 3.5 +/- 1.8 and 3.3 +/- 2.3 pulses/12 h; P less than 0.02). LH amplitude was similar in all 3 groups. Mean serum FSH concentrations were slightly but not significantly lower in group C. We conclude that reduced gonadotropin secretion during the follicular phase may indeed affect E2 and P4 secretion at later stages of the menstrual cycle. The patterns of alteration associated with disturbed E2 and P4 secretion in normally menstruating women are similar to those that occur in women with hypothalamic amenorrhea.
The authors have further analyzed women diagnosed as having luteal phase insufficiency in hope of determining the value of specific screening tests as well as determining the degree of heterogeneity of pathophysiologic mechanisms involved in the disorder. Twelve women with the disorder were identified, 6 with two consecutive midluteal serum progesterone (P) levels less than 10 ng/ml (group 1) and 6 with two consecutive late luteal phase endometrial biopsies out of phase (group 2); 4 infertile women with normal serum P and late luteal biopsies also were studied (group 3). All underwent serum sampling for P and luteinizing hormone (LH) at 20-minute intervals for 24 hours, beginning at 9:00 A.M. of day 7 post-LH surge. No significant differences were noted among the three groups for LH area under the curve, pulse frequency, or pulse amplitude. Furthermore, no differences were ascertained for P area under the curve. However, individuals were identified who had one or more hormonal abnormalities but no abnormal biopsy, as well as patients with normal hormonal profiles but having abnormal endometrial development. Receiver Operating Characteristic curves demonstrated that pooled morning serum P levels provided optimal predictive ability of biopsy results. The authors conclude that luteal phase insufficiency is a heterogeneous disorder, and that neither endometrial biopsy nor serum hormonal analysis obviates the need for the other.
Neurons expressing luteinizing hormone-releasing hormone (LHRH), found in the septal-preoptic nuclei and hypothalamus, control the release of gonadotropic hormones from the anterior pituitary gland and facilitate reproductive behaviour. LHRH-expressing neurons are also found in the nervus terminalis, a cranial nerve that is a part of the accessory olfactory system and which projects directly from the nose to the septal-preoptic nuclei in the brain. During development, LHRH-immunoreactivity is detected in the peripheral parts of the nervus terminalis before it is found in the brain. Using a combination of LHRH immunocytochemistry and tritiated thymidine autoradiography in fetal mice, we show that LHRH neurons originate in the medial olfactory placode of the developing nose, migrate across the nasal septum and enter the forebrain with the nervus terminalis, arching into the septal-preoptic area and hypothalamus. Clinically, this migratory route for LHRH-expressing neurons could explain the deficiency of gonadotropins seen in 'Kallmann's syndrome' (hypogonadotropic hypogonadism with anosmia).
Fifteen ovulating women had serial ultrasound scans to measure follicular, endometrial, and uterine growth, as well as biochemical indices including estradiol (E2) and the free androgen index, throughout a natural and a clomiphene-citrate-induced cycle. Despite higher E2 levels in the 5 days preceding ovulation, the clomiphene cycles were characterized by absence of the normal increase in uterine volume and an inhibition of endometrial thickening. It is proposed that the anti-estrogen effect of clomiphene inhibits the normal cyclical growth of the uterus and endometrium.
The functional integrity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes was assessed by determining pulsatile LH, ACTH, and cortisol secretion during the early follicular phase in athletic women with regular menstrual cycles (CA; n = 9), athletic women with amenorrhea (AA; n = 9), and regularly cyclic sedentary women (CS; n = 8). The CA and AA women were not significantly different in body composition, exercise training, psychometric tests, or dietary consumption. The CA women had shorter luteal phases (P less than 0.05) and lower urinary excretion of pregnanediol glucuronide than the CS women. In the AA women, urinary estrone glucuronide, pregnanediol glucuronide, and LH excretion were low throughout a 30-day period. The CA women had a 24-h pattern of pulsatile LH secretion characterized by reduced frequency (P less than 0.05) and increased amplitude (P less than 0.05), yielding an overall increased 24-h mean level (P less than 0.05), but interpulse intervals similar to those in the CS women. During sleep, LH pulse frequency slowed in the CS and CA women, while pulse amplitude increased and the mean serum LH level decreased in both groups. The AA women had even fewer pulses (P less than 0.05) of normal amplitude occurring at much more variable (P less than 0.01) interpulse intervals. Sleep-associated changes in LH pulsatility were absent. Responses to a 10-microgram bolus GnRH dose revealed blunted (P less than 0.05) FSH release in CA and augmented (P less than 0.05) LH release in AA women. The groups did not differ in any 24-h ACTH pulse pattern parameter or in cortisol pulse frequencies. Yet, early morning (0200-0800 h) serum cortisol levels were higher (P less than 0.05) in both groups of athletes, and this elevation was extended through the day (0800-2000 h; P less than 0.001) and evening (2000-0200 h; P less than 0.05) in the AA women. The plasma ACTH and serum cortisol responses to bolus human CRH administration were blunted in the CA and AA women [change from baseline (delta) in ACTH, P less than 0.05 and P less than 0.01; delta cortisol, P less than 0.01 and P less than 0.01, respectively], but adrenal sensitivity (delta cortisol/delta ACTH ratio) was increased (P less than 0.05). The plasma ACTH and serum cortisol responses to meals also were blunted in the athletic groups (P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Oral clomiphene citrate (CC) and vaginal progesterone suppositories (PS) are common treatment modalities in luteal phase dysfunction (LPD). Little is known regarding the relative efficacy of these agents. To study the use of CC and PS in the management of LPD, a retrospective cohort study of patients presenting with infertility was undertaken. Sixty-five patients in whom LPD was diagnosed and corrected, as judged by endometrial biopsies, were studied; 35 were treated with PS and 30 with CC. Using Student's t-tests and chi-square analyses, the two treatment groups were demographically comparable. Using life-table analysis, no one therapeutic approach proved superior. Clomiphene citrate and PS are comparable treatment modalities in the setting of LPD given correction of endometrial lag.
DlJ. ring the last stage of puberty, the hypothalamic-pituitary-ovarian axis acquires the ability to respond to high levels of estradiol; this results in a sharp increase in the pituitary output of luteinizing hormone (LH). It is believed that within a mature follicle, the LH surge triggers a complex set of events that results in two apparently independent phenomena: ovulation and luteinization. The term ovulation will imply rupture of the follicular wall and release of an oocyte, whereas luteinization will imply the morphologic and biochemical shift in the …
Luteal phase deficiency is an ovulatory dysfunction problem that is subtle but real. It may be the most common ovulatory problem in women. Luteal phase deficiency has been clearly demonstrated in the research setting (1) in spontaneous cycles, (2) when follicular maturation has been impeded, and (3) when luteotrophic influences have been suppressed. The diagnosis of LPD in the clinical setting remains problematic and controversial primarily because there is no practical diagnostic method that has been validated. This article has reviewed the methods that have been used to diagnose LPD. BBT charts are insensitive; these charts reliably diagnose LPD only when there are persistent short luteal phases. There is disagreement whether ovarian follicular size, as determined by ultrasonography, is decreased in LPD; however, ultrasonographic diagnosis of LPD would require daily scans through ovulation, which makes this approach impractical. Mild hyperprolactinemia is a probable cause of LPD in a minority of patients; a physician should obtain a PRL level in LPD women with the realization that there is considerable sampling variability. Determination of serum gonadotropin levels (LH or FSH or both) is not practical for the clinical diagnosis of LPD. Random serum P levels, whether single or multiple, are not helpful in the diagnosis of LPD in individual patients. The secretory pattern of P results in such wide confidence limits that P samples from individuals cannot be compared to normal in a useful manner. Most of the controversy about the diagnosis of LPD has centered around the use of individual serum P levels. The timed endometrial biopsy relies on the endometrium as a bioassay of P over time. The endometrial biopsy has not been carefully validated in terms of its sensitivity or accuracy for the diagnosis of LPD. However, it remains the best current method for the diagnosis of LPD when the standard guidelines for its use are followed. As opposed to the other tests for LPD, awareness of the usefulness of the biopsy has increased as we have learned more about CL physiology. No current research method for the diagnosis of LPD appears to be a practical method that could be applied in the clinical setting. Specific secretory proteins from the endometrium and methods to measure hormone secretion that circumvent the secretory pattern hold promise for improved methods to diagnose LPD in the future.
Pulsatile administration of gonadotrophin releasing hormone (GnRH) is a very effective treatment for induction of ovulation in hypothalamic amenorrhoea (HA). Thirty-seven women have been treated for a total of 117 cycles which resulted in 42 pregnancies--four treatment failures occurred. If these cycles are excluded, the 42 pregnancies were obtained within 2.3 cycles. One twin pregnancy occurred and no hyperstimulation was observed. The treatment was administered intravenously with a dosage schedule based on the grading of HA. We concluded that pulsatile GnRH was safe and very successful in induction of pregnancy in HA. Other indications (polycystic ovary syndrome and luteal phase defect) remain much less suitable for this treatment.
The existence of luteal phase defect has been the focus of much debate, mainly because of inconsistencies in its diagnosis and management. This study was performed to compare progesterone profiles in women with luteal phase defect with those of women with normal cycles and to establish a discriminatory level of serum progesterone that may aid in the diagnosis of this condition. Compared with patients with luteal phase defect cycles, women with normal cycles produced significantly more progesterone in the luteal phase. The serum progesterone level (less than or equal to 21 nmol/L) was the optimal discriminatory level between luteal phase defect and normal cycles and provided a diagnostic test with 70% sensitivity and 71% specificity. In women with recurrent abortion, the incidence of luteal phase defect was 40%, but with treatment 81% of pregnancies were successful. The findings in this study support the existence of luteal phase defect as a clinically significant entity in recurrent first-trimester spontaneous abortion and one that can be treated successfully with the administration of progesterone. The histologic diagnosis of luteal phase defect may also be confirmed with serum progesterone.
Hammarbäck S et al., 1988·Acta Obstet Gynecol Scand·
A treatment with the GnRH-agonist, buserelin, was given intranasally in a dosage of 400 micrograms once daily, to induce anovulation in 26 women with premenstrual tension syndrome; 23 patients completed the study course. The design was double-blind and cross-over. Daily symptom ratings were made for two pretreatment, diagnostic cycles and continued for up to six cycles or 6 months. The rating scale used was an earlier described visual analogue scale. Blood samples for estradiol and progesterone radio-immunoassay were taken once weekly throughout the study. Results show beneficial effects of both placebo and GnRH-agonist, compared with the pretreatment situation. The GnRH-agonist was, however, significantly better than placebo. At the end of the treatment periods the patients while still taking placebo, still showed cyclical symptom changes, whereas during the GnRH-agonist treatment the cyclical changes had disappeared. The results indicate that a factor from the corpus luteum must be involved in the etiology of cyclical mood changes. The results also show that inhibition of ovulation by mean of GnRH-agonists is one possible way to treat premenstrual tension syndrome.
A deficiency in follicle stimulating hormone (FSH) levels during the early follicular phase of the menstrual cycle has been shown to result in luteal phase defect (LPD). A short course of human urinary FSH (uFSH) (Metrodin, Serono Laboratories) was given for a maximum of six cycles to 18 women with endometrial-biopsy-proven (EBX-proven) LPD. Adjunctive therapy in the form of midcycle human chorionic gonadotropin was given after the third therapy cycle. The uFSH therapy reduced the mean EBX lag time (2.0 +/- 0.6 days with therapy vs. 4.1 +/- 0.4 pretherapy, P less than .01), normalized the follicular phase length (15 +/- 0.4 days vs. 17.2 +/- 0.8 pretherapy, P less than .25) and increased the luteal phase length (12.7 +/- 0.4 days vs. 10.8 +/- 0.2 pretherapy, P less than .001). Twelve of 46 cycles (26%) in which uFSH was given without adjunctive therapy were anovulatory. Seven patients conceived; the result was seven viable pregnancies, all delivered at term. The cumulative pregnancy rate approached 48% by the sixth therapy cycle. uFSH therapy is useful for the correction of LPD and yields an acceptable pregnancy rate.
The S1-nuclease analysis was used to investigate the pattern of inhibin expression in the rat. In a first series of experiments, expression of the alpha, beta A, and beta B subunits of inhibin were monitored in various tissues from male and female rats. Two observations emerge from these studies. First, expression of inhibin subunits was found in gonadal and extragonadal tissues. In addition to the ovary and testis, inhibin alpha, beta A, and beta B RNAs were detected in the placenta, pituitary, adrenal, bone marrow, kidney, spinal cord, and brain. Detection of inhibin RNAs in the brain and spinal cord suggested that these subunits may exert neuroregulatory functions in the central and peripheral nervous systems. Furthermore, the presence of inhibin alpha and beta subunits in the placenta and the pituitary gland, two cell types that have clearly been shown to be regulated by exogenous inhibin, may reflect existing paracrine and/or autocrine processes active in these tissues. The second observation is that expression of inhibin subunit RNAs may vary by severalfold in a tissue-specific fashion. for example, alpha-subunit RNA levels are abundant in the gonads, whereas beta A-subunit RNA is predominant in the placenta and bone marrow. Finally, it is noted that expression of testicular inhibin RNA subunits decreases during sexual maturation. We conclude that the dimers comprised of inhibin subunits possess diverse functions and may act as growth/differentiation factors as well as a hormone.
Attempts to induce ovulation have been made since the early 1920s, but the major breakthrough came in the early 1960s with the introduction of clomiphene citrate and the gonadotropins. Additional progress was made in the early 1970s with the introduction of bromocriptine and in the early 1980s with the introduction of pulsatile GnRH. At the present, 'pure' FSH and GnRH agonists are being evaluated as adjuncts to HMG for induction of ovulation. As more insight is gained in the neuroendocrine control of the ovulating cycle, we may soon be able to induce ovulation by direct manipulation of the central nervous system.
Kennedy JL et al., 1987·Obstet Gynecol Clin North Am·
Methods to induce ovulation in anovulatory women have blossomed over the last three decades. The introduction of clomiphene citrate in 1960 allowed us for the first time to provoke follicle development in patients with normo or hyperestrogenic forms of anovulation. The development of human menopausal gonadotropins in the early 1960s gave us a much more powerful tool with which to influence ovulation in all forms of ovulatory disturbances. Elucidation of the pulsatile secretion of gonadotropin-releasing hormone together with its isolation and synthesis has allowed us to streamline our methods of inducing ovulation in hypothalamic amenorrheic patients by using endogenous control mechanisms to maximize both safety and effectiveness. However, there are problems yet to solve. Polycystic ovarian disease has long eluded our efforts to resolve its pathophysiology as well as to devise a consistently effective and safe means of treatment. Methods to restore ovulation in patients with polycystic ovarian disease refractory to clomiphene citrate is the quest of future investigations.
Enriched small and large cell fractions were prepared from mature corpora lutea from 15 women in the midluteal phase by enzymatic dissociation, followed by Percoll gradient centrifugation. The steroidogenic function of each cell type was assessed by measuring the gonadal steroids released into the incubation medium. The large cell fraction was estimated to be 97% pure, with minimal contamination by small cells, whereas the small cell fraction was approximately 68% pure, being contaminated with 10% large cells and 22% nonsteroidogenic cells. In the unstimulated state, large cells were approximately 2-fold more potent in progesterone formation and aromatase activity, but only half as potent in androstenedione and testosterone formation as an equal number of small cells. When stimulated with hCG, the small cells responded with significant increases in progesterone, androstenedione, and testosterone release, but the large cells did not. Both cell types secreted estrone and 17 beta-estradiol in the presence of androgen substrate, but the addition of FSH significantly stimulated aromatization only in large cells. Thus, small and large human luteal cells have steroidogenic properties similar to those exhibited by follicular thecal and granulosa cells, respectively.
An integrated luteal progesterone (ILPL) was calculated on the basis of a luteal progesterone (P) level with the assumption that the daily plasma P level in the luteal phase closely approximates a sine curve. The midluteal P-amplitude (K) was also obtained mathematically. Daily luteal P levels from five normal ovulatory cycles were assessed for the biologic variation of ILPL and K, then compiled to construct a normogram of the ILP during the luteal phase. The coefficient of variation of K and total ILPL in each cycle ranged from 9.7% to 24.3% and 3.5% to 13.2%, respectively. Fifty-two infertility patients were evaluated for their luteal function by the luteal P and estradiol (E2) level, K, ILPL, endometrial biopsy (EBX)-lag-day, as well as the lengths of follicular phase, luteal phase (L#), and cycle. Thirty-nine patients had EBX-lag day less than or equal to 2 days and were designated as infertile-normal (INF-NL) luteal phase, while the remaining 13 patients who had EBX-lag day greater than 2 days were considered as luteal phase defect (LPD). Significant (P less than 0.05) differences were observed between INF-NL and LPD in: luteal length (13.2 +/- 0.31 versus 11.0 +/- 0.58 days, respectively), and total ILPL (170 +/- 8.3 versus 113 +/- 8.5 ng/ml-day, respectively). No differences were seen in luteal P, E2 and K levels, nor in follicular and cycle length. Significant (P less than 0.05) correlations were observed between total ILPL and luteal P, E2, L#, and K; while a negative correlation was noted between follicular and luteal length.(ABSTRACT TRUNCATED AT 250 WORDS)
In order to evaluate the relationship between the urinary luteinizing hormone (LH) surge as detected by the OvuSTICK (Monoclonal Antibodies, Inc., Mountain View, CA) method and daily cervical mucus parameters, ten spontaneously ovulating women undergoing infertility evaluation were followed during their cycles with twice daily urinary LH testing as well as daily ultrasound, mucus evaluation, and hormonal assays of serum LH, progesterone (P), and estradiol (E2). Maximal cervical mucus scores, as determined using a modified Insler score, were noted to coincide consistently with the urinary LH surge as detected by twice daily testing and to precede ultrasound evidence of ovulation by 0 to 24 hours. Mucus scores rapidly declined in the 24-hour period following the urinary LH surge. Detection of the urinary LH surge may therefore help identify that period of time during which cervical mucus parameters are optimal and therefore facilitate the timing of artificial insemination, intercourse, or postcoital testing.
Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.
Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.
The bioavailability of micronized progesterone (P) was studied by measuring sequential serum P concentrations after a single bolus of 50-200 mg P given sublingually, orally (capsule and tablet), vaginally and rectally (suppositories) during the follicular phase in a group of normally menstruating women. When compared to other modes of P administration, the area under the curve during the first eight hours was twice as high with the rectal route. With 50 and 100 mg P given sublingually and 100 and 200 mg ingested as tablets, peak levels and area under the curve were twice as high with the higher dosage. The response was more sustained with the higher dosage. All subjects exhibited a significant increase in serum P levels over baseline that persisted for at least eight hours. P levels were still increased over baseline at 24 hours in all subjects after the administration of 100-mg vaginal and rectal suppositories and 200-mg tablets. These findings are in general agreement with previous reports showing that luteal phase serum P concentrations can be reached easily with non-parenteral modes of administering micronized P and that oral P administration could become an attractive alternative to the currently used oral mode of administering synthetic progestins.
Reproductive change during conditioning exercise (physical training provides a model of hypothalamic adaptation to alterations in the external and internal environment. Parallels exist between the reproductive changes with exercise and those occurring with physical illness, undernutrition and psychological trauma. Although menstrual cyclicity may be disrupted in younger women, luteal phase shortening, anovulation and decreased premenstrual symptoms within normal ovulatory cycles are the most frequent observations noted. Baseline LH, prolactin and oestradiol tend to be lower, and other hormones unchanged, in trained women. Testosterone may be decreased within the normal range in men. Recent evidence shows that LH pulse frequency, amplitude and area under the LH curve are decreased in both female and male runners. Interrelationships between increases in central dopamine, endorphin and probably some hypothalamic message(s) relating to nutritional state appear to modulate these reproductive changes. The clinical and therapeutic response to reproductive alterations in the context of exercise differs when these are seen as adaptive and not as disease processes (Prior and Vigna, 1985b).
The luteinized unruptured follicle syndrome is a form of anovulation and a subtle cause of female infertility. The syndrome cannot be diagnosed by traditional progesterone-dependent ovulation detection methods. Without the use of invasive procedures or sophisticated equipment, the luteinized unruptured follicle syndrome may go unnoticed. The patient diagnosed as ovulatory, on the basis of traditional ovulation detection methods, who does not conceive may be experiencing the luteinized unruptured follicle syndrome, and thus infertility. The syndrome's incidence, detection, etiology, and treatment are described.
We have previously shown that prophylactic supplementation of progesterone beginning in the luteal phase of patients treated with human menopausal gonadotropins (hMG) could reduce the risk of spontaneous abortions. The present study was initiated with 100 patients to evaluate the efficacy of a new progesterone therapeutic regime in patients requiring either hMG or clomiphene citrate. A significantly decreased risk of spontaneous abortion (6% vs. 28%) was seen in 50 patients prophylactically treated with progesterone as compared with 50 control patients. The progesterone regimen was then tried on 566 consecutive patients who were treated and conceived with hMG or clomiphene citrate, and approximately the same risk (6.2% by 20 weeks) was found. This incidence of spontaneous abortion is even less than the accepted risk for the general population.
Endocervical gland estrogen receptor (ER) deficiency has been proposed as a possible cause for the poor cervical mucus (CM) in some infertile women with cervical factor. Cytosol ERs were measured in endocervical tissue obtained by biopsy within 3 days of ovulation (determined by the endogenous luteinizing hormone [LH] surge) in five infertile women with persistent poor preovulatory CM (group 1) and in endocervical tissue obtained in the late follicular phase in eight ovulatory women with excellent CM (group 2). ER concentrations were measured in Fmol/mg protein by the dextran-coated charcoal separation method (New England Nuclear Kit, Boston, MA). CM score evaluation and measurement of serum estradiol (E2) and progesterone (P) levels were performed concomitantly. Serum E2 levels of 123.4 +/- 29.3 pg/ml (mean +/- standard error of the mean [SEM]) in group 1 were comparable to E2 levels of 123.3 +/- 15.0 pg/ml in group 2. Serum P concentrations of 0.9 +/- 0.27 ng/ml in group 1 were comparable to 0.79 +/- 0.29 in group 2. A CM score of 4.6 +/- 0.69 in group 1 was significantly lower than 11.6 +/- 0.53 in group 2 (P less than 0.01). The cytosol ER was negative in four of five women in group 1, whereas in group 2, ER was positive in six, borderline in one, and negative in one subject. This study suggests that cytosol ER may be deficient in some women with cervical factor.
Reproductive function in humans changes markedly during life and is usually divided into four stages. During the initial stage, which begins early in fetal life and ends in infancy, gonadotropins and gonadal steroids are secreted at levels similar to those seen in early and mid-adolescence. In the second stage, which lasts from infancy through the first decade of life, reproductive function first regresses and then becomes quiescent. Puberty, the third stage, is heralded by a nocturnal increase in the secretion of gonadotropins and sex steroids. This nocturnal predominance gradually diminishes and disappears during the fourth stage — adulthood. In men, . . .
A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2 level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.
The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.
Two hundred seventy-four infertile patients and 43 women with two or more previous first-trimester abortions underwent a luteal function evaluation by basal body temperature, plasma progesterone, estradiol and prolactin determination, and endometrial biopsy (repeated in a later cycle when the first was defective). An endometrial luteal phase deficiency was detected in 37 (13.5%) of the infertility cases and in 14 (32.5%) of the patients with recurrent miscarriage. However, the endometrial defect was associated with normal hormonal levels in the great majority of patients (86.3%).
The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.
Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, raised luteinising hormone: follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.
Luteal phase deficiency, diagnosed by endometrial biopsy, was found in 1 out of 25 control fertile women and in 46 out of 355 infertile patients, a difference that was not significant. It was also found in 19 [corrected] out of 60 patients with early recurrent abortion which was significantly higher than in controls and in infertile patients. Pregnancy outcome was evaluated in treated and untreated groups of patients diagnosed as having luteal phase deficiency. Our data suggest that treatment improved the results of pregnancy in patients with recurrent abortion, but not in infertile patients.
Fotherby K et al., 1986·Journal of obstetrics and gynaecology
2 recent studies largely dispel concern about the restoration of fertility after discontinuation of injectable contraceptives. After cessation of use of depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate there is some delay in fertility restoration, but fertility is not impaired once the progestogen is cleared from the body. Pharmacokinetic data suggest that norethisterone enanthate exerts less of an inhibitory effect on the hypothalamic-pituitary-ovarian system than DMPA, so that ovulation returns earlier after discontinuation of the former injectable. There appears to be no significant difference between nulligravid and parous women in the return of fertility, indicating that use of injectable contraceptives does not need to be restricted to women who have completed their families. In Pardthaisong's study of over 1000 Thai women, the median delay until conception after contraceptive discontinuation was 3 months among oral contraceptive users, 4.5 months for the IUD, and 5.5 months for DMPA users. 36 months after discontinuation, only 6.4% of the 796 DMPA former users surveyed had failed to conceive. In a smaller scale study by Fotherby et al, the conception rate among discontinuers of norethisterone enanthate did not differ significantly from that among nonusers of contraception or users of nonsteroidal methods once an 8-week period for the clearance of norethisterone from the body had elapsed. The mean time to ovulation is similar to the clearance for norethisterone; for DMPA, in contrast, the mean time to ovulation is considerably longer than that of the clearance. In discontinuers of DMPA, the mean time for the return of ovulation (210 days) is only slightly less than the mean time for the return of fertility (260 days). However, for norethisterone enanthate, the mean time to conception is about 170 days compared to just over 80 days for the return of ovulation.
Ovulation was induced with one-quarter tablet (12.5 mg) of clomiphene citrate given for five days to three oligoovulatory patients who had consistently formed functional ovarian cysts when given 50 and 25 mg of clomiphene citrate for five days. Two of the patients had polycystic ovary syndrome and the other had hypothalamic dysfunction associated with an eating disorder. On clomiphene citrate 12.5 mg for five days, one patient conceived, another produced inadequate cervical mucus but later conceived after in vitro fertilization and embryo transfer, and the third woman, who had concomitant fallopian tube disease, ovulated but has not conceived. Women oversensitive to clomiphene citrate can be effectively treated with very low doses of the drug. Perhaps other oligoovulatory patients may benefit from lower than currently recommended clomiphene citrate doses.
Progesterone (P) has not been administered orally because of reportedly poor bioavailability and a rapid clearance rate. Unfortunately, the synthetic derivatives, although orally active, have a number of disadvantages and fail to mimic natural P completely. To investigate the bioavailability and short-term toxicity of oral micronized P, a standardized dose of 200 mg of micronized P was administered to nine healthy postmenopausal women and one male subject. Serial determinations of serum P concentrations demonstrated rapid absorption of P. Peak concentrations of P rose from a negligible baseline level to 17.0 +/- 4.9 ng/ml at an average of 2.8 +/- 0.35 hours after administration. The peak concentrations of P were equivalent to those observed in the midluteal phase in normal control cycles (14.1 +/- 2.7 ng/ml). All subjects exhibited significant elevation of P over baseline levels that persisted for at least 6 hours after the single oral dose and returned to initial levels by 24 hours. There was no significant change in estradiol, follicle-stimulating hormone, luteinizing hormone, cortisol, aldosterone, lipids, or hepatic enzymes during the 24-hour study interval.
In a consecutive series of 167 patients reaching the stage of embryo transfer after in vitro fertilization and embryo transfer, 19 clinical pregnancies ensued. The serum progesterone (P) levels were significantly greater on the first and second (P less than 0.01) and third (P less than 0.05) postaspiration days for those who conceived. Higher circulating levels of P were achieved on days 1, 2, and 3 (P less than 0.05) by the daily injection of P, 50 mg in oil, given for 5 consecutive days, beginning immediately after follicle aspiration. Both pregnancy and nonpregnancy cycles demonstrated high circulating P levels, but the study implies that relatively higher levels are required for conception, and such levels can be achieved by the use of intramuscular P.
To examine the site of action of clomiphene citrate (CC), LH and FSH pulsatile amplitude, frequency, and responsiveness to GnRH (10 micrograms, iv) were studied in 11 women during the early follicular phase of the menstrual cycle. Six women received CC (150 mg/day) on cycle days 2, 3, and 4, while 5 women received placebo tablets. Blood samples were drawn at 10-min intervals for 8 h before and after the treatment regimen on cycle days 2 and 5, respectively. All women treated with CC had multiple follicular development, as determined by ultrasound. Peripheral levels of estradiol did not change after CC treatment, while progesterone levels decreased slightly. Mean levels of LH increased from 7.5 +/- 0.9 (+/- SEM) to 10.7 +/- 1.4 mIU/ml (P less than 0.05), and FSH increased from 6.7 +/- 0.9 to 10.1 +/- 0.9 mIU/ml (P less than 0.01). After exposure to CC, the pulse frequency of LH during an 8-h period increased significantly (3.3 +/- 0.7 on day 2 vs. 6.8 +/- 0.8 on day 5; P less than 0.01), while the pulse frequency of FSH increased from 3.8 +/- 0.6 to 5 +/- 1.4, as determined by computer pulse analyses. The pulse amplitude of LH and FSH was not significantly altered. In the placebo-treated group, neither pulse amplitude nor pulse frequency changed significantly between cycle days 2 and 5. Pituitary sensitivity to exogenous GnRH did not change after CC treatment. Since the pulsatile frequency of LH is governed by hypothalamic influences, these findings provide compelling evidence for a hypothalamic site of action for CC, probably by inducing an increase in the frequency of GnRH secretion.
Gonadal steroids are altered by the reproductive system's adaptation to conditioning exercise. Contraceptive options for the athletic woman include all measures appropriate for the sedentary woman. Barrier methods (always with spermicidal jelly) are the preferred choice. The cardiovascular risks, decreased aerobic performance, and shorter time to muscular exhaustion related to oral contraceptives make this a less desirable option. Potential complications from the steroid changes of intense exercise include: low oestrogen and progesterone with risk of loss of trabecular bone and early osteoporosis, and absent progesterone with low normal oestrogen levels associated with risk of endometrial or breast cancer. Therapeutic options for the amenorrhoeic or young athlete include supplemental oral calcium, cyclic oral progesterone, or possibly cyclic physiological oestrogen and progesterone. The anovulatory (usually older) athlete with regular menses needs cyclic progesterone. Medroxyprogesterone 10mg on days 16 to 25 of the cycle or for 10 days monthly can potentially prevent endometrial and breast cancer, give predictable cycles, improve trabecular bone balance and stimulate the return of ovulatory cycles. A practical approach to anovulatory infertility in the athlete includes a 10% reduction in exercise intensity and/or an increase in percentage body fat to 18 to 20%. Cyclic vaginal progesterone (25mg bid) can then treat short luteal phase cycles. With improved understanding of the hormonal adaptations to conditioning exercise, we will be better able to outline contraceptive and therapeutic options in the future.
Substantial evidence now exists to indicate that the endogenous hypothalamic opioidergic mechanism(s) represents one of the important controlling systems for release of gonadotropin-releasing hormone. Modulations of frequency and amplitude of the secretory activity of gonadotropin-releasing hormone appears to be mediated through an inhibitory action of endogenous opioids, and the functional coupling of the opioidergic and gonadotropin-releasing hormone systems is an ovarian steroid-dependent event. There is also evidence to implicate suprahypothalamic mechanism(s) that enhance endogenous opioid inhibition of secretion of gonadotropin-releasing hormone. Although exogenous opioid peptides and their synthetic analogs consistently induce the secretion of prolactin, blockade of opioid receptors in humans by naloxone failed to elicit a decrement in the levels of prolactin under a variety of conditions. On the contrary, naloxone induced a remarkable increment in the secretion of prolactin via an increased frequency of pulsatile release which is synchronized with pulses of luteinizing hormone. These observations suggest that a common neuroendocrine mechanism is involved in the opioidergic control of the secretion of both luteinizing hormone and prolactin in women.
Dennerstein L et al., 1985·Br Med J (Clin Res Ed)·
A double blind, randomised, crossover trial of oral micronised progesterone (two months) and placebo (two months) was conducted to determine whether progesterone alleviated premenstrual complaints. Twenty three women were interviewed premenstrually before treatment and in each month of treatment. They completed Moos's menstrual distress questionnaire, Beck et al's depression inventory, Spielberger et al's state anxiety inventory, the mood adjective checklist, and a daily symptom record. Analyses of data found an overall beneficial effect of being treated for all variables except restlessness, positive moods, and interest in sex. Maximum improvement occurred in the first month of treatment with progesterone. Nevertheless, an appreciably beneficial effect of progesterone over placebo for mood and some physical symptoms was identifiable after both one and two months of treatment. Further studies are needed to determine the optimum duration of treatment.
A prospective longitudinal and standardized study is presented, dealing with ultrasonographic and hormonal characteristics of the luteinized unruptured follicle (LUF) syndrome. Among 600 cycles monitored in 270 infertility patients, 40 cycles in 27 patients showed no evidence of follicle rupture, in spite of signs of luteinization, as reflected by basal body temperature recordings and progesterone determinations. In this study, 20 LUF cycles in 20 infertile patients were compared with 45 ovulatory cycles in 45 control women. During the follicular phase, no substantial difference in follicle growth was found, but after the luteinizing hormone peak, LUF follicles, instead of rupturing, showed a typical accelerated growth pattern. Both mean luteinizing hormone peak levels and midluteal progesterone levels were significantly lower in LUF cycles than in the control cycles. However, the duration of the luteal phase was not affected. Both central and local factors can be held responsible for the lack of follicle rupture. Ultrasound offers new possibilities as a noninvasive method in diagnosing the LUF syndrome.
Serum hormone concentrations were determined at intervals during the last 17 days of the menstrual cycle in 35 patients with premenstrual tension (PMT) and 11 control subjects without symptoms. The maximum mean concentration of oestradiol occurred 17 days before menstruation in the patients and 14 days before in the controls. The maximum concentrations of progesterone were similar in the two groups but the mean concentrations rose earlier in the cycle in the patients with PMT. These results suggested that the patients tended to ovulate earlier in the cycle than the controls and on the basis of the ovulatory surge in gonadotrophins two groups could be identified, group A who showed signs of ovulation 14 days or less before menstruation (17 patients, 9 controls) and group B who ovulated more than 14 days before menstruation (18 patients, 2 controls). There were no significant differences between the groups in prolactin, thyroid stimulating hormone or testosterone levels, but cortisol concentrations were uniformly higher in both groups of patients compared with those in the controls. Follicular growth was assessed with ultrasound in 18 patients and 16 control subjects. Mean follicular diameters were significantly lower in the patients than in the control group at the time of ovulation. Oestradiol determinations done at the same time correlated with the diameters and were also significantly lower in the patient group. The results suggest that ovulation tends to occur prematurely in women with PMT.
A 34-year-old male with a pituitary adenoma was investigated and demonstrated to have hypersecretion of both gonadotrophins in the basal state. Immunocytochemical staining and electron microscopic examination were positive for tumour cells secreting FSH and LH. Presenting symptoms included visual disturbances, loss of libido, impotence, cold intolerance, frontal headaches, change in skin pigmentation and excessive weight gain. The patient denied alteration in hair distribution, had no acral features, galactorrhoea or gynaecomastia. Surgical extirpation resulted in complete amelioration of his symptoms over a three year follow-up period. Basal and stimulated pituitary function testing results returned to normal post-operatively. A review of the literature documents six other cases of pituitary tumour secreting both LH and FSH in the basal state. More commonly, the pituitary adenoma secretes FSH only. The literature is reviewed with regard to both types of tumour.
More than 100 years after the first description of endometriosis, the pathophysiology of the disorder still remains an enigma. In addition to infertility, an increased frequency of clinically apparent spontaneous abortions (32% vs. 8-15% in the normal population and 19% in the infertile one) has been found in women with endometriosis and secondary infertility. Treatment of endometriosis with conservative surgery, danazol or both results in a frequency of spontaneous abortion within the range of the normal population's. Although the factors involved in the pathophysiology of endometriosis are probably multiple, abnormal corpus luteum function is a common mechanism that might explain both the infertility and the spontaneous abortions. Several studies suggested a relationship between endometriosis and corpus luteum function, which may be mediated by prostaglandins. However, not all the data have been supportive. We developed a hypothetical scheme (modified from Drake) that outlines possible mechanisms of endometriosis mediated by the adverse effects of increased prostaglandins. Further investigation of this scheme may provide new information about the pathophysiology of endometriosis.
Pittaway DE et al., 1984·The Journal of reproductive medicine
More than 100 years after the first description of endometriosis, the pathophysiology of the disorder still remains an enigma. In addition to infertility, an increased frequency of clinically apparent spontaneous abortions (32% vs. 8-15% in the normal population and 19% in the infertile one) has been found in women with endometriosis and secondary infertility. Treatment of endometriosis with conservative surgery, danazol or both results in a frequency of spontaneous abortion within the range of the normal population's. Although the factors involved in the pathophysiology of endometriosis are probably multiple, abnormal corpus luteum function is a common mechanism that might explain both the infertility and the spontaneous abortions. Several studies suggested a relationship between endometriosis and corpus luteum function, which may be mediated by prostaglandins. However, not all the data have been supportive. We developed a hypothetical scheme (modified from Drake) that outlines possible mechanisms of endometriosis mediated by the adverse effects of increased prostaglandins. Further investigation of this scheme may provide new information about the pathophysiology of endometriosis.
Twenty-five infertile women conceived while taking tamoxifen (TMX). Daily serum profiles of 5 of the 25 TMX-induced conception cycles were elucidated and compared with those found in 5 normal cycles. In spite of lower levels of follicle-stimulating hormone and luteinizing hormone during the follicular phases, estradiol concentrations were higher in the TMX-induced conception cycles. It is suggested that this may be due to a direct ovarian effect of TMX as one of its major mechanisms in the course of folliculogenesis. On the other hand, progesterone concentrations on days 6 and 7 during the luteal phases were also higher in the TMX-induced conception cycles. It is suggested that this may be due to a luteotropic influence at the blastocyst stage.
Tamoxifen (Norvadex), synthesized by the Imperial Chemical Industries Ltd., is a triphenylethylene derivative having a clomiphene-like structure and displays anti-estrogenic activities. In this study we used tamoxifen for the treatment of anovulatory infertility and investigated the clinical results. Induction rate of ovulation recorded 100% in the patients with sporadic anovulatory cycle, 83.3% in those with persistent anovulatory cycle, 70% in those with the first grade amenorrhea type I and 66.7% in those with the first grade amenorrhea type II. However, tamoxifen was absolutely ineffective against the second grade amenorrhea. The patients with sporadic or persistent anovulatory cycle responded to 40 mg-daily tamoxifen-treatment, recording 100% of ovulatory induction rate. The patients with the first grade amenorrhea also responded to 60 mg-daily treatment, indicating 70% of ovulatory induction rate. The rate of pregnancy established in the women desiring pregnancy marked 15.4%, and 2 out of 4 women with successful pregnancy experienced spontaneous abortion. Out of 4 patients who did not respond to the previous clomiphene treatment, 3 women accomplished ovulatory induction with tamoxifen. The endocrinological dynamics in the tamoxifen treatment were similar to those in the clomiphene treatment.
Pulsatile secretion of LH in women has been shown to vary during the menstrual cycle. LH pulse frequency during the luteal phase is markedly reduced compared to that in the follicular phase. The objectives of the present study were to determine if similar changes in pulsatile LH secretion occur in the monkey, and whether endogenous opiates are involved in producing these changes. In order to document if LH pulse frequency is reduced in the nonhuman primate luteal phase, serial blood samples were collected from 10 rhesus monkeys at 15-min intervals for 6 h at 3 different times of the luteal phase (early, mid-, and late). This pattern of secretion was contrasted to that observed during the ensuing early follicular phase. LH pulse frequency during the luteal phase was significantly reduced compared to the early follicular phase. Mean pulse frequency (+/- SE) was 0.84 +/- 0.16 pulses/6 h in the luteal phase vs. 2.99 +/- 0.58 pulses/6 h in the early follicular phase. When endogenous opioid activity was blocked during the luteal phase by a 5-h continuous infusion of naloxone (2 mg/h), an opiate antagonist, LH pulse frequency was increased to 2.48 +/- 0.25 pulses/5 h. This frequency was markedly different from the frequency of 0.85 +/- 0.17 pulses/5 h observed in the control period which immediately preceeded the naloxone infusion. The mean amplitude of the LH pulses in the luteal phase, which was significantly greater than that observed in the early follicular phase (20.9 +/- 1.9 ng/ml and 11.7 +/- 0.3 ng/ml) was not affected by naloxone (23.5 +/- 2.4 ng/ml vs. 25.3 +/- 1.9 ng/ml). Infusion of naloxone for longer periods (9 h) in 3 additional monkeys caused an increase in LH pulse frequency which was maintained in 2 of the monkeys, whereas the third animal exhibited only an acute response (a single pulse). These results indicate that the reduction in LH pulse frequency that occurs in the luteal phase of the rhesus menstrual cycle is an event in which endogenous opiates participate. Our previous finding that beta-endorphin release from neurons in the median eminence is stimulated during the luteal phase of the monkey, together with the present results, suggest that beta-endorphin functions as a modulator of pulsatile LH secretion in the primate menstrual cycle.
The antiestrogenic effect of clomiphene citrate (CC) on cervical mucus was evaluated in women receiving 150 mg CC daily for 5 days. Daily cervical mucus scores and serum estradiol (E2) concentrations were determined in control (n = 25) and CC (n = 24) cycles. E2 concentrations were significantly higher in the CC-treated women (mean +/- standard error of the mean, 1254 +/- 102 pg/ml versus 337 +/- 18 pg/ml, P less than 0.0001). Despite supraphysiologic E2 concentrations, however, cervical mucus scores were significantly reduced in the CC-treated group (P less than 0.01). These data indicate that CC exerts a direct suppressive effect on cervical mucus despite markedly increased E2 concentrations.
Cervical mucus forms channels when dried under a coverslip. The aim of the present work was: 1) to prove mucus canalization both in spontaneous ovulatory cycles and during ovulation induction with gonadotropins; 2) to prove the estrogen dependence of this phenomenon; 3) to check the importance of the proteidic and electrolytic concentration on chaneling; and 4) to use this phenomenon clinically, shortening the time in which it occurs. The number and arrangement of channels vary during the cycle. The phenomenon is estrogen-dependent. The comparison between estradiol values and the number of channels during spontaneous ovulatory cycles and treatment with gonadotropins showed a linear relationship. Treatment with estradiol 17 beta-valerate and ethinyl estradiol induced channel formation in women with primary amenorrhea. Canalization and ferning disappeared after dialysis or treatment with proteolytic enzymes. It follows that the two phenomena have similar characteristics. Canalization increases daily, as does estradiol, whereas ferning maintains the same grade for a longer period, and when a grade of + + + is reached, it provides no further indications. With the use of a thermostat, canalization occurred in only a few hours. Chaneling, a more precise index, could therefore substitute for ferning, particularly when monitoring the induction of ovulation.
Tamoxifen at a dose of 10 mg/day for 5 days was given to five infertile women in the luteal phase. Daily serum samples were obtained during the luteal phase for radioimmunoassay of progesterone (P), estradiol (E2), follicle-stimulating hormone, luteinizing hormone (LH), and prolactin levels. The integrated luteal phase concentrations of serum P and E2 before and after cycles of tamoxifen treatment increased from 87.8 +/- 16.2 ng/ml and 1120 +/- 164.4 pg/ml to 131.6 +/- 18.9 ng/ml and 1461 +/- 205.2 pg/ml, respectively (P less than 0.01 and P less than 0.05). No apparent increase in circulating LH levels was seen in one of the five cases, but this patient's serum P and E2 levels rose nonetheless. This suggests that the significant increase in circulating P and E2 induced by tamoxifen is not consistently associated with an increase in serum LH concentration.
Luteinizing hormone (LH) receptor concentrations in ovarian follicles and corpora lutea were measured in 51 patients with histologically proven endometriosis and in 41 control patients. The LH receptor concentrations in cases of endometriosis were lower during the early (0.43 +/- 0.11 [mean +/- standard error] versus 1.31 +/- 0.27 fmol/mg protein; P less than 0.001) and late (0.48 +/- 0.10 versus 1.59 +/- 0.22 fmol/mg protein; P less than 0.001) follicular phase, and during the late luteal phase (2.62 +/- 0.55 versus 4.62 +/- 0.65 fmol/mg protein; P less than 0.05) of the cycle than in control patients. In contrast to the control patients, the LH receptor concentration during the follicular phase remained constant in endometriosis, being lower in patients with extensive or severe disease than in patients with moderate or mild disease (0.28 +/- 0.07 versus 0.61 +/- 0.21 fmol/mg protein; P less than 0.05). Endometriosis-associated infertility might be a consequence of a defect in the mechanism mediating LH action in the ovaries.
Mansfield MJ et al., 1984·Journal of Reproductive Medicine
Amenorrhea and oligomenorrhea in the adolescent female are often the result of anovulation due to an immature hypothalamic-pituitary-ovarian axis. A careful history, physical examination and selected laboratory tests can help to differentiate this type of transient menstrual irregularity from the large number of endocrine and anatomic abnormalities that also present in this age group. The HPO axis is not fully mature at menarche. Since the positive feedback response to estrogen, which allows ovulation, is frequently absent in the immediate postmenarchial period, menstrual irregularity is common: 55% of cycles are anovulatory in the 1st year. With further maturation of the HPO axis a pattern of regular ovulatory cycles emerges. Basic evaluation is indicated if menarche does not occur by age 16 or if secondary sexual development does not begin by age 14. Secondary amenorrhea is the absence of menses for at least 3 months in a patient who previously had established cycles. Causes of amenorrhea in adolescents include pregnancy, drugs and systemic diseases, hypothalamic and pituitary amenorrhea, postpill amenorrhea, hyperprolactinemia, androgen resistance, congenital anomalies of the genital tract, and androgen excess.
Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).
Filicori M et al., 1984·J Clin Invest·
Open Access
The pattern of episodic gonadotropin release was studied in 15 normal female volunteers during the luteal phase of the menstrual cycle with 24 h of blood sampling for follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 10-min intervals. Six subjects (two in the early, two in the mid-, and two in the late luteal phase) also had each of these specimens processed for progesterone levels. A progressive slowing of LH pulsations was present across the luteal phase with the mean LH pulse frequency declining from 15.2 pulses/24 h in the early to 8.4/24 h in the late luteal phase. A trend towards reduction in the amplitude of LH pulses was also observed (12.3 +/- 2.2 SD mIU/ml in the early vs. 8.6 +/- 3.4 mIU/ml in the late luteal phase; NS). In addition, LH pulses of heterogeneous amplitude were identified during the same 24-h study. The mean +/- SD of the larger and of the smaller LH pulses was 16.9 +/- 4.7 and 2.3 +/- 1.0 mIU/ml, respectively (P less than 0.001). While the slowing of the frequency of all LH pulses correlated well (r = 0.80, P less than 0.001) with the day of the luteal phase and poorly with the actual plasma progesterone levels, the incidence of the small LH pulses was highest in the mid-luteal phase and correlated well with the mean progesterone plasma levels (r = 0.63, P less than 0.01). In the early luteal phase, the pattern of progesterone secretion was stable over the 24-h studies and showed no relationship to episodic LH release. In contrast, in the midand late luteal phase, plasma progesterone concentrations rapidly fluctuated during the 24-h studies from levels as low as 2.3 to peaks of 40.1 ng/ml, often within the course of minutes. Progesterone increments closely attended episodes of LH release, as documented by the significant (P less than 0.05) cross-correlation between LH and progesterone levels, at time lags of 25-55 min. The results of this study indicate that in the human luteal phase: (a) the frequency of pulsatile release of LH declines progressively and correlates well with the duration of exposure to progressively and correlates well with the duration of exposure to progesterone; (b) the amplitude of LH pulses varies with the appearance of an increased percentage of smaller pulses correlating well with the acute level of progesterone; (c) in the early luteal phase, the pattern of progesterone secretion is stable; (d) in the midand late luteal phase, progesterone secretion is episodic, and correlates with LH pulsatile release; and (e) single progesterone estimations in the midand late luteal phase do not accurately reflect corpus luteum adequacy.
Diagnosis, choice of therapy, and pregnancy outcome were analyzed in 79 women evaluated for luteal phase inadequacy. Criteria for the diagnosis were established, and groups at risk for luteal inadequacy were identified. Treatment choices, tailored to the suspected cause, included progesterone suppositories in 54 women, with 23 pregnancies and 19 deliveries; clomiphene citrate in 6 women, with 2 pregnancies and deliveries; and combined treatment in 7 women, with 5 pregnancies and 4 deliveries. Eight women received no treatment, including three who underwent endometrial biopsy in the cycle of conception and who subsequently delivered. These data suggest that careful diagnosis and the proper choice of treatment are important, and that progesterone supplementation may result in improved pregnancy outcome for patients with infertility and pregnancy wastage who have luteal phase inadequacy.
Among 150 patients admitted for ovum aspiration, in vitro fertilization, and embryo transfer in Perth, Western Australia, 14 were found to have had at least one ovulated follicle at the time of laparoscopy. Based upon ultrasound estimation of follicle diameter 24 hours previously, ovulation occurred in 6 of 22 follicles less than 1.7 cm in mean diameter and in 16 of 19 follicles greater than 1.7 cm in mean diameter. When the ruptured follicles were flushed with heparinized fertilization medium, oocytes were collected in 13 of the 22 dispersed follicles. Twelve oocytes developed pronuclei 16 hours after the addition of spermatozoa, and 11 cleaved to the 4-cell stage within 44 hours of insemination. Oocytes were recovered from 6 of 11 patients stimulated with clomiphene alone and from all 3 patients stimulated with clomiphene supplemented with human menopausal gonadotropin. These observations suggest that oocyte release and follicle rupture are not necessarily synonymous events and that the incidence of retained oocytes in ovulated follicles following stimulation with clomiphene or clomiphene plus human menopausal gonadotropin could be on the order of 60%.
Yovich JL et al., 1984·Aust N Z J Obstet Gynaecol·
Luteal phase lengths and hormonal profiles (progesterone, oestradiol-17 beta, beta HCG and prolactin) have been documented in 77 cases derived from a series of patients undergoing IVF. Nineteen pregnancies were generated during this series and 12 healthy infants have already been delivered. Luteal phase lengths were 14.5 +/- 0.5 days with 14.3% demonstrating mid-luteal progesterone levels of less than 31 nmols/l, considered to be low for successful conception. A random study of luteal support regimens comparing HCG or medroxyprogesterone acetate (MPA) with nil therapy was studied in a series of 44 consecutive embryo transfers during which 10 pregnancies were achieved. No difference was noted in the pregnancy rates for the 3 groups but the pregnancy outcome was better in those who had HCG support and this was more apparent in the overall series of 19 pregnancies. A significant luteotrophic effect was noted with HCG support regimens whilst MPA appeared to have a luteal suppressant action. Six pregnancies which aborted with blighted ova were derived from cycles in which the luteal phase progesterone levels were low raising the possibility that a poor hormonal environment may predispose to blighted ova.
By studying the changes of microscopic and ultramicroscopic structure of cervical mucus and the corresponding changes of ovarian hormone levels throughout the cycle, a close correspondence was found between micro and ultramicrostructures. The optical structure of non canalized mucus and the electronic features of membranous mucus maintained a similarly unvaried morphology in spite of the striking changes in hormonal levels during the cycle. On the contrary, a varied morphology corresponding to the changes of cyclic levels of ovarian hormones was observed in the optical structure of canalized mucus and in the electronic features of filamentous mucus. Therefore, whatever its micro or ultramicroscopic features, the dehydrated mucus showed two components, one dependent and the other independent of ovarian hormones. A similar conclusion has also been reached for fresh mucus components.
Microsomal membranes sedimented at 40 000 g were prepared from human myometrium samples. The progesterone binding properties of microsomal suspensions were determined by incubating microsomes and [3H]progesterone at 4 degrees C. Dextran-coated charcoal was used for the separation of bound and free steroids. Membrane-associated progesterone binding sites of high affinity were identified in microsomes prepared from pregnant and nonpregnant uteri. The binding was saturable (Kd approximately 4 X 10(-9) M, concentration of binding sites 400-900 fmol/mg microsomal protein) and specific for natural progesterone. Of 21 steroids tested only 21-hydroxy-4-pregnene-3,20-dione, 17 alpha-hydroxyprogesterone and testosterone showed moderate competition against progesterone with relative affinities between 7.0-20.0% (R.A. of progesterone 100%). 5 alpha-Dihydroprogesterone and 5 alpha-dihydrotestosterone showed weak cross reaction (relative affinities 2.5 and 2.0%, respectively). Corticosteroids, estrogens and the 5 synthetic progestins tested showed only weak competition with relative affinities lower than 1.0%. These microsomal progesterone binding sites of high affinity and limited capacity resemble steroid hormone receptors but they are different from the soluble cytosolic progesterone receptor of human uterus in terms of steroid specificity. The physiological function of this microsomal progesterone receptor is unknown.
In some series the most appropriate therapy for luteal phase defects is supplemental progesterone in the luteal phase. Clomiphene's efficacy is more controversial since in one series only 8% achieved a successful pregnancy versus 45% in another study. Pelvic sonography was used to evaluate follicular development and release of the ovum in 50 infertile women with luteal phase defects. The results showed that only 40% had "pure" luteal phase defects whereas 52% had immature follicles and 8% had unruptured follicles. Sixty-two percent of the patients had previous therapy for a luteal phase defect and failed to conceive. Sixty-eight percent of this group did conceive when ultrasound was used to determine the appropriate therapy. Thus ultrasound can be employed to determine if the women with a luteal phase defect should be treated with a fertility drug, e.g., clomiphene or just with luteal phase progesterone support. Supplemental progesterone might still be needed with clomiphene based on repeat endometrial biopsy results.
Thirty-one women with severe premenstrual syndrome had low sex hormone binding globulin (SHBG) binding capacities 30.2 +/- 9.4 nmol DHT bound/l. The SHBG binding capacities rose when they were treated with three different doses of progesterone. On 400 mg (17 women) SHBG level was 45.11 +/- 11.80. On 800 mg (8 women) SHBG binding capacity rose to 64.75 +/- 14.30 and on the six women who took 1200 mg progesterone daily SHBG binding capacity was 78.5 +/- 23.10. These results are discussed.
In 121 women attending the infertility clinic between 1978 and 1982, 127 cycles with luteal phases of 10 days or more were investigated by a complete basal body temperature (BBT) chart, three plasma progesterone assays taken between 11 and 4 days before menses, and a dated endometrial biopsy (EB) taken at the time of the last blood sample. All parameters were normal in 78 women (64.4%) categorized as group I 'normal luteal phases (NLP)'. There were some discordances between the three parameters in the remaining 43 women: 8 had normal BBT but low progesterone levels and delayed EB. They form group II 'inadequate luteal phases'. 29 women (23.9%) had delayed EB despite normal progesterone levels: forming group III 'dysharmonic luteal phases (DLP)'. 6 women had advanced EB and normal progesterone levels: group IV. Apart from endometrial maturation, there was no difference between NLP and DLP, neither in clinical parameters (length of the follicular phase, date and duration of the thermal shift, length of the luteal phase), nor in progesterone levels. Fertilization occurred in four DLP biopsied cycles: pregnancies went normally to term, giving birth to normal babies. Therefore, the DLP syndrome, characterized by normal midluteal progesterone levels and a delayed endometrial development, is not incompatible with normal nidation and gestation.
Fourteen women experiencing early pregnancy failure have been studied during the time of conception and at frequent intervals until spontaneous abortion occurred. Serial measurements of serum estradiol, progesterone, 17 alpha-hydroxyprogesterone, prolactin, human placental lactogen (hPL), and human chorionic gonadotropin (hCG) were determined; regular sonar scanning allowed the time of fetal death to be determined to within 7 days in six patients and a diagnosis of blighted ovum to be made in the remainder. In all patients serum progesterone and estradiol concentrations were within the normal range up to 7 weeks but appeared to decrease from about 8 weeks' gestation whether or not a living fetus was present. The placenta continued to produce hCG and hPL but, despite the continuing presence of hCG, the levels of 17 alpha-hydroxyprogesterone declined to concentrations below those associated with normal pregnancy. These data suggest that the placenta may require a particular stimulus to take over production of progesterone and estradiol.
In women with premenstrual syndrome, negative changes start soon after ovulation gradually increasing as the corpus luteum develops, and reach a maximum during the last 5 days of the luteal phase. They decline rapidly once menstruation starts, disappearing within one or two days of ovarian steroids reaching baseline levels. Positive moods are at maximum when preovulatory estradiol reaches its peak. A comparison of hormone levels in women with high and low degrees of cyclical mood change showed no difference in progesterone, estradiol, testosterone, or androstenedione.
The application of centrifugal elutriation to the separation of pituitary cells has produced a fraction that is enriched with LH and FSH gonadotropes. In this study, stains were performed on serial sections of fractions taken from six elutriation experiments with 1:10,000-1:30,000 anti-bLH beta or 1:2,000-1:8,000 anti-hFSH beta and the avidin-biotin-peroxidase complex technique. Over 900 serially sectioned gonadotropes were analyzed. In the initial cell suspensions, 59.6% of the gonadotropes contained both LH and FSH; 18% contained LH, and 23% contained FSH. Fewer than 3% contained ACTH. The elutriation fractions contained several subtypes of gonadotropes. A few small (8 micron), poorly granulated LH or FSH cells were eluted with the smallest cells (10-12%) at flow rates of 15.7 ml/min. Medium sized gonadotropes (10-10.5 micron) that eluted at flow rates of 19.8-30.5 ml/min were infrequent (3-6%) and resembled the larger gonadotrope. An analysis of serially sectioned fields showed that only 15.2%-22% of the small and medium sized gonadotropes contained both LH and FSH, whereas 30-40% contained only LH and 46-50% stored only FSH. The gonadotrope-enriched fraction was eluted at 37-39.5 ml/min; 78% of these gonadotropes (diameter, 14-15 micron) contained both LH and FSH, 10% contained only LH, and 12% contained FSH. Finally, large cells (diameter, 15-16 micron) that contained FSH only were found in the Wash fraction. These studies demonstrate that smaller gonadotropes tend to store only one of the hormones whereas most of the larger cells either store LH and FSH together or FSH alone. These heterogeneous storage patterns may correlate with studies by others who measured different responses to GnRH in gonadotropes separated by size on a unit gravity sedimentation gradient. They may also reflect different secretory phases of gonadotropes from the mixed group of cycling female rats.
A prospective study is presented in order to determine the frequency of the luteinized unruptured follicle (LUF) in a population of 66 regularly cycling women. They were monitored by daily ultrasound for a total of 183 cycles, and the LUF was detected in 9 cycles, giving an incidence of 4.9%. The results of daily changes of luteinizing hormone, estradiol, and progesterone provide support for the thesis that the LUF behaves steroidogenically as a corpus luteum and that the luteal phase duration is normal. Continued monitoring in 35 cycles revealed a recurrence in only one case during a fourth subsequent cycle. Thus, the findings indicate that the LUF is a sporadic and infrequent phenomenon. It is therefore an uncommon cause of infertile cycles in potentially fertile women and represents a biologic variable rather than a syndrome. Based on ultrasonic and endocrine observations, a mechanism is proposed for the resolution of the LUF.
The concentrations of pregnanediol-3-glucuronide (PGD) and pregnanolone (PN) were measured in daily morning urine specimens from 66 infertile women (40 with varying degrees of endometriosis and 26 control subjects) and correlated with daily changes in basal body temperature (BBT) and with midluteal levels of serum progesterone (P). PN and BBT rose at midcycle in women with endometriosis, as expected, indicating secretion of some P at that time. However, PGD, the major endpoint of P metabolism, was delayed in its excretion. Endometrial biopsies were similarly delayed (out of phase) in women with endometriosis, and a significantly higher incidence of follicular luteinization was seen. It appears that while P secretion begins at midcycle, the bulk of P secretion is delayed, perhaps because of the process of follicular luteinization, and that a shortened functional luteal phase thus exists in women with endometriosis.
Daily estimations of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone were made in the serum of eight infertile patients from day 1 through the follicular phase during menstrual cycles before and after tamoxifen therapy. Tamoxifen therapy was found to shorten the follicular phase from 15.4 +/- 0.8 days (mean +/- standard error of the mean) to 14.0 +/- 0.6 days (difference not significant) and to lengthen the luteal phase from 12.8 +/- 0.4 days to 14.1 +/- 0.8 days (P less than 0.05). The mean estradiol concentration in the eight patients during tamoxifen treatment cycles rose on day 8 (3 days after starting tamoxifen treatment) and increased significantly (P less than 0.05) from day 10 to midcycle. The integrated follicular phase estradiol concentration in the tamoxifen treatment cycle increased to 2450.1 +/- 208.1 pg/ml/cycle, and was significantly higher (P less than 0.025) than that in the nontreatment cycle. In contrast, the concentrations of follicle-stimulating hormone, luteinizing hormone, and prolactin during the follicular phase and at the midcycle peak of tamoxifen treatment cycles were not significantly different from those of the nontreatment cycle. These results suggest that the mechanism of tamoxifen in improving folliculogenesis may involve a direct action on the ovary without intervention of the hypothalamic-pituitary system.
During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.
Thirteen women with luteal phase defects (LPD) confirmed by endometrial biopsies and 14 with histologically normal endometria were studied for early follicular and midfollicular phase follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and for midluteal phase progesterone, estrogen, testosterone, and prolactin levels. The results showed that the women with LPD had significantly lower FSH levels and FSH/LH ratios in the early and midfollicular phases. LH levels, however, were similar in the LPD and normal women. During the midluteal phase, the LPD women showed significantly lower levels of progesterone and estrogen and normal levels of testosterone and prolactin. These findings reaffirm the prevailing concept that events surrounding follicular growth and development can indeed influence the quality of that cycle's corpus luteum. Furthermore, LPD as a result of hyperprolactinemia appears to be a different entity from that due to inadequate follicular phase FSH.
A group of 22 women with anovulatory cycles was treated with tamoxifen in 46 cycles. We elucidated daily hormone profiles in 5 of the 33 tamoxifen-induced ovulatory cycles in order to make a comparison with those found in 5 normal cycles. Serum follicle-stimulating hormone and luteinizing hormone (LH) rose during or a few days after the tamoxifen therapy, and thereafter serum estradiol levels rose gradually over the normal ranges during the follicular phase and reached an extremely high preovulatory peak which triggered an LH surge. This increased estradiol production exerted its usual negative feedback on LH secretion. Following ovulation, serum progesterone rose and fell in a manner similar to that in the normal cycles, with occasional values that exceeded the normal range. The endocrine significance of these findings is discussed.
The physiological requirement for activation of pituitary gonadotrophin secretion by pulsatile LHRH stimulation is discussed, and compared with the effect of pituitary stimulation by LHRH agonists. Initial stimulation is followed by a phase of progressive pituitary and gonadal inhibition. This inhibition is fully reversible at the end of agonist treatment. Clinical applications of high dose suppression are the treatment of precocious puberty and hormone-dependent tumours (mammary and prostatic carcinoma). In women, agonist administration by nasal spray is a reversible method of inhibiting ovulation, and may also be useful in the treatment of endometriosis. Clinical advantages of agonist therapy are favourable biological tolerance, lack of side effects and rapid reversibility.
The cause of infertility has remained obscure in women with endometriosis in whom the tuboovarian relationship is unaltered. Abnormal corpus luteum function has been one mechanism implicated in the pathophysiology of endometriosis in infertilityl-3 and may also be a possible explanation for the high frequency of spontaneous abortions among women with untreated endometriosis.4 However, we have observed only an occasional occurrence of luteal phase deficiency in women with an ultimate diagnosis of endometriosis. In order to verify this observation, we examined the incidence of luteal phase defects (LPDs) in. our infertility population.
Ovarian hormones have been implicated in a number of neoplastic conditions. Chronic anovulation syndrome, a spontaneous biologic experiment of unopposed secretion of estrogen by the ovaries, was identified in a cohort of 1270 patients, and the risk of these patients having neoplasia was studied. Of the 1270 patients studied, 30 had a subsequent malignancy develop; the expected number was 29.8. When the individual types of subsequent malignancy were analyzed, the endometrium was the only site at increased risk. The relative risk of developing carcinoma of the endometrium after the diagnosis of chronic anovulation syndrome is 3.1 (95% confidence interval 1.1 to 7.3). The long-term risk of developing adenocarcinoma of the endometrium might be considered when treating patients who have this syndrome.
Inadequate levels of circulating progesterone (P) seen in clinical practice can be increased by P supplementation. When supplementation is via the vaginal route, its presentation may be in many different suppository bases. We have measured circulating P in the follicular phase to compare delivery from the vagina after P was presented in three different bases (glycerinated gelatin, cocoa butter, and polyethylene glycol). The mean peak level achieved and the area under the curve were highest after supplementation from polyethylene glycol-based suppositories. The duration of elevation above baseline was similar with all three suppositories. It is concluded that the suppository base is important in controlling the amount of this steroid absorbed from a given amount presented by this route.
Ultrasonographic measurement of follicle growth and estradiol concentrations have been shown to correlate well in spontaneous and Clomid-induced ovulatory cycles. However, little is known about these changes during human menopausal gonadotropin (hMG) therapy. Twenty-five women who did not ovulate when treated with clomiphene were treated with hMG during 70 treatment cycles. Eleven patients had withdrawal bleeding after progesterone administration (group 1) and 14 did not bleed (group 2). Follicle growth was monitored with intermittent serum estrogen determinations and daily ovarian ultrasound with an ADR Model 2140 real-time sector scanner. The mean dominant follicle size at the time of human chorionic gonadotropin (hCG) injection was 21.2 mm +/- 0.6 (SEM) and was not different between the two groups. Mean serum estrogen level at the time of hCG injection was 1,121 pg/ml and correlated with follicle volume. At the time of hCG injection in group 2, one dominant follicle was present in 65% and two were present in 35% of the patients. Among those in group 1, two or more dominant follicles were present during all cycles. Mean serum estrogen levels were significantly higher in group 1 patients than those in group 2. This "chemical hyperstimulation" was induced in order to delay ovulation until adequate follicular size had been achieved. All cycles were ovulatory. Five patients in group 1 and eight in group 2 conceived. The use of ultrasound enables the physician to evaluate follicular growth and development daily and thus to individualize treatment and to reduce the need for estrogen monitoring.
The incidence of luteal phase defects in 366 infertility patients was 12.7%. Life-table analysis was used for determination of the conception rate with clomiphene citrate therapy, and with this method, evidence was found for the presence of two subgroups with respect to response. The crude conception rate was 40.9%. In a group of patients with a luteal phase defect and no other infertility factors, those that conceived had a significantly larger mean biopsy delay than those who did not (6.28 days versus 4.32; P less than 0.02). In a group with a histologic delay of 5 days or more, the conception rate was 79%, while the rate was only 8.9% in those with a less severe deficit (P less than 0.001). Theoretic considerations for clomiphene citrate therapy are discussed.
Van der Meer YG et al., 1983·Journal of Psychosomatic Obstetrics & Gynecology·
A double-blind cross-over placebo controlled trial was carried out to compare progesterone 200 mg with a placebo, both given in rectal suppositories, in 20 patients with the pre-menstrual syndrome (PMS). Each kind of suppository was used twice daily from mid-cycle to the onset of menstruation during two successive cycles. Six patients did not complete the trial. Daily scores for a number of psychological and somatic symptoms were recorded by the participants. Mean symptom scores in the last seven days of the pre-menstruum did not differ significantly between the two treatment periods. The participants did not express a significant preference for the progesterone therapy. Mean blood levels of FSH, oestradiol, prolactin and LH, determined on the first day of menstruation did not differ between the two periods of treatment. Side effects, in the form of electrolyte abnormalities or hepatic or renal function disturbances, were not seen. In this trial, progesterone 200 mg twice daily by the rectal route was not more effective than the placebo.
Journal Article THE NEUROENDOCRINOLOGY OF OPIOID PEPTIDES Get access ASHLEY GROSSMAN, BA BSc MRCP, ASHLEY GROSSMAN, BA BSc MRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for other works by this author on: Oxford Academic PubMed Google Scholar LESLEY H REES, MD MSc MRCPath FRCP LESLEY H REES, MD MSc MRCPath FRCP Departments of Endocrinology and Chemical Endocrinology St Bartholomew's Hospital, London Search for other works by this author on: Oxford Academic PubMed Google Scholar British Medical Bulletin, Volume 39, Issue 1, 1983, Pages 83–88, https://doi.org/10.1093/oxfordjournals.bmb.a071796 Published: 01 March 1983
In studying the structural changes of human cervical mucus during the ovulatory cycle, they have been observed to be directly related to ovarian hormone changes. Mucus structural changes, if taken according to their sequence during the cycle, clearly express the anatomic and functional events occurring in the ovary. If each structure is considered separately, only the mucus of the preovulatory period can be considered an indication of the corresponding ovarian processes, presenting peculiar morphologic characteristics. The observation of a similar morphologic appearance in the mucus of the early follicular and luteal phases leads one to believe, in spite of the influence of totally different hormone levels, in the likely existence of a mechanism of interference between estrogens and progesterone during the postovulatory period of the cycle.
The possibility that beta-endorphin, an endogenous opiate, is involved in the regulation of the menstrual cycle was examined. Daily serum beta-endorphin levels, in conjunction with luteinizing hormone, progesterone, and 17 beta-estradiol were measured during 26 hormonally normal menstrual cycles. Twenty-one cycles showed a preovulatory peak and postovulatory trough of beta-endorphin, 2 cycles had a postovulatory peak, and 3 had a postovulatory peak with sustained elevation. The raw data were standardized by conversion to "Z-scores," and the composite values were computed for each of the three classes described above. Significance within these three classes was assessed using a one-way analysis of variance with an F-ratio at 95% confidence limits. The composite plot of the 26 cycles showed a statistically significant preovulatory peak occurring 2 days prior to the luteinizing hormone surge and a postovulatory trough of beta-endorphin 5 days later. These results suggest that beta-endorphins play a significant role in the neurochemical mechanisms of gonadotropin release.
A push-pull perfusion (PPP) system was used to carry out the first examination of LHRH release from the mediobasal hypothalami (MBH) of conscious, freely moving rats during stages of the estrous (E) cycle and after ovariectomy (Ovx). Female rats received push-pull cannula (PPC) implants into the MBH and then were allowed to recover for 2–10 weeks before PPP experiments. During that time, E cycles were determined by daily inspection of vaginal smears. After exhibiting two consecutive E cycles, rats were fitted with indwelling jugular catheters between 0830–1030 h and subjected to PPP of the MBH and hourly bleeding for more than 6 h. LHRH and LH levels were determined by RIA in perfusates and plasma, respectively. PPP and bleeding sessions were performed on the afternoon of proestrus (Pro; n – 10), diestrous day I (DI; n – 5), diestrous day II (DII; n – 5), estrus (E; n – 5), or more than 28 days after Ovx (n – 5). LHRH output was detectable in at least some samples in all rats whose PPC tips resided within 0.5 mm of the rostrolateral median eminence. Basal LHRH output (<0.2 to 1.2 pg.12 min) appeared to be pulsatile in all groups. During Pro, higher LHRH levels permitted pulse frequency determinations (average Pro interpulse interval, 48.0 min). Overall LHRH output during Pro was elevated (P< 0.01) compared to that in all other groups and was distinctly biphasic; a putative priming pulse (P < 0.05) occurred 2–3 h before the occurrence of a larger main peak (1.6–7.0 pg-12 min) at approximately 1600–1730 h (lights on from 0500–1900 h). Proestrous (Pro) LH levels in rats bearing PPC implants were only 10–30% of those in intact rats regardless of PPP. Nonetheless, these rats did exhibit temporally normal Pro LH surges concident with LHRH release. In DI and DII rats, LHRH pulse amplitude increased moderately for a brief period in the late afternoon (P < 0.01 only when data was normalized to the largest peak). LHRH output in E rats was low and mostly undetectable. Pulse amplitude in ovariectomized (Ovx) rats remained constant and low throughout the afternoon, while LH levels were elevated to typical post-Ovx values. We conclude from this study that (1) a biphasic LHRH surge occurs on the afternoon of Pro which may act to prime and then stimulate pituitary gonadotrophes, (2) small but significant increases in LHRH pulse amplitude occur between 1500–1900 h in DI and DII rats, but not in Ovx or E rats, and (3) LH, but not LHRH, release is increased in Ovx rats, suggesting that the negative feedback effects of ovarian steroids operate primarily at the level of the pituitary gland.
Twelve oligomenorrhic women with polycystic ovary syndrome (PCO) in whom clomiphene (250 mg daily for 5 days) and 10,000 IU human chorionic gonadotropin had failed to induce ovulation were treated with clomiphene and dexamethasone. Eight of the 12 women underwent complete hormonal assessment during treatment. Six of the 12 ovulated and 1 conceived. Serum total and unbound estradiol and testosterone (T), serum dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding-globulin binding capacity (SHBG-BC), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were measured during clomiphene and dexamethasone therapy. SHBG-BC increased in response to clomiphene whether or not ovulation occurred. After treatment with clomiphene and dexamethasone there was a significant decrease in serum T, unbound T, and DHEA-S 2 weeks after dexamethasone administration, but there were no change in LH, FSH, or PRL. In patients who ovulated after clomiphene and dexamethasone, T and unbound T increased again after clomiphene was begun despite the continuation of dexamethasone. The women who ovulated after clomiphene and dexamethasone treatment had significantly higher pretreatment levels of DHEA-S than those who did not ovulate. Clomiphene and dexamethasone treatment may be beneficial to women who have elevated levels of DHEAS and who fail to ovulate with maximum doses of clomiphene.
Whereas follicle rupture never occurred before the 37th hour after an ovulatory stimulus (either the onset of the LH surge or hCG administration) in control patients, ovulation was observed at 26 to 36 h in women submitted to ultrasonography during the late follicular phase. Premature ovulation was observed in 5 out of 23 and 8 out of 19 cycles when ultrasonography occurred during the 3 days preceding or in the 36 h following ovulatory stimulus. This as yet unexplained observation leads us to reconsider the advisability of ovarian scan during the late follicular phase of the menstrual cycle.
Concentrations of beta-endorphin were measured in the venous effluent of the hypothalamus (hypophyseal portal blood) at various phases of the menstrual cycle and after ovariectomy in rhesus and pigtailed monkeys. In the rhesus, beta-endorphin concentrations were high during the mid- to late follicular phase [737 +/- 256 pg/ml (mean +/- SE)] and the luteal phase (1675 +/- 1108) of the menstrual cycle, but were undetectable (less than 133) at menstruation. Concentrations were also high in pigtailed monkeys during stages of the menstrual cycle other than at menstruation (4870 +/- 1090 pg/ml), but undetectable (less than 133) 4--12 months after ovariectomy. These results indicate that beta-endorphin concentrations in hypophyseal portal blood are related to menstrual cycle events, probably changes in ovarian steroids; this in turn suggests that beta-endorphin may participate in the ovarian feedback regulation of gonadotropin secretion.
A preliminary study of 'screened' women with two consecutive miscarriages revealed an incidence of abortion in 47.4% in a subsequent pregnancy whilst hCG therapy in a similar group of women where biochemical monitoring with plasma progesterone suggested a potentially jeopardized pregnancy resulted in a continuing pregnancy in 92.3% of treated women. An urgent need for a true randomized double-blind evaluation of this therapy has been established in order to re-examine the therapeutic nihilism which currently pervades the management of women with recurrent abortion.
A group of 17 patients with suspected luteal phase deficiency was treated with tamoxifen. Tamoxifen therapy was found to lengthen the luteal phase in all patients and resulted in pregnancy in 6 of 17 patients. The integrated luteal phase progesterone (P) concentration in the nontreatment cycle of seven patients was significantly lower (P less than 0.01) than that of five normal women. Therapy with tamoxifen increased the P concentration to 186.0 +/- 24.4 ng/ml/cycle (mean +/- standard error of the mean), i.e., twice that of the control cycle. The mean estradiol (E2) concentration at the midcycle peak was about twice that observed during the nontreatment cycle. The glycogen content of the endometrial tissue at the midluteal phase in the tamoxifen cycle was significantly higher (P less than 0.025) than that of endometrial tissue in the nontreatment cycle, indicating improvement of the endometrial function.
Hormonal profiles were obtained throughout 26 conception cycles and 27 non-conception control cycles. The pregnancies followed treatment (clomiphene or bromocriptine) in 12 women but were spontaneous in the remaining 14. No sustained significant difference between the various types of conception cycle was found for LH, FSH, oestradiol or progesterone concentrations. Prolactin concentrations varied widely, suggesting that mean cycle prolactin concentrations ranging from 45 to 760 mi.u./l are compatible with conception. Although there were no significant differences in progesterone secretion within the conception cycles, there were highly significant differences between the conception cycles and the non-pregnant control cycles. Mean progesterone concentrations in the conception group were higher (P less than 0.005) than those in the control women over Days 3-8 following the LH peak. This difference could only be partly accounted for by heterogeneity within the control group (15-20% of the control cycles had low progesterone concentrations and were probably subfertile. It is suggested that the higher conception cycle progesterone concentrations during the early part of the luteal phase may constitute a preimplantation component of the maternal recognition of pregnancy in women.
Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.
Many studies have been published on luteal phase deficiency, and the emphasis in most of them is on progesterone deficiency. In this study 144 patients (455 cycles) with infertility were studied. The patients were divided into four groups. Group 1 consisted of patients with high estradiol and high progesterone levels in the midluteal phase. Group 2 consisted of patients with high estradiol and low progesterone levels. Group 3 consisted of patients with low estradiol and low progesterone levels. Group 4 consisted of patients with low estradiol and high progesterone levels. As expected, patients in groups 2 and 3 showed a low conception rate with outphased endometrial biopsy. However, group 4, in spite of the normal progesterone levels, had a low conception rate with an outphased endometrium. We conclude that estradiol deficiency during the luteal phase is a major factor in infertility, and replacement therapy with progesterone alone in these patients may not improve fertility.
Sex hormone binding globulin (SHBG) binding capacity was measured in 50 women with severe premenstrual syndrome and 50 age-matched controls. The binding capacity was significantly lower (P = 0.001) in the patients. This finding suggests that the levels of SHBG binding capacity could be useful in the diagnosis and may help to explain the aetiology of the premenstrual syndrome.
A progesterone solution was administered by intravaginal instillation, intramuscular injection, and sublingually to estrogen-deficient women, with or without estradiol (E2) replacement, and serum progesterone (P) concentrations were measured by radioimmunoassay. Intravaginal application to postmenopausal subjects receiving E2 gave the highest values of serum P: 10 times baseline at 15 minutes and 30 to 40 times at 1 to 2 hours, with sustained levels, for 7 hours and decline to 10 times baseline at 24 hours. Intravaginal application to hypoestrogenic women gave similar results, but of much lower magnitude (highest value, 20 times baseline). Intramuscular injection, in contradistinction, showed gradually increasing levels over the study period, up to 30 times basal values at 24 hours. It contrast, sublingual application produced very modest serum increases, to approximately 10 times baseline within 2 hours and return to basal value at 24 hours. Since the most rapid and highest levels were observed by vaginal application to postmenopausal women receiving estrogen, and considering that the vagina has been similarly shown to be very effective for estrogen absorption, it is conceived that full hormone replacement could be accomplished in the deficient states by cyclic vaginal application of both steroids.
Previously, we demonstrated that selective suppression of serum follicle-stimulating hormone (FSH) in monkeys treated with charcoal-extracted porcine follicular fluid (pFF) in the early follicular phase induced luteal defects resembling those which occur spontaneously in women and monkeys. Here, we assessed whether luteal phase defects arising in association with induced FSH deficiencies during the early follicular phase can be treated by early FSH therapy. Rhesus monkeys were treated with pFF and human menopausal gonadotropin (hMG) (FSH:luteinizing hormone [LH], 3:1) on cycle days 1 to 3 or day 4, respectively. Daily femoral blood samples were analyzed for LH, FSH, and estradiol by radioimmunoassay. In the monkeys treated with the pFF-hMG combination, a single ovulation was uniformly noted at laparoscopy, and initial luteal phase elevations in serum progesterone levels were nearer those of normal ovulatory cycles than after pFF alone. These results suggest that FSH/LH treatment in the early follicular phase compensated, in part, for the pFF-induced deficiency in endogenous FSH levels.
This study was intended to correlate different clinical and biologic parameters to better define luteal insufficiency (LI) and to contribute to a better understanding of its origin. Endometrial patterns were used as the basis for classification of clinical cases. Of 328 outpatients with menstrual disorders and/or infertility, 88 were considered to have LI. Their cycles were compared with 79 normal cycles. Two different principal endometrial patterns of LI are described: pure LI, when the endometrium is more than 2 days out of phase; and LI with persistent estrogenic influence, when the histologic estrogenic stigmata are excessive during the luteal phase. Basal body temperature charts demonstrated menstrual cycle disturbances: either ovulation delay or a slow increase in temperature (longer than 2 days). Plasma steroid concentrations also demonstrated a perturbation of the entire menstrual cycle: progesterone levels were statistically significantly lower in LI than in normal cycles and this defect was worse when the estrogenic influence was persistent; the preovulatory estradiol peak was disturbed in all circumstances, as was the concentration of endometrial steroid receptors. These simultaneous abnormalities strongly suggest a central origin of LI.
To test the postulate that endogenous opioid peptides may be involved in the neuroendocrine mechanisms controlling the frequency and amplitude of LH pulses, saline and an opioid receptor antagonist, naloxone, were infused sequentially, each for 6-h intervals, in six normal cycling women during the luteal phase of the menstrual cycle. During naloxone infusion (1.6 mg/h), there was a significant (P less than 0.01) increase in both the frequency and amplitude of LH pulses compared to those in saline controls. FSH pulses were not discernible in individual subjects; however, a significant increment in FSH levels occurred concomitantly with the increase in LH. These data strongly suggest that endogenous opiates, through an inhibition of hypothalamic LRF, participate in the endocrine events leading to the low frequency of episodic LH secretion characteristic of the luteal phase of the human menstrual cycle.
In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin-releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post-naloxone. The LH response to naloxone in individual subjects showed a significant (P less than 0.01) quadratic (U-shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.
Since the isolation of the enkephalins five yr ago, there has been an explosive increase in knowledge concerning the effects of the opiates and opioid peptides. This review deals with the interactions of opiates with the endocrine system in rat and man. The opioid peptides have been demonstrated to exert a variety of effects on pituitary hormone secretion in rat and man. In the rat, opiates stimulate growth hormone, prolactin and ACTH release and inhibit the release of the glycoprotein hormones. In man, the physiologic role of the endogenous opiates appears to be involved predominantly in ACTH and gonadotrophin regulation. Opiate effects are mainly exerted at the level of the hypothalamus but further modulating effects may occur at the pituitary and at end-organs. Opiate-induced hormonal effects appear to be mediated through dopaminergic and/or serotonergic mechanisms. Recent studies have also suggested a possible local neuromodulatory role for the opioid peptides in the control of carbohydrate metabolism and reproductive processes.
The fertile period of the human menstrual cycle consists of those days on which sexual intercourse can result in a pregnancy. Its duration is determined by the functional life span of the gametes within the female reproductive tract. Various mechanisms control gamete transport and survival in the reproductive tract of the human female. The ovarian hormones estradiol and progesterone have an important role in regulating these mechanisms. The nature of cervical mucus and its governing influences on sperm transport and survival following coitus are of prime importance in defining the fertile days of the menstrual cycle. Man's early concepts of the fertile period were often based on erroneous theories of the female reproductive cycle. It is only since the late 1920's that a true understanding of ovulation and the menstrual cycle has evolved. Current approaches in natural family planning to recognizing the fertile and infertile days of the menstrual cycle are discussed and evaluated.
A review of the extensive literature on the subject indicates that sex hormones have been associated with a wide variety of adverse clinical conditions following usage during pregnancy. About 230 cases of female pseudohermaphroditism have been reported following use of hormones with androgenic potency, but masculinization observed with estrogens in a few females may represent only adrenal-stimulated pseudohermaphroditism. Feminization of males, mostly by progestogens in some 45 cases, is unproven at present. Realizing the limitations of the published studies when all present data are considered, there seems no justification for undue concern over the induction of nongenital congenital malformations through hormone use in pregnancy. The available data on the association to cardiac, limb, and CNS defects, and to several malformative syndromes, are not convincing: the effects appear to be remarkably nonspecific, the studies are contradicted by a large number of negative reports, and an increased incidence of defects with increased usage has not materialized. A possible exception are the CNS malformations associated with the use of the antifertility agent clomiphene, and careful surveillance is warranted at present. While a reasonable interpretation from this review would be that hormones present no major teratogenic hazard, elimination of hormonal exposure whenever possible during pregnancy is suggested.
Two cases of ovum retention occurring in postovulatory follicles are described. The ova were recovered at laparoscopy by aspiration of decompressed ovulatory follicles, one during a natural cycle and the other following a programmed clomiphene/human chorionic gonadotropin cycle. Each patient had a normal luteal phase with an increased progesterone level indicative of ovulation. The implications of these findings and their relevance to human fertility studies are discussed.
Rajaniemi HJ et al., 1980·J Clin Endocrinol Metab·
Wedge resection was performed in 12 patients with polycystic ovarian disease, and cell samples from the cystic follicles were assayed for LH(hCG) receptor using [125I]iodo-hCG as a ligand hormone. Simultaneously to wedge resection, blood samples were taken for serum FSH, LH, 17 beta-estradiol, progesterone, and testosterone RIA measurements. Serum LH was regularly elevated (16.0-57.1 U/liter), whereas FSH (5.2-11.5 U/liter) was within the normal reference range. The LH to FSH ratio was between 2.1-7.8. The 17 beta-estradiol concentrations (0.12-0.23 nmol/liter) were within the normal reference range found during the early follicular phase. Only 3 patients had progesterone levels exceeding the assay sensitivity limit of 0.1 nmol/liter. Ony 3 of the 11 patients assayed for serum testosterone had values exceeding the upper limit of the reference range. Seventy-seven percent of the ovarian follicular samples showed specific binding of [125I]iodo-hCG. The number of receptors in positive samples averaged 0.67 +/- 0.11 fmol/mg homogenate protein, which is clearly lower than that in normal preovulatory follicles. Scatchard analyses revealed a single class of binding sites, with a mean equilibrium association constant of 5.4 X 10(9) M-1 at 37 C. These results suggest that the derangement of follicular development in patients with polycystic ovarian disease probably is not due to the lack of appearance of the LH(hCG) receptor. It is possible that the tonic elevation of serum LH results in a decrease in the number of available receptor sites; this would be one step in the process leading to ovarian changes characteristic of this disease.
Leyendecker G et al., 1980·J Clin Endocrinol Metab·
In previous studies it could be demonstrated that in severe hypothalamic amenorrhea, which is associated with absent or deficient hypothalamic secretion of Gn-RH, ovarian function could be restored by chronic intermittent (pulsatile) administration of Gn-RH. In order to apply chronic intermittent administration of Gn-RH as a new mode of treatment of infertility in hypothalamic amenorrhea on an outpatient basis a portable device ("Zyklomat") was constructed consisting of a peristaltic pump, a computerized timing device and a Gn-RH containing bag, which delivers 50 microliters of a Gn-RH containing solution once every 90 minutes via an i.v. catheter into the circulation. It is the purpose of this communication to present this new method of treatment and the successful induction of the first two pregnancies with this method in two patients with severe hypothalamic amenorrhea.
Plasma progesterone concentrations drawn at the time of endometrial biopsy in 26 infertility patients with histologically documented luteal phase inadequacy were compared with those of 26 infertility patients with normal biopsies. Although as a group the former patients had lower progesterone values and shorter cycles, there was considerable overlap. Therefore, although plasma progesterone determinations and temperature charts are useful in the detection of ovulation and in the interpretation of the biopsy results, a properly obtained endometrial biopsy is essential for the diagnosis of luteal phase inadequacy.
Three hundred and ninety-six patients were evaluated for primary and secondary infertility between December 1976 and May 1979 at a large referral center. Timed late luteal endometrial biopsies were routinely obtained as part of the work-up and were repeated for confirmation if subsequent menses did not occur within 2 days of the expected date. If both biopsies were abnormal, a diagnosis of luteal phase defect (LPD) was made and patients were treated with vaginal progesterone suppositories for a minimum of 6 months. LPD was discovered in 32 of 396 patients (8.1%); among those patients whose infertility was not complicated by other abnormalities, 9 of 13 conceived (70%) and 7 of 13 carried to term (54%). These data suggest an incidence higher than generally recognized and a very encouraging response to replacement therapy.
Crowley WF Jr et al., 1980·J Clin Endocrinol Metab·
The administration of small doses of LHRH at 2-hourly intervals over a 27 day period to a 24-year old patient with Kallman's syndrome resulted in ovulation as indicated by: (1) a biphasic temperature response, (2) anatomical changes in the ovaries demonstrated by ultrasound, and (3) the pattern of circulating gonadotropin and gonadal steroid concentrations.
In rhesus monkeys with hypothalamic lesions (which appear to abolish the endogenous production of gonadotropin-releasing hormone), normal ovulatory mestrual cycles were reestablished by an unvarying, long-term replacement regimen consisting of one intravenous pulse of synthetic gonadotropic-releasing hormone per hour. This finding is in accord with the hypothesis that the pattern of pituitary gonadotropin secretion throughout the menstrual cycle (basal secretion interrupted, once every 28 days on the average, by a preovulatory surge) is not directed by alterations in hypothalamic gonadotropin-releasing hormone secretion but by the ebb and flow of ovarian estrogens acting directly on the pituitary gland.
Myometrial tissues from pregnant and nonpregnant mature and immature rats were examined for the presence of gap junctions by thin section and freeze-fracture microscopy before and after incubation in vitro. Gap junctions were not present in any tissues fixed in situ or shortly after removal from animals. The junctions were present in tissues incubated for 2 h in vitro, and the number and size of the junctions increased with increasing incubation times up to 48 h. Tissues from immature rats incubated in vitro formed gap junctions in much reduced numbers as compared to tissues from pregnant or nonpregnant mature animals. Injection of immature animals with estrogen with or without progesterone, but not with progesterone alone, increased the number of gap junctions found in tissues when incubated in vitro. In vitro treatment of tissues from immature animals with estrogen also stimulated the formation of gap junctions. Progesterone treatment in vitro had no effect on gap junction formation in any myometrial tissues. However, progesterone added in vitro in the presence of estrogen decreased the number of gap junctions as compared to the numbers formed with addition of estrogen alone in treated tissues from immature or pregnant animals. The addition of indomethacin 5,8,11,14-eicosatetraynoicacid and arachidonic acid partially inhibited the formation of gap junctions in tissues from pregnant animals incubated in vitro. A stable endoperoxide of PGH2 and arachidonic acid, but not PGE1, PGE2, PGF(2α), or thromboxane β2, overcame the inhibition of gap junction formation produced by indomethacin. These results are consistent with the hypothesis that steroid hormones and prostaglandin interact to modulate gap junction formation in the myometrium.
Twenty-five women scheduled for hysterectomy for nonmalignant disease participated in the study. Sperm storage in endocervical crypts was examined in three groups of nine women pretreated with estrogen and inseminated with normal semen, nine women pretreated with gestagen and inseminated with normal semen, and seven women pretreated with estrogen and inseminated with abnormal semen. The number of crypts containing spermatozoa (colonized crypts) and the sperm density per crypt were examined in serially sectioned cervices. In estrogen-pretreated cervices both the percentage of colonized crypts and the sperm density were significantly higher than in gestagen-pretreated cervices. Large and giant crypts proved to be the main storage facility for spermatozoa. The localization of crypts along the endocervical canal did not influence sperm storage. The quality of semen appeared to be of critical importance to sperm storage. The percentage of colonized crypts and sperm density were severly reduced in patients inseminated with abnormal semen.
The plasma concentrations of progesterone and 5-alpha-pregnane-3,20-dione (5-alpha-dihydroprogesterone) were measured from as early as 12 weeks through 41 weeks of gestation in primigravid women. Two groups of primigravid women were assessed, those with uncomplicated pregnancies and those who developed pregnancy-induced hypertension. Plasma levels of progesterone and 5-alpha-dihydroprogesterone rose progressively throughout gestation in both groups of women. The ratio of the level of progesterone to that of 5-alpha-dihydroprogesterone in individual plasma samples of women with uncomplicated pregnancies was 7.0 from 12 to 15 weeks' gestation while at 35 to 41 weeks' gestation the ratio had declined to 4.6. Similar results were obtained in plasma samples of women who ultimately developed pregnancy-induced hypertension. Since no differences in plasma levels of progesterone or 5-alpha-dihydroprogesterone were detected between primigravid women with uncomplicated pregnancies and those who developed pregnancy-induced hypertension, we conclude that neither progesterone nor 5-alpha-dihydroprogesterone concentrations in plasma are of value in identifying women at risk of developing pregnancy-induced hypertension.
Patients with different types of luteal phase defects were studied with the use of the radioimmunoassay for the beta subunit of human chorionic gonadotropin (hCG) to determine if unsuspected subclinical pregnancies were more common in a particular type of defect. A type I luteal phase defect is always characterized by a chronologic lag in endometrial development when repeatedly studied with timed endometrial biopsies. A type II luteal phase defect is always characterized by an in phase endometrium when repeatedly studied by timed endometrial biopsies but always has less than a 14 day luteal span. All blood samples were drawn at least 7 days after ovulation/conception. In 22 cycles in which patients had a type I luteal phase defect, no subclinical pregnancies were detected. In 18 cycles in which a type II luteal phase defect was present, 12 instances of unsuspected subclinical pregnancy were detected and all ended in spontaneous abortion. This study shows that unsuspected subclinical pregnancies ending in abortion do occur and are quite commonly associated with the type II luteal phase defect.
Lymphocyte reactivity was measured in human mixed lymphocyte (MLC) and mitogen-stimulated cultures in the presence of various steroids. When present during the entire culture period at concentrations between 1 and 20 µg/ml progesterone, estradiol, and testosterone blocked 3H-thymidine (3H-TdR) incorporation. Estriol and 16 α-hydroxy progesterone were without suppressive effects. The kinetics of steroid mediated suppression of thymidine incorporation and DNA synthesis was investigated at various times during lymphocyte activation. When progesterone was present only at the beginning of culture, subsequent DNA content, but not thymidine incorporation was suppressed. However, if added late during the activation process, progesterone reduced thymidine incorporation independent of cellular DNA content. If present during the entire culture period both were suppressed. Cortisol, but not progesterone irreversibly inhibited lymphocyte thymidine incorporation if added during the first 12 hr of culture. A reversible blockade of lymphocyte thymidine uptake could be observed with progesterone even during the final hours of mitogen or MLC cultures. Thus, effects of steroid hormones on cellular DNA synthesis and thymidine incorporation appear to be independent processes. Cell fractionation experiments demonstrated that progesterone blocked the uptake of 3H-TdR into the lymphocyte nucleoside pool thereby reducing its availability for incorporation into DNA. This study is consistent with the hypothesis that lymphocyte proliferation at the maternal fetal-interface during pregnancy may be under specific regulation by progesterone. The relatively high local concentrations of the hormone produced by trophoblast are immunosuppressive whereas the substantially lower peripheral steroid levels are entirely inadequate to suppress systemic immunity. We suggest that at least one important role of progesterone in maintaining pregnancy is its regulation of cellular immunity in the maternal-fetal bed.
Conflicting results have been published regarding changes in plasma progesterone during the last trimester of pregnancy. Some have demonstrated a fall in plasma progesterone before labor, and this has been taken as a possible explanation of the onset of labor. It has been suggested that the various results could be due to differences in methods for progesterone determination. In this study the progesterone levels were determined by both RIA and CPB. In 11 women the plasma progesterone, human placenta lactogen, and serum estriol were measured weekly during the last trimester of normal pregnancies and immediately after delivery. All samples were analysed radioimmunologically. In order to compare the radioimmunoassay and competitive protein binding techniques (RIA and CPB), the progesterone levels were determined by both methods. This was also done for 80 successive plasma progesterone routine samples drawn from women who were not pregnant or who were in the early stages of pregnancy. Both methods showed a significant rise in the plasma progesterone level during the last 6 weeks before spontaneous labor. However, the values obtained were lower when assayed by CPB than by RIA, presumably because of a higher specificity and a cross reaction in RIA. Serum estriol exhibited increasing values throughout pregnancy, but without a significant rise during the last few weeks. Plasma HPL settled at a constant level during the last few weeks before labor.
Plasma progesterone, 17-hydroxyprogesterone, 20alpha hydroxypregn-4-en-3-one levels were determined twice weekly up to 16 weeks gestation, where possible, in a twin pregnancy, in two patients who aborted spontaneously and in three patients who were treated with 'progesterone supplements' because of abnormal vaginal cytology. There was no correlation between vaginal smears and the plasms hormone levels and there was no evidence to suggest that progesterone supplements influenced clinical outcome. Compared with normal mean values the only difference was a significantly rise in progesterone and 20alpha hydroxypregn-4-en-3-one levels in the twin pregnancy after the 12th week and a precipitate fall in all hormone levels just prior to abortion. Plasma hormone levels could not be used to predict outcome.
In rhesus monkeys with hypothalamic lesions that abolish gonadotropic hormone release by the pituitary gland, the constant infusion of exogenous gonadotropin-releasing hormone (GnRH) fails to restore sustained gonadotropin secretion. In marked contrast, intermittent administration of the synthetic decapeptide once per hour, the physiological frequency of gonadotropin release in the monkeys, reestablishes pituitary gonadotropin secretion. This phenomenon is attributable to the pattern of GnRH delivery rather than to the amounts of this hormone to which the cells of the pituitary are exposed. Moreover, the initiation of continuous GnRH administration in animals with lesions and in which gonadotropin secretion is reestablished by intermittent GnRH replacement can result in a "desensitization" or "down regulation" of the processes responsible for gonadotropin release.
In gravid women who are destined to develop pregnancy-induced hypertension (PIH), normal pregnancy-associated refractoriness to the pressor effects of administered angiotensin II (A-II) is lost several weeks before the onset of hypertension. From a study of the determinants of A-II pressor responsiveness in normal gravid women, it appears likely that the loss of resistance to A-II is principally unrelated to plasma renin activity or to plasma A-II levels. However, it recently has been shown that the vascular refractoriness to A-II in normal women can be reduced significantly by the administration of the prostaglandin synthetase inhibitors, indomethacin or aspirin. In seven women who had developed PIH and who had lost their refractoriness to A-II, the infusion of 5alpha-pregnan-3,20-dione (5alpha-DHP) was associated with restoration of refractoriness to the pressor effects of A-II. Moreover, in five normotensive gravid women beyond 28 weeks' gestation in whom the refractoriness to A-II was reduced by the administration of indomethacin, the intravenous infusion of 5alpha-DPH was associated with restoration of refractoriness to the pressor effects of A-II. These observations are consistent with the view that a progesterone metabolite(s) may be important in the maintenance of normal blood pressure during human pregnancy.
17 beta-Estradiol (E2) and progesterone (P) concentrations in blood and in the myometrium of human pregnancy at term (n=33) and in a few samples (n=5) around midterm of pregnancy were determined. E2 concentration in the myometrium (per g wet wt) at midterm was lower than the concentration in the plasma (per ml) so that the myometrium to plasma (My:Pl) ratio was 0.7. Relative to plasma concentration, the myometrial E2 increased little from midterm to term so that My:Pl was only 0.2 at term. Although P concentration in the myometrium was much greater than that in the plasma at midterm, My:Pl ratio being 2.2, it was lower than that in plasma at term so that My:Pl ratio was only 0.6. A fairly good correlation between plasma steroids and the myometrial steroids was observed at midterm but was distorted at term, probably due to saturation of the tissue-binding capacity. Steroid concentrations determined on the basis of protein showed a good correlation to the values expressed on the basis of wet weight. Whereas myometrial E2 concentration was significantly influenced by the distance from placenta, P concentration was not.
Ovariectomized rhesus monkeys bearing hypothalamic lesions which had abolished endogenous LHRH production, as evidenced by a profound reduction in gonadotropin secretion, but in which LH and FSH secretion was reestablished by a chronic intermittent iv infusion of synthetic LHRH (1 microgram/min for 6 min every hour) were used to investigate the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion. The administration of estradiol to such animals, while continuing the LHRH replacement regimen, resulted in a decline in circulating LH and FSH levels, followed by an unambiguous discharge of these hormones. The time course of this biphasic pattern of gonadotropin secretion was remarkably similar to that observed in response to estradiol administration in otherwise intact ovariectomized animals. These results suggest that, in the rhesus monkey, estradiol can exert both its negative and positive feedback actions on gonadotropin secretion at the level of the pituitary gland.
A clinical description of luteinized unruptured follicles is presented. This abnormality in ovulation is characterized by normal endocrinologic presumptive signs of ovulation: biphasic basal body temperature curves, secretory endometrium, and laboratory evidence of progesterone production by elevated urinary pregnanediol or plasma progesterone levels. In a group of 102 such infertile women, laparoscopy performed 3 to 5 days after apparent ovulation revealed the absence of a corpus hemorrhagicum in 30 women, and the absence of a sigma on a corpus hemorrhagicum in an additional 32 women. These findings were evidence that a follicle had not ruptured and an ovum had not escaped. Of 28 patients undergoing follicular stimulation with clomiphene citrate or human menopausal gonadotropin after this diagnosis, 15 conceived.
Wedge resection (WR) was performed in 12 women with polycystic ovarian disease (PCOD), and Incision was done in 4 PCOD patients without any resection of ovarian tissue. Serum LH, FSH, estradiol-17beta (E2), progesterone, and urinary 17 ketosteroid (17KS) were measured serially before and after surgery. Neither WR nor Incision had any effect on FSH levels. Serum LH levels which had been hypergonadotropic preoperatively, became markedly lower 7--14 days after surgery in 12 wedge-resected and 2 incised patients. Within 7 days after WR there was a significant fall of E2 and a decrease of 17KS. In addition to those hormonal changes observed after WR, BBT charts turned out to be diphasic after the oral administration of dydrogesterone (Duphaston) in 12 out of 17 PCOD patients. The present data suggest that the reduction of the serum LH, induced by an interaction between the ovarian steroidogenesis and the suprapituitary mechanisms, might be involved in the occurrence of ovulation after WR in PCOD patients.
A study of serum estradiol, progesterone, 17alpha-hydroxy-progesterone, testosterone, dihydrotestosterone, dehydroepiandrosterone (DHA), delta4-androstenedione (delta4-A), FSH, and LH was carried out in one of three sisters having polycystic ovarian disease for a period of 18 days before wedge resection, at the time of surgery, and for 24 days following wedge resection. The mean levels of 17alpha-hydroxyprogesterone, testosterone, DHA, delta4-A, and LH were remarkably elevated prior to wedge resection. There was considerable day-to-day variation. Serum LH varied from 12.5 to 70.5 mIU/ml with a mean of 41.03 +/- 3.55 mIU/ml. Serum estradiol and progesterone levels were generally higher than those found in the early follicular phage. Wedge resection resulted in a fall in serum estradiol, progesterone, 17alpha-hydroxyprogesterone, DHA, and delta4-A. Ovarian secretion of the last four steroids was confirmed by a study of the ovarian vein blood obtained at the time of surgery. An estradiol peak occurred on the 14th post wedge resection day with smaller increases in 17alpha-hydroxyprogesterone, DHA and delta4-A. An increase in serum LH occurred on the 15th post wedge resection day with a peak on Day 16 accompanied by increases in FSH and progesterone. The postovulatory rise of progesterone was accompanied by reduction of serum LH levels to those generally found in the early part of the menstrual cycle. Various hypotheses for the ovulatory failure are discussed.
A study of serum estradiol, progesterone, 17alpha-hydroxy-progesterone, testosterone, dihydrotestosterone, dehydroepiandrosterone (DHA), delta4-androstenedione (delta4-A), FSH, and LH was carried out in one of three sisters having polycystic ovarian disease for a period of 18 days before wedge resection, at the time of surgery, and for 24 days following wedge resection. The mean levels of 17alpha-hydroxyprogesterone, testosterone, DHA, delta4-A, and LH were remarkably elevated prior to wedge resection. There was considerable day-to-day variation. Serum LH varied from 12.5 to 70.5 mIU/ml with a mean of 41.03 +/- 3.55 mIU/ml. Serum estradiol and progesterone levels were generally higher than those found in the early follicular phage. Wedge resection resulted in a fall in serum estradiol, progesterone, 17alpha-hydroxyprogesterone, DHA, and delta4-A. Ovarian secretion of the last four steroids was confirmed by a study of the ovarian vein blood obtained at the time of surgery. An estradiol peak occurred on the 14th post wedge resection day with smaller increases in 17alpha-hydroxyprogesterone, DHA and delta4-A. An increase in serum LH occurred on the 15th post wedge resection day with a peak on Day 16 accompanied by increases in FSH and progesterone. The postovulatory rise of progesterone was accompanied by reduction of serum LH levels to those generally found in the early part of the menstrual cycle. Various hypotheses for the ovulatory failure are discussed.
Intrauterine pressure was monitored in vivo in oestrogen-treated ovariectomized ewes before, during and after treatment with progesterone (50 mg s.c./day for 3 days). Progesterone reversibly reduced the frequency and amplitude of myometrial activity and abolished uterine reactivity to oxytocin (i.v.) and PGF-2alpha (intrauterine infusion). The rate of rise of intrauterine pressure during active pressure cycles was significantly reduced. These results confirm that the action of progesterone on the ovine myometrium is comparable to the classic progesterone 'block'. The intrauterine infusion of PGF-2alpha (10 microgram/min), which elicited a marked mechanical response in the control animals, failed to stimulate the progesterone-'blocked' uterus, suggesting that the inhibition produced by progesterone is due to a direct action of the hormone on the uterine muscle and not to an indirect mechanism operating through endometrial prostaglandin output.
A study was made of the effects on the preovulatory surges of LH and FSH exerted by morphine sulfate (M) administered at 1400 h on proestrus, the beginning of the critical period for gonadotropin release in cycling rats in our colony. Various doses of M were given ip and jugular venous blood was collected under ether anesthesia for radioimmunoassay of plasma levels of LH and FSH. To verify ovulation, oviducts were examined the following day for the presence of ova. A high dose of M (60 mg/kg) totally abolished the LH surge and partially prevented the FSH surge while completely blocking ovulation. With intermediate doses of M (20-30 mg/kg) about half of the rats showed undiminished elevations of plasma LH at 1800 h and complete ovulation the next morning, whereas the other half revealed almost total blockade of LH release and no ovulation. Following a low dose of M (10 mg/kg) a small but significant (P < 0.05) augmentation of LH levels was observed in two of three experiments and all animals receiving this dose ovulated. Pretreatment with naloxone (10 mg/kg) did not itself affect LH or FSH release or ovulation but reversed the effect of the high dose of M and permitted complete ovulation. At 1800 h the pituitaries of control and Mblocked rats responded about equally to exogenous LHRH (100 ng iv) in 15 min increments of plasma LH and FSH and all of the rats ovulated. A timecourse study indicates that the onset of the LH surge may be somewhat delayed but the amplitude was undiminished following administration of a low dose of M. These findings indicate that M exerts dose-dependent effects on the preovulatory discharge of pituitary gonadotropins in the cycling rat.
Journal Article Luteinizing Hormone Releasing Hormone (LHRH) in Pituitary Stalk Blood of Rhesus Monkeys: Relationship to Level of LH Release Get access J. D. NEILL, J. D. NEILL 1Department of Physiology and Division of Neurological Surgery, School of Medicine, Emory University Atlanta, Georgia 30322 Search for other works by this author on: Oxford Academic Google Scholar J. M. PATTON, J. M. PATTON 1Department of Physiology and Division of Neurological Surgery, School of Medicine, Emory University Atlanta, Georgia 30322 Search for other works by this author on: Oxford Academic Google Scholar R. A. DAILEY, R. A. DAILEY 1Department of Physiology and Division of Neurological Surgery, School of Medicine, Emory University Atlanta, Georgia 30322 Search for other works by this author on: Oxford Academic Google Scholar R. C. TSOU, R. C. TSOU 1Department of Physiology and Division of Neurological Surgery, School of Medicine, Emory University Atlanta, Georgia 30322 Search for other works by this author on: Oxford Academic Google Scholar G. T. TINDALL G. T. TINDALL 1Department of Physiology and Division of Neurological Surgery, School of Medicine, Emory University Atlanta, Georgia 30322 Search for other works by this author on: Oxford Academic Google Scholar Endocrinology, Volume 101, Issue 2, 1 August 1977, Pages 430–434, https://doi.org/10.1210/endo-101-2-430 Published: 01 August 1977 Article history Received: 14 February 1977 Published: 01 August 1977
Plasma levels of progesterone were measured during the luteal phase in 10 of 15 women with clinical histories of at least three spontaneous abortions in the last three gestations, and in 15 healthy nonpregnant women during the same phase of the ovarian cycle. Progesterone values found in the women with habitual abortion were lower (P less than 0.05-0.005) than in the nonpregnant group almost throughout the period of observation. The habitually aborting women who became pregnant again aborted between the seventh and 12th weeks. Their progesterone concentrations were less than 6 ng/ml, 48-72 hours before vaginal bleeding or abortion. These values were compared with those found during the first 12 weeks in normal pregnancy (P less than 0.001). The results suggest a useful method of evaluating the treatment of habitual abortion.
A total of 30 to 50 per cent of premature labors occur without identifiable predisposing conditions. To evaluate the hormonal status of these pregnancies, serum progesterone (P) and estradiol (E2) were measured by radioimmunoassay singly in 60 premature labor patients and serially in 19 normal pregnancies. Premature labor patients as a group have significantly lower P and E2 levels than controls. Pregnancies complcated by idiopathic premature labor (IPL) (p less than 0.01), premature labor secondary to abruptio-marginal separation (A-MS) (p less than 0.05), and premature rupture of membranes (PROM) (p less than 0.05) have significantly lower P levels than controls. Patients with IPL and A-MS have significantly lower P levels (p less than 0.01) than PROM patients. No significant change in P or E2 occurs immediately prior to normal term labor. Conclusions are that (1) premature labor patients have significantly lower Pand E2 levels than controls, (2) the degree of P depression varies according to the type of premature labor and (3) IPL is characterized by premature labor with no identifiable predisposing factors.
The plasma concentrations of oestrone, oestradiol-17β and progesterone, and the urinary excretion of oestrone, oestradiol-17β, oestriol and pregnanediol have been determined in normal Japanese and British adolescent, pre-menopausal, menopausal and post-menopausal women.
The amounts of plasma oestrogen in British and Japanese women were not significantly different except in the adolescent group. In this latter category the mean level of plasma oestrone and oestradiol-17β in the luteal phase was significantly higher in Japanese compared with British women. The mean excretion of urinary oestrogens in the two races was similar for all age groups studied, as was plasma progesterone and urinary pregnanediol.
The mean ratio of oestriol to oestrone and oestradiol-17β for Japanese was higher than that for British women in the two pre-menopausal groups, although the difference was not statistically significant. The difference in the incidence rates of breast cancer in Britain and Japan does not appear to be related to differences in plasma levels of oestrogens or progesterone.
Progesterone, at five times normal 24 h endogenous production rates, was administered daily to 37 rats over Days 2 to 10, 11 to 17 or 2 to 21 of gestation: term is Day 23. Peanut oil, the vehicle, was administered alone to 18 control rats over Days 2 to 21. The effect of treatment on fetal, placental and corpus luteal weights was examined on Day 22 of gestation. The administration of progesterone had no apparent effect on the maternal weight gain with pregnancy, myometrial, fetal or placental weights. No external malformations or abnormalities of the internal genitalia were detected in any of the fetuses examined. The mean number of dead fetuses per litter, 0.72 ± 0.19 (SEM) in the control rats, was significantly increased to 1.57 ± 0.34 and 2.25 ± 0.54 in rats treated with progesterone over Days 11 to 17 and 2 to 21 respectively. Male fetuses were about 7.4 percent heavier than female fetuses in the control rats but this difference was significantly less in rats treated with progesterone over Days 11 to 17(3.4 percent). Progesterone treatment had no apparent effect on the mean corpus luteal weight per rat. Over all groups combined, the mean corpus luteal weight was negatively related to the number of corpora lutea per rat. This relationship was unlikely to have been due to local nutritional or overcrowding factors since there was no apparent relationship between corpus luteal weight and the number of corpora lutea in the one ovary.
Serum progesterone was measured by competitive protein-binding assay in 331 cases of normal pregnancy ranging from 6 to 42 weeks. Serial estimations of serum progesterone were performed in nine cases of severe hypertensive disorder of pregnancy, eight cases of twin pregnancy, three cases of twin pregnancy complicated by severe hypertensive disorder of pregnancy, three cases of triplet pregnancy, three cases of previous bad obstetric history, one case of anencephaly, and seven cases of intrauterine fetal death. Serum progesterone remained within normal range in severe hypertensive disorder of pregnancy and the levels were indistinguishable in cases of fetal growth retardation from those without growth retardation. In twin and triplet pregnancies, serum progesterone was within normal range or elevated and was usually higher than normal in twin pregnancies after weeks 33 to 34. Serum progesterone levels were normal in anencephalic pregnancy and in most cases of intrauterine fetal death. The findings are discussed with reference to placental hormonal activity. It is concluded that serum progesterone is a poor index of placental function.
Androstenedione, testosterone, progesterone and human chorionic gonadotrophin (HCG) in plasma and total oestrogens, luteinizing hormone (LH) and HCG in urine were measured in five women during conceptual cycles and in early pregnancy. There were increased levels in plasma and urine of all the hormones measured between 12 to 48 days after ovulation except progesterone. The concentration of this hormone in plasma decreased during this time. The possible sources of these hormones in early pregnancy are discussed.
In summary, the luteal phase defect is a deficiency of corpus luteum progesterone steroidogenesis, either in amount or duration, or both. The clinical manifestations include either primary infertility or repeated first trimester abortions. The diagnosis can only be made clinically on the basis of a well-timed endometrial biopsy that is read histologically as 2 or more days out of phase with the next period in at least two cycles.
This study was designed to investigate the effect of varying concentrations of estradiol, administered to normal women, upon the gonadotropin response to synthetic gonadotropin-releasing hormone (GnRH or LRF). Beginning at 4 pm on the first day of the menstrual cycle, 19 studies were performed in subjects who received injections of estradiol benzoate (E2B every 12 h for 6 days). Concentrations of E2B administered (mug/kg/12 h) were: 0.3, 0.6, 1.25, 2.5, 3.75, and 5.0. Mean serum estradiol concentrations achieved at these respective concentrations of E2B were 43, 53, 91, 145, 195, and 305 pg/ml. Twelve h after the last E2B injection, an intravenous bolus of 100 mug GnRH was administered. Gonadotropin response to this dose of GnRH after E2B was compared with each subject's response in the early follicular phase of a previous (control) cycle during which no exogenous estradiol was administered.
Forty-eight uterine strips were excised from 24 New Zealand white rabbits and studied in vitro. Sixteen strips were examined when eight animals were 25 days pregnant, 24 strips when 12 animals were about 12 hours postpartum, and eight strips about 12 hours after four animals received a single dose of 5 mg. progesterone (P) at spontaneous delivery. When after repeated exposures to electric fields (60 cycles per second, alternating current, of optimum strength, four seconds' duration at intervals of 30 seconds) the approximately 0.5 Gm. strips developed approximately 40-50g wall tension (WT) in steady state, the field strength was reduced in graded steps from 12 v per 5 cm. to 10, 8, 6, 4 and 3 v per 5 cm. and WT recorded. By measuring the effect on WT of "decreasing electric field stimulation" (DEFS), myometrical excitably and threshold were characterized and quantitated. The technique is based on the relationship between the fraction of myometrial cells activated in the total cell population and WT. As the stimulus is decreased in graded steps from optimal to increasingly suboptimal, DEFS activates fewer and fewer cells reflected by the decrease in WT. Threshold is defined by the strength of the minimum electric field which provokes WT and subthreshold by the field strength which fails to excite. Thus fractional WT averages the excitability of cells in the tissue and thus DEFS characterizes this important parameter of uterine function and quantitates threshold under a variety of regulatory conditions. The comparative study of excised uteri in three different endocrine states showed that the regulatory conditions of normal pregnancy (P levels 9 ng. per milliliter) suppressed excitability and increased threshold (to 6 v per 5 cm.). Post partum (P levels 1 ng. per milliliter) excitability increased and threshold decreased (to 4 v per 5 cm.), unless P treatment prevented this characteristic change by suppressing excitability and increasing threshold (to 6 v per 5 cm.). Both regulatory agents, prostaglandin F2alpha (PGF2alpha) and its analogue ICI 81008, increased excitability and decreased threshold significantly in picogram per milliliter concentrations. However, this effect was observed only when the P levels were low. These compounds had little effect, even in manogram per milliliter concentrations, when the P levels were high. The studies also revealed a close relationship between threshold and spontaneous uterine activity. Low threshold promoted while high threshold suppressed spontaneous activity. In similar concentrations the oxytocic actions of PGF2alpha and ICI 81008 were similar but the effect of ICI 81008 was prolonged through strong binding at myometrical sites.
In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for this therapeutic regimen were: (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then given in the following manner: two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.
Progesterone metabolites and estriol were determined in urine and faeces collected daily from three pregnant women (33–37 weeks) before and during ampicillin administration (2 g/day orally).
Two of the three subjects showed marked changes in their faecal steroid excretion during ampicillin administration: the faecal progesterone-metabolite pattern changed from containing 69–79% unconjugated metabolites and 19–26% glucuronides under control conditions, to high steroid sulphate content (28–44%); the faecal elimination of 3β-hydroxy-5α-pregnan-20-one and 5α-pregnane-3β,20α-diol glucuronide all but ceased; two 16α-hydroxylated progesterone metabolites were detected in significant amounts in faeces during ampicillin administration but not under normal conditions. Steroid sulphate hydrolysis, epimerization of 3α,5αto 3β,5α-steroids and 16α-dehydroxylation are all well known actions of intestinal bacteria on biliary steroids. It thus seems clear that the changes found in the faecal progesterone metabolite pattern are due to the reduction of the intestinal flora by ampicillin.
Under control conditions the bulk of the faecal estriol was unconjugated. During ampicillin administration this excretion remained unchanged but in addition large quantities of conjugated estriol appeared in the faeces, apparently as a result of inhibition of bacterial deconjugation.
Ampicillin administration also caused decreased urinary excretion of estriol and pregnanediol glucuronide. It seems likely that these well documented effects of ampicillin on urinary steroid excretion are caused by an interruption of the enterohepatic circulation of steroids which results from the inhibition of intestinal steroid metabolism described above.
The ability of morphine to block ovulation in animals prompted investigation of the frequency and mechanisms of menstrual abnormalities in women addicted to narcotic analgesics. Menstrual histories obtained from 76 former heroin addicts receiving daily methadone maintenance revealed that more than one-half of these women had experienced menstrual abnormalities while taking heroin or methadone. In order to determine the specific physiologic effects of narcotic analgesics on reproductive function, detailed endocrinologic studies were carried out in seven of these patients who complained of amenorrhea or irregular menses while receiving methadone. Four of the seven women manifested abnormalities of the control of gonadotropin secretion. Three of these four failed to exhibit cyclic gonadotropin release, as evidenced by an absence of increased levels of follicular phase follicle-stimulating hormone, midcycle gonadotropin peaks or luteal phase progesterone increments. In the fourth patient a prolonged follicular phase (30 days) of the menstrual cycle was detected. One of these four patients also had low basal gonadotropin levels and failed to exhibit luteinizing hormone increments greater than control levels in response to ethinyl estradiol (positive feedback). The remaining three women exhibited normal patterns of gonadotropin secretion during the observation period. In these women, menstrual bleeding occurred in response to withdrawal from luteal phase (10 to 20 ng/ml) progesterone levels and to exogenous ethinyl estradiol, suggesting normal uterine responsivity to progesterone and estrogen. Although not documented, it is likely that oligo-ovulation was the cause of the irregular menses in these three patients. Amenorrhea is commonly associated with methadone ingestion or heroin addiction and appears to be related to an alteration of the hypothalamic mechanisms controlling gonadotropin secretion. Tolerance to these effects of methadone may develop after chronic ingestion.
Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.
The plasma concentration of progesterone (P) has been measured by radioimmunoassay in maternal peripheral vein (M.P.V.) at early pregnancy and in M.P.V. umbilical artery (U.A.) and umbilical vein (U.V.) at term pregnancy. In early preganacy marked hour-to-hour fluctuation of plasma progesterone was noted. At term pregnancy plasma P levels of U.V. were higher than those of U.A. and the umbilical venous arterial differences of plasma P did not differ between male and femal fetuses. Administration of hydrocortisone and ACTH to patients scheduled to undergo cesarean section had no effect on M.P.V., U.A., and U.V. plasma P concentration. On the basis of the differences between U.V. and U.A. plasma P concentrations and reported umbilical flow it was estimated that the secretion rate of P into the fetal circulation is approximately 23 mg. per 24 hr. and would amount to approximately 10 per cent of the reported total daily production rate of P at term pregnancy. The fraction of P which is unbound to the plasma proteins was estimeated by equilibrium dialysis at 37 degrees C. The per cent unbound P in M.P.V. plasma of pregnant patients at term was not different from that of nonpregnant patients but was 40 per cent lower than that in umbilical cord plasma (P LESS THAN 0.01), and the ratio between the concentrations of unbound P and estradiol in M.P.V. increased as pregnancy progressed. Plasma P in re-eclamptic patients who subsequently sustained intrauterine fetal death had no value in assessing placental function.
5alpha-Pregnane-3,20-dione and progesterone were isolated from a pregnancy plasma pool and were identified by using a combination of chromatographic techniques and mass spectrometry. Antibodies to progesterone were obtained in rabbits by immunization with progesterone-1alpha-carboxyethyl-thioether-thyroglobulin. The raised antibodies were of high affinity and one of them cross-reacted (137%) with 5alpha-pregnane-3,20-dione. This property was used to develop radioimmunoassays for measuring circulating levels of both progesterone and 5alpha-pregnane-3,20-dione in pregnancy plasma. The levels of both progesterone and 5alpha-pregnane-3,20-dione increase throughout pregnancy, but a highly significant increase is observed only after the 32nd week of gestation.
To develop a practical yet statistically valid means of indicating ovulation and adequacy of corpus luteum function concentrations of plasma progesterone (P) were measured daily during the luteal phase of 30 normal and abnormal menstrual cycles. During a normal cycle any 3 P measurements taken from 11 days before the first day of the following menses (M) to Day M-4 gave a total equal to or greater than 15 ng/ml. An abnormal cycle was considered one in which the total P (for 3 measurements) was less than 15 ng. Individual levels were often at 3 ng/ml in normal cycle and above 3 ng/ml in abnormal cycles indicating that the single P measurement proposed by Israel et. al. would not always be valid.
Swain MC et al., 1974·J Obstet Gynaecol Br Commonw·
The luteal phase plasma progesterone levels of 341 control patients were compared with those in 25 patients with early and 12 patients with advanced breast cancer. There was a significant increase of ovulatory failure and luteal deficiency in patients with advanced breast cancer.
The irregular menses experienced by obese and/or hirsute women were studied by daily measurement of serum LH, FSH, estradiol (E2) and progesterone (P). During 8 cycles of 24 to 157 days, each episode of menstrual bleeding was preceded by hormonal evidence of follicular maturation and corpus luteum formation. The premenstrual fluctuations of LH and E2 were not different from those observed in normal cycles. Although the luteal phase was of more than 10 days' duration, progesterone secretion was subnormal during each cycle. Serum FSH was low throughout the time preceding the LH/FSH surge. These data suggest that inadequate corpus luteum progesterone secretion may be characteristic of the menstrual cycles in oligomenorrheic, obese infertile women.
A group of infertility patients were evaluated by an endometrial biopsy, timed with a basal body temperature chart, serum luteinizing hormone radioimmunassay to pinpoint ovulation, and daily serum progesterone values during a control and a treatment cycle. Progesterone in the suppository or intramuscular form and 17-hydroxyprogesterone caproate* were administered during the luteal phase to a group of volunteer patients with normal corpus luteum function to determine if these compounds would depress serum progesterone levels as do certain progestational agents. There was no apparent inhibition of corpus luteum function as no decrease in progesterone production occurred. Despite the additive effect of progesterone administration demonstrated by elevated serum levels, endometrial biopsies remained in phase when dated from the estimated day of ovulation.
Lindberg BS et al., 1974·Acta Obstet Gynecol Scand·
Plasma progesterone levels were estimated by competitive protein binding in 815 samples from healthy pregnant women with uncomplicated pregnancies. This series includes 32 patients who were followed serially throughout pregnancy. The mean level increased from 47 ng/ml in week 22 to 148 ng/ml in week 41. The spread was large. Individual patients showed very large variations between two consecutive weeks.
Diurnal variations were examined in 7 patients and short-time variations during one hour in 5 patients. Large but non-systematic variations were found in most cases. The maximal difference between values observed over a 24-hour-period was 123 ng/ml and during one hour 150 ng/ml.
Plasma progesterone levels were studied in 87 cases of toxemia of pregnancy, 6 cases of hypertension, 54 cases of Rh-immunization, 37 cases of diabetes and 5 cases of fetal growth retardation of unknown origin. The results indicate that no constant changes occur in plasma progesterone levels in these groups or in cases of impending fetal death.
As the normal limits are very wide, the intraindividual variations large, and the progesterone values in high risk pregnancies are inconclusive, plasma progesterone estimates during the latter part of pregnancy seem to be of limited value.
During human pregnancy large amounts of progesterone are produced by the placenta (1, 14). The production rate during the third trimester lies between 200 and 300 mg/day (9). Part of the progesterone produced is metabolized to pregnanediol and excreted in the urine as the 3-glucuronidate (16). The percentage of conversion to pregnanediol seems to vary with the stage of gestation and is influenced by pathological alterations in risk pregnancies (2, 5).
Large day to day variations in the urinary pregnanediol levels have been found. It is thus hardly surprising that the clinical value of serial determinations of urinary pregnanediol in late pregnancy has been limited.
Recently useful methods for the assay of progesterone in plasma have been developed and applied to physiological and clinical studies. A number of reports dealing with the prognostic value of progesterone determinations in complicated pregnancies have been published (8, 12, 17). The number of cases investigated is, however, small and the results are, in many respects, inconclusive. The aim of the present investigation was to determine the normal limits during the latter half of uncomplicated pregnancies, circadian and short-time variations, and to evaluate the prognostic value of progesterone determinations in plasma in high risk pregnancies.
This paper gives in narrative style those phases of the corpus luteum story in which the author was an active participant. The first part deals with the exciting days at the University of Rochester where the pure hormone was isolated in 1933 and where many of the effects of the hormone on target tissues were elucidated. The origin of the name, progesterone, is given as a fine example of international cooperation in the selection of a name which has been universally accepted. The accidental discovery of the ‘Blue Color Test’ for DHIA and the development of the Allen-Correction at Washington University in St. Louis are recounted as sideline adventures in science. The final part recounts the steps, extending over a period of 40 years, which have clarified the role of the human corpus luteum in pregnancy.
Hagemenas FC et al., 1973·J Clin Endocrinol Metab·
Progesterone levels in the human fetoplacental unit at term were determined by a competitive protein binding method. Progesterone levels in the umbilical vein were always higher than in the umbilical artery. The concentration of progesterone in the umbilical vein of male and female fetuses was identical. However, the umbilical venous-arterial difference in progesterone levels was significantly greater in female than in male fetuses. The fetal genotype therefore may affect the fate of progesterone available to the fetus.
This article has been designed to review recent developments in the field of hypothalamic hormones involved in the control of reproductive functions. A brief resume of early physiologic and anatomic studies was presented initially to give a better understanding of the concept of hypothalamic regulation of the release of gonadotropic hormones from the pituitary gland. Recently, an advance was achieved with the isolation from porcine hypothalami of a decapeptide which has both FSH-releasing hormone (FSH-RH) activity and LH-releasing hormone (LH-RH) activity. Its amino acid sequence was determined to be (pyro) gluhis-trp-ser-tyr-gly-leu-arg-pro-gly-NH2. The decapeptide corresponding to this structure was synthesized and shown to stimulate the release of LH and of FSH in laboratory and domestic animals and human beings. Natural and synthetic FSH-RH/LH-RH also stimulated the synthesis of both gonadotropins in tissue cultures of rat pituitaries in vitro. It was postulated that this decapeptide represents the hypothalamic hormone which regulates the release of both LH and FSH from the anterior pituitary gland. Complex effects of sex steroids on the release of LH and FSH were reviewed briefly. It was suggested that the over-all control of secretion of FSH and LH is most likely mediated by the interaction of hypothalamic FSHand LH-releasing hormone with sex steroids. Clinical studies performed with natural and synthetic LH-RH/FSH-RH were reviewed. These studies, particularly induction of ovulation, suggest that LH-RH should find practical application in the treatment of sterility. Subsequent synthesis of LH-RH/FSH-RH by several laboratories and drug houses should provide enough material for large-scale clinical evaluation of this hormone. Some comments were made concerning probable clinical use of LH-RH. Finally, some speculations were offered about the possibility of developing new birth control methods based on LH-RH/FSH-RH, its analogues, or its derivatives.
Adamopoulos DA et al., 1972·Clin Endocrinol (Oxf)·
Studies on pituitary and ovarian function as assessed by the urinary output of total gonadotrophic activity, the three classical oestrogens, pregnanediol and, in some cases, testosterone and epitestosterone, were conducted in eight patients suffering from premenstrual tension. Major abnormalities in endocrine function were not a feature of the condition. Ovulation, as judged by pregnanediol assays, was absent in seven out of the fifteen cycles investigated. Contrary to traditional belief, the symptoms of premenstrual tension could exist in the presence of cycles with anovulatory hormonal patterns.
To describe normal relationships between the various plasma unconjugated estrogens and progesterone during the second half of human pregnancy, the plasma concentrations of progesterone, 17-hydroxyprogesterone (17-OHP), and unconjugated estrone (E1), estradiol (E2), and estriol (E3) were measured in 126-310 normal women. Progesterone and unconjugated E1, E2, and E3 increased gradually throughout later pregnancy; 17-OHP increased only after the thirty-third week. At term the mean value of progesterone was 9 times higher than that 17-OHP. Throughout pregnancy the mean value of E2 was higher than that of E1 or E3. During the second half of pregnancy the ratios of progesterone to estradiol and estriol and of estradiol to estriol remained unchanged, indicating no preferential increase of plasma concentration of maternal or fetal hormones.
A study was undertaken to determine whether solitary progesterone as says performed on serum samples obtained in the midluteal phase would provide the clinician with a convenient indicator that ovulation had occurred in that cycle. After a normal luteal-phase range was establish ed, single luteal-phase serum progesterone sampling was performed in 51 infertile women with regular menses and 35 oligomenorrheic women undergoing clomiphene citrate therapy. In the follicular phase of the cycle, progesterone levels were consistently less than 2 ng/ml. Between 11 and 4 days prior to the onset of menses in presumptively ovulatory cycles, serum progesterone levels were always 3 ng/ml or greater. Progesterone values in this range were always accompanied by a secretory endometrium and can be considered presumptive evidence of ovulation. This rapid, easily performed technique enables 1 technician to assay 30 or more samples for progesterone in a single working day and the results are available within 24 hours. This assay technique is easier to perform and more reproducible than a urinary pregnanediol assay, and it is expected that clinical laboratories will soon perform serum progesterone assays as a routine procedure.
Following the total removal of luteal tissue, circulating plasma progesterone, intrauterine pressure, oxytocin response, and clinical progress in abortion were determined sequentially in 12 first-trimester pregnant patients. 3 patients were ovariectomized for the removal of ovarian cysts and 9 were luteectomized during tubal ligation in an attempt to terminate pregnancy in spontaneous abortion. 7 patients had corpora lutea which averaged 21 plus or minus 1mm in diameter at operation when performed at Day 49 plus or minus 2 (mean S.E.) of pregnancy. These patients responded to ovariectomy or luteectomy by a continuing decrease in progesterone, evolution in intrauterine pressure, oxytocin response, progress in cervical dilitation and, abortion. Abortion occurred with a mean lapse time of 5 plus or minus 1 days after operation. In contrast, 5 patients whose corpora lutea averaged only 11 plus or minus 1mm in diameter when removed at Day 61 plus or minus 4 of pregnancy showed only transient decrease in progesterone after operation. This decrease was followed by an increase in progesterone; no progress in the evolution of intrauterine pressure, oxytocin response, cervical dilatation, and abortion. It appears that so long as the corpus luteum serves as the major source of progesterone, it is indispensable in the maintenance of pregnancy in human subjects as it is in the clinical model animal, the rabbit. However, with the shift of progesterone production from the corpus luteum to the placenta (the luteoplacental shift) the human corpus luteum becomes dispensable. These findings identify the corpus luteum and its secretory product, progesterone, as feasible targets of fertility control strategy.
PROSTAGLANDINS (PGs) are being used increasingly as abortifacients although their precise mechanism of action is uncertain. One of the compounds frequently used is PGF2α, which has been shown to stimulate the myometrium in vitro1 and in vivo2. Whether or not the direct action of this agent on the uterine muscle alone is responsible for the interruption of pregnancy is not clear, but the long interval between infusion and abortion3 suggests that other mechanisms might be involved; for example, a luteolytic effect4–6. The prompt increase in uterine activity after treatment with prostaglandin, however, argues that the direct effect plays some part in the abortifacient action. Little is known of the influence of other myometrial regulatory agents such as the ovarian steroids on the uterine response to PGs. Accordingly we examined the influence of progesterone on myometrial responses to prostaglandin F2α in the rabbit, a species in which progesterone is known to have a blocking action on the uterine muscle7.
One hundred and thirty-five patients diagnosed as ovulatory failure have been treated in our clinic since 1966. One hundred and eighteen of these have been treated with clomiphene citrate, or more recently, its cisisomer, and 17 patients with long-standing secondary amenorrhea or primary amenorrhea have been treated with human menopausal gonadotropins, in combination with human chorionic gonadotropins. Of the latter group, 14 of the 17 were shown to be capable of response to exogenous gonadotropins and 12 of these ovulated and 7 (50 per cent) became pregnant. The over-all ovulatory rate with clomiphene citrate or its cisisomer was 78 per cent, with a pregnancy rate of 31 per cent. The results of our present investigation with clomiphene citrate in 10 and 20 mg. dosage are presented in detail, and compared with our previous experience with clomiphene. It appears that cisclomiphene 20 mg. is as effective as clomiphene citrate 100 mg., but has the decided advantage of fewer side effects associated with its use. With the human menopausal gonadotrophins, no major complications, such as ovarian overstimulation or multiple pregnancies, were encountered, and we feel this is attributed to careful selection of patients and daily tracking of total urinary estrogens.
Plasma progesterone concentration was determined in the maternal peripheral vein, umbilical vein, uterine vein, and both ovarian veins at elective cesarean section in term pregnancy. In 10 cases plasma from both ovarian veins was analyzed. In all but one the ovarian vein draining blood from the corpus luteum contained greater concentrations of progesterone than did the blood from the side without the corpus luteum. It has been suggested for some time that the corpus luteum of pregnancy continues to function throughout pregnancy. Our data appear to support this concept.
From among a group of women with apparently normal menstrual cycles, 7 cycles with short luteal phases were identified. These cycles were characterized by grossly normal FSH and LH patterns although the FSH/LH ratio was below normal. Mean plasma progesterone increased to less than 2 ng/ml shortly after the LH peak; thus, the peak level was lower and the peak occurred earlier than in the normal cycle. Plasma 17-hydroxyprogesterone increased at the time of the LH peak although the mean peak level was only 60% that of normal cycles. There was no secondary increase of 17-hydroxyprogesterone during the luteal phase. These observations are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum formation or function.
Plasma levels of progesterone* were measured during normal human pregnancy by a sensitive and rapid competitive protein binding technique. During the first half of gestation 440 determinations in 321 women and in the second half of gestation, 209 determinations in 160 women were performed.
The average plasma level of progesterone in the 5th week of gestation was 24.8 ± 7.3 (s) ng/ml which is above the normal range of the luteal plateau of the menstrual cycle (10–20 ng/ml). Between the 5th and the 9th week of gestation the plasma concentration decreased significantly. From the 9th to the 32nd week of gestation the plasma level of progesterone increased from 16.7 ± 7.4 (s) to 125.2 ± 37.9 (s) ng/ml. During the last 8 weeks of gestation the plasma levels of progesterone did not show any significant rise. One woman was followed up from the day of ovulation to the 8th week of gestation. An increase in progesterone levels was observed about 10 days after ovulation. Morning samples of progesterone, which were taken before the 20th week of gestation, when the woman was still in bed, were found to be somewhat higher than levels found during the remainder of the day.
Progesterone concentrations in a few abnormal pregnancies are also reported.
One hundred and seventy-two plasma progesterone determinations were performed in normal pregnancy, labor, and the puerperium. One hundred and nineteen of the assays were done on isolated samples; 53 of the assays were done in 11 serial studies. While the concentration of progresterone in peripheral blood increased progressively with advancing pregnancy, no apparent decrease in the hormone level occurred at or near the onset of labor or during its progress. A significant decrease in plasma progesterone one hour after the delivery of the placenta continued to decline to menstrual cycle levels by 72 hours post partum.
For years the gynecological endocrinologist has been seeking an effective gonadotrophin for the treatment of ovarian dysfunction and anovulation in the human. 7
Animal preparations have been self-limiting because of allergic reactions, antihormone formation, failure to obtain a uniform response from a standard dose, and the absence of data on animal specificity.
A breakthrough occurred in 1958 when Gemzell et al. reported a human pituitary gonadotropin which induced follicular growth and estrogen production in the ovaries of amenorrheic women. The human source does not permit widespread application of this material. A few years later, Pergonal (HMG ),* a human menopausal urine gonadotropin which had similar effects,16 was developed; but standardization of HMG has been difficult and the extraction process complicated and expensive.
A most important contribution was made in 1959 by Tyler et al., who were able to induce ovulation in 6 patients with severe anovulatory problems, and in 1960 by Kistner and Smith, who successfully induced ovulation in 4 patients with the Stein-Leventhal syndrome, by using the estrogen antagonist MER 25.t Related compounds were further investigated and clomiphene citrate (Clomidt) proved more effective and had fewer side effects. 5, 12
The exact mechanism of action of the drug is stilI in doubt. It is postulated that clomiphene acts either directly on the hypothalamic-pituitary axis, causing an increase in gonadotropin output,9, 12, 17 or sensitizes the ovary to respond more readily to endogenous gonadotropins. 6
Smith and Kistner believe that Clomid directly influences the enzyme systems involved in ovarian steroidogenesis, or merely acts as a potentiator of gonadotropins. Pildes believes that there is a change in the synthesis of estrogen in both the adrenals and ovaries at the pre-estradiol phase of steroid synthesis.
Dickey et al. postulate a direct anti-estrogen effect in the system involved in estrogen metabolism, with subsequent stimulation of the hypothalamic-pituitary axis due to a fall in estrogen levels. Probably more than one mechanism of action is responsible for the response to the drug.
We first used clomiphene in the treatment of infertile patients with impaired ovarian function in May 1962. Because of the frequent side effects such as large ovarian cysts, reported by the early investigators, its use was limited to women with major endocrine defects and in cases where all other treatments had failed. With more experience and smaller dosages, 50-200 mg. daily for a short period of time, 3-5 days of each cycle, the drug was effective and most of the side effects were eliminated.14 With a program of at least monthly checkups, the drug proved safe and we have extended its use to infertile patients with only minor problems of ovarian dysfunction.
All patients, prior to treatment, have a thorough infertility and endocrine evaluation. The patient who is a proper candidate for this drug should be one with a moderately intact pituitary-ovarian axis and norm~or low total urinary gonadotropin levels, although we have had several patients with mildly elevated total gonadotropin who have responded. The patient should have a fair endogenous estrogen production. Thyroid function is usually normal or mildly subnormal. The 17-ketosteroid concentration is usually normal, although 32.5% of our patients who conceived did show levels of 13.0 mg. 24 hr. or more. Several of these decreased to normal levels after treatment with clomiphene; Pildes has reported a similar finding. Of our patients who conceived, 35.5% showed a diabetic or a prediabetic glucose tolerance curve on initial evaluation.
Pituitary tumors should be ruled out. Patients with ovarian damage due to chronic infection are not likely to respond. Since clomiphene citrate is detoxified in the liver, one should be hesitant to prescribe the drug to a patient with chronic liver disease.
Visualization of the ovaries by culpotomy with ovarian biopsy or culdos-copy is helpful in establishing the diagnosis, especially in patients who fail to respond.
Clomiphene citrate [1-p(β-diethylaminoethoxy) phenyl-1,2-diphenyl-2-chloroethylene citrate], because of its ability to induce ovulation, was administered to 26 patients with excessive anovulatory uterine bleeding. Of the 129 menstrual cycles during which the drug was administered, 105 cycles (81.3%) were ovulatory and were followed by normal uterine bleeding. After clomiphene was discontinued, observations made in 52 cycles showed that only 20 (38.4%) were ovulatory
Summary. The manner whereby progesterone acts as an inhibitor of cleavage of mammalian ova was studied using rabbit ova in vitro. Progesterone blocked cleavage when it was present in the culture medium at concentrations of 10 µg/ml more, and exerted this same effect on all stages up to the morula. The growth of blastocysts was not affected. The action was reversible: ova resumed cleavage within 2 to 3 hr after removal to progesterone-free media. The reversal was time-specific and was used to phase the subsequent cleavage of ova inhibited for varying periods of time. The inhibition was overcome by increasing the concentrations of amino acids or of the serum component in the medium. Supplementing the progesterone media with oestradiol did not reverse the inhibition. Autoradiographs of sections of ova that were kept in C-labelled progesterone for 8 hr, showed silver grains concentrated on the surface of the ovum and the zona pellucida. It is concluded that progesterone blocks cleavage by limiting the supply of protein or amino acids and thus inhibiting protein synthesis within the ovum. Presumably this is done by the progesterone aggregating on the surface of the cell or its protective coating. The inhibitory action appears to be timed in relation to some event that precedes mitosis by an hour or two. It is therefore suggested that the protein synthesis involved is related to formation of the mitotic apparatus or to chromosome condensation.
Gonadotrophins were prepared from human postmenopausal urine with the kaolin-acetone method and purified by adsorption of impurities on diethylamine ethyl cellulose (DEAE-C).
The last step, namely chromatography on the column of permutit, resulted in a significantly improved specific activity.
The immunoelectrophoresis showed that the purified HMG is not homogeneous and that the constituents are glycoproteins which migrate into the region α1, α2and β globulins.
Induction of ovulation in the human has been of considerable research interest for several decades. Various hormonal regimens and other procedures have been tried in the past.1 • 2 In spite of all these trials, the problem of ovulatory failure remains a frustrating dilemma for the physician. Recently, the induction of ovulation with clomiphene citrate in about 70% of anovulatory women was reported by our group.3- 6 It was felt that an important breakthrough in this difficult field of endeavor was at hand. 7- 9 Our observations have been confirmed by other groups of investigators.10- 12 The present report embodies a detailed analysis of the results of administration of this agent to 200 women, of whom 179 were anovulatory. The results of our studies on the probable mode of action of this drug are also discussed.
IT APPEARS TO BE WELL ESTABLISHED that the synthetic nonsteroidal analogue of chlorotrianisene (Tace), which has been given the generic name of clomiphene citrate (MRL/41)*, is capable of stimulating ovarian secretory activity in women.1-4 Perhaps the most convincing evidence for this is found in the high incidence of cystic ovaries observed among treated patients, together with the associated microscopic ovarian and endometrial changes, indicating that the cystic structures produced are functional.2,3 The striking similarity between the histopathology of this response to clomiphene and the ovarian response to administered gonadotropins of both human and animal origin has been pointed out by Southam and Janovski.2 With both forms of treatment, the degree of ovarian response to a given dosage appears to be unpredictable and all patterns of atypical stimulation have been observed. In view of this analogy, it has been logical to assume that the ovarian response
A new progestational steroid, the acetophenone derivative of 16α,17α;- dihydroxyprogesterone, was compared with several progestogens for masculinizing effects on the offspring of rats treated during pregnancy. The results were similar to those obtained with progesterone and 17α-hydroxyprogesterone caproate: this new steroid did not alter the normal male:female sex ratio and did not virilize the internal or external sex structures of the newborn. The present results confirm those of others in finding that 6α-methyl-17α-hydroxyprogesterone acetate, 17α-ethinyl-19-nortestosterone and 17aethinyl- 19-nortestosterone acetate increased the number of male and intersex offspring, as determined by ano-genital measurements and masculinization of internal and external sex organs.
The content of progesterone was determined in the peripheral venous blood of pregnant women from the 11th week after the last menstrual period up to the day of birth. There was a steady increase in the blood level from the 11th to the 35th week, but thereafter the level rose more rapidly, and remained high during labour itself. The significance of this rise after the 35th week is not fully understood. It may reflect a decrease in the rate of progesterone metabolism which occurs at this time. The blood level in three cases of twin pregnancy tended to be higher than the corresponding levels for single pregnancies. After removal of the placenta during elective caesarean sections, it was found that the blood progesterone level rapidly fell below the limits of sensitivity of the method. It has been estimated that the half-life of progesterone in the circulating blood must be 5 min or less.
Normal Pregnancy. Eleven pregnant women were studied at weekly intervals for periods ranging from 24 to 32 weeks. Three hundred and ten estimations were done in this group. An additional 68 assays were made in 40 patients at various stages of pregnancy, a total of 378 estimations being done in 51 patients, 189 in primigravidae and an equal number in multigravidae. Two of the patients in the first group had been attending the sterility clinic before becoming pregnant. None of the patients were suffering from hypertension …
A partially purified follicle-stimulating hormone preparation (human pituitary FSH) has been obtained from human pituitaries. The ovarian response to this preparation was studied in 7 amenorrheic women. The effect of human chorionic gonadotropin (HCG) was studied in addition. In 4 patients exhibiting no endometrial activity or only slight proliferation, HCG alone did not induce ovulation and had no effect on the size of the uterus, on the endometrium, or on the urinary excretion of estrogen and pregnanediol. In 2 patients showing endometrial proliferation, the administration of HCG alone was followed by ovulation, a secretory transformation of the endometrium, and a marked increase in urinary pregnanediol excretion. The administration of human pituitary FSH alone to 2 patients resulted in an increase in the size of the uterine cavity, in polycystic enlargement of the ovaries, and in a pronounced increase in urinary estrogen output. Treatment with human pituitary FSH followed by HCG produced in all patients polycystic enlargement of the ovaries, ovulation in 4 out of 5, and a secretory transformation of the endometrium in 3 out of these 5 patients. Ovulation was accompanied by a marked increase in the urinary excretion of both estrogen and pregnanediol.
SUMMARY 1. The action of progesterone on the development of the mouse ovum from the eight-celled stage to the blastula has been studied in vitro . 2. Concentrations of progesterone below 2 μg/ml. produced no observable effect, whereas some toxicity was observed at 4 μg/ml. and few ova survived higher concentrations. 3. Herniation of the zona pellucida by the developing blastula is described; this process was inhibited by 4 μg/ml., but not by 2 μg/ml. of progesterone. 4. Blastulae appear to be more sensitive to the action of progesterone than are earlier stages. 5. Oestrogens afforded no demonstrable protection against the toxic action of progesterone when added to the culture medium. 6. The possible physiological significance of these findings is discussed.
In 1899 Gustav Born advanced the theory that the corpus luteum of the ovary is a gland of internal secretion, its activity being a prerequisite for the implantation and early development of the fertilized ovum. Conclusive proof of the theory was provided by Fraenkel ('10) in demonstrating that cauterization of the corpora lutea in pregnant rabbits leads to the resorption of the fertilized ova, provided that the operation took place during the first 7 days of gestation. He extended the period of the indispensable role of the corpora lutea in the …
AMENORRHEA and sterility are frequent accompaniments of morphine addiction in the human female (Menninger-Lerchenthal, 1934; Pescor, 1938). The mechanisms by which these effects are induced, however, are not clearly understood. In experimental animals results are contradictory. Myers and Flynn (1928, 1931) failed to observe any disturbance of estrous cycles, ovulation or fertility despite 132 days of chronic morphine treatment in rats, and their results were confirmed by Forster (1928). In contrast, treatment of mice daily for a two-month period with morphine has been reported to suppress estrus and induce atrophy of the ovary and uterus (Ko, 1934). Similar observations were noted in the rabbit (Bun, 1937).
The finding by Everett and Sawyer (1950) that “spontaneous” ovulation in the rat involves a neurogenic timing factor with a 24-hour rhythmicity offers a new approach to the study of the control of ovulation.
PREGNANEDIOL was first isolated by Marrian (1) in 1929, when he was engaged in thepurification of “oestrin” from pregnancy urine. He described the properties of this new “unidentified solid alcohol” very precisely, and his first analyses came surprisingly near to the right formula, C21H36O2,at a time when the greater part of steroid chemistry was still unknown. To-day, looking back on twenty years of chemical, biologic, and clinical research, it is comparatively easy to see the principal features of the interesting pattern which centers around the pregnanediol molecule. The first clue to the biologic significance of pregnanediol is given by its structural formula which shows a striking resemblance to that of the corpus luteum hormone, progesterone. Pregnanediol is nothing else but reduced progesterone, with all the double bonds of the latter saturated by hydrogen. Thus, the obvious inference would be that urinary pregnanediol is a metabolite of progesterone. This important fact is the reason why so many workers are interested in pregnanediol determinations.
My attention has been increasingly directed to a large group of women who are handicapped by premenstrual disturbances of manifold nature. It is well known that normal women suffer varying degrees of discomfort preceding the onset of menstruation. Employers of labor take cognizance of this fact and make provision for the temporary care of their employees. These minor disturbances include increased fatigability, irritability, lack of concentration and attacks of pain. In another group of patients, the symptoms complained of are of sufficient gravity to require rest in bed for one or two days. In this group, particularly, pain plays the predominant rôle. There is still another class of patients in whom grave systemic disorders manifest themselves predominantly during the premenstrual period. REPORT OF CASESCase 1. —A young, unmarried woman suffered from frequent convulsive attacks, which later occurred exclusively within ten days preceding menstruation. Neurologic investigation resulted in a diagnosis
Bouchard TP et al., 2026·Journal of ovarian research·
Open Access
Reproductive hormones of the fertile window are often referenced to women in regular cycles, but this may not be representative of the hormonal profiles of women in different circumstances like polycystic ovarian syndrome, the postpartum period, and the perimenopause transition. This observational cohort study sought to identify the variability in the reproductive hormones in various clinical circumstances and to establish potential thresholds for each category based on hormone measurements with the Mira urinary hormone monitor. A total of 57 women (ages 22-51) in various circumstances (regular cycles, polycystic ovarian syndrome, postpartum and perimenopause) tracked Mira urine hormone measurements (estrone-3-glucuronide, luteinizing hormone, pregnanediol glucuronide), contributing 444 cycles of data. Using additive mixed models, hormone values were stratified by the four different reproductive categories. The perimenopause and polycystic ovarian syndrome groups demonstrated relative hypoestrogenic states, while the perimenopause group showed low luteal pregnanediol glucuronide and the polycystic ovarian syndrome/polyendocrine metabolic ovarian syndrome (PCOS/PMOS) group showed high luteal pregnanediol glucuronide. The perimenopause group had significantly higher luteinizing hormone values throughout the whole cycle. The fertile window hormone thresholds vary depending on a woman's specific reproductive category. Women in different circumstances should not necessarily use the same hormonal thresholds for the fertile window and ovulation. A larger dataset with ultrasound correlation to ovulation is required to delineate the fertile window with more precision. Hormone differences across the menstrual cycle could be used for targeted treatments in polycystic ovarian syndrome and perimenopause women.
Malliou-Becher MN et al., 2026·Human reproduction (Oxford, England)
What are the variations in ovulation time and menstrual cycle characteristics among and within various individuals over the course of 12 menstrual cycles? There are considerable variations in both cycle length and ovulation time, with pronounced intra-individual variability over a 12-cycle observation period. Although it is commonly believed that healthy women have regular cycles with a predictable mid-cycle ovulation, more recent research shows a significant variation in cycle length and ovulation time. Previous studies have focused only on cycle length, often excluding cycles outside the 25-35-day range, thus limiting the understanding of natural variation; they have also lacked precise ovulation diagnostics or included small sample sizes, making it difficult to capture the full scope of cycle and ovulation variability. Similarly, a recent big data study, while valuable, was limited by a self-selected group and the absence of accurate ovulation diagnostics, reducing its generalizability. STUDY DESIGN, SIZE, This study was designed as a prospective long-term observational study, which involved collecting data from 1923 women with a total of 43 999 menstrual cycles from January 1985 to July 2019. After fulfilling the inclusion criteria, the main group consisted of 1051 women, all of whom contributed data for 12 cycles (12 612 cycles), including 420 conception cycles. PARTICIPANTS/MATERIALS, SETTING, Participants in the study were between 18 and 44 years of age at study entry and did not take any reproductive hormones. Women who were postpartum, breastfeeding, amenorrheic, or within a 3-month period after stopping hormonal contraception were excluded. Participants agreed to keep cycle records according to the symptothermal method, 'Sensiplan'. Ovulation time was determined using an evidence-based algorithm based on evaluating cervical mucus patterns and basal body temperature shifts, with ovulation time defined as the day before the temperature rise. Data analysis was descriptive, using absolute and relative frequencies, standard deviation, percentiles, and ranges. Age dependency was assessed using unpaired sample t-tests and one-way ANOVA. Linear regression was used to assess long-term trends. MAIN In 62.4% of women, cycle lengths varied by 1 week or more within 12 cycles. Accordingly, the time of ovulation varied by 1 week or more within 12 cycles in 54.8% of women, with 96.5% experiencing fluctuations of 4 days or more over the 12 months. The median spontaneous cycle length was 28 days, with a mean of 29.66 days (SD = 7.55). Only 52.7% of women consistently had cycle lengths between 23 and 35 days across all 12 cycles. Ovulation occurred most frequently between Days 12 and 16, with almost half of conceptions (45.7%) occurring after Day 16. A one-way analysis of variance revealed a significant reduction in mean cycle length with increasing age (P < 0.001), showing the shortest median cycle length of 27 days being in women aged 40-44 years. Age also impacted ovulation time, with women aged 35-39 years showing more stable ovulation patterns compared to younger women. Over the 34-year study period, average cycle length increased slightly but significantly (β = 0.0161, P = 0.0306), corresponding to approximately half a day. Intra-individual variability also showed a slight, but non-significant, upward trend (β = 0.0262, P = 0.2173). LIMITATIONS, Comorbidities such as hyperprolactinemia, obesity, and PCOS were not systematically excluded. However, by including only women with at least 12 cycles, the study largely avoided severe hormonal disorders. This study highlights the considerable individual variation of ovulation time and cycle length over 12 menstrual cycles. These findings contribute to a better understanding of fertility awareness, and highlight the implications for family planning and reproductive health management. STUDY FUNDING/COMPETING INTEREST(S): The authors declare no conflicts of interest. No funding was provided. N/A.
This narrative review examines the evidence for medical optimization of inflammatory conditions, vitamin deficiencies, endocrine disorders, immune dysregulation, oligo-ovulation, and luteal phase factors to improve fertility outcomes in women attempting to conceive through natural or timed intercourse. Overall, there is a paucity of data with respect to these categories among patients pursuing timed intercourse, precluding our ability to draw strong recommendations. However, there is strong evidence supporting treatment of endocrine disorders, specifically overt thyroid dysfunction and hyperprolactinemia, as well as oligo-ovulation. Conversely, treatment of subclinical hypothyroidism is not recommended. The current data are insufficient to support empiric use of antiinflammatory medications, corticosteroids, thyroid hormones, or vitamins or supplements to improve chances of pregnancy in a general infertility population.
Valenti M et al., 2026·Am J Obstet Gynecol·
Open Access
Endometriosis is a chronic, gynecologic condition in which tissue similar to the lining of the uterus implants throughout the body. Women with endometriosis have a higher prevalence of infertility and a greater risk of early natural menopause compared to those without endometriosis. This study aimed to evaluate preoperative serum AMH levels among women with and without incident endometriosis and to assess whether levels differ by surgical staging and typology. The ENDO (Endometriosis: Natural History, Diagnosis, and Outcomes) study was conducted between 2007 and 2009. The ENDO study consisted of an operative and population cohort (n=600). Only those in the ENDO operative cohort from the Utah site were used for this analysis, and included women aged 18 to 44 years who were scheduled for gynecologic surgery, irrespective of clinical indication (n=476). AMH levels were measured from stored serum collected before surgery using a quantitative enzyme-linked immunosorbent assay. After excluding participants with missing outcome data (n=51), unilateral oophorectomy (n=8), or those within the population cohort (n=69), 348 participants remained for the analysis. Surgically confirmed endometriosis diagnosis, staging (American Society for Reproductive Medicine I-IV), and typology (superficial, deep, ovarian) were ascertained by the operative report. Outliers for AMH (>14.0 ng/mL) were excluded from the analyses and AMH values were log-transformed. Multivariable linear regression models adjusted for age (squared and continuous), body mass index, serum cotinine levels, and exogenous hormonal contraceptive use were conducted. Percentage differences in AMH were calculated as (exp[β]-1)×100, and 95% confidence intervals were reported. Compared with no endometriosis, incident endometriosis diagnosis was associated with lower AMH levels (-19.8%; 95% confidence interval, -37.0 to 1.0); however, this association was not statistically significant. Stage III to IV disease was associated with 40.1% lower AMH levels (95% confidence interval, -58.9 to -12.7). Ovarian endometriomas were most strongly associated with lower AMH levels (-54.3%; 95% confidence interval, -69.4 to -31.8), with a more pronounced association among those with infertility (-72.6%; 95% confidence interval, -85.4 to -48.5). Deep (-24.1%; 95% confidence interval, -48.2 to 11.0) and superficial (-15.5%; 95% confidence interval, -34.6 to 9.3) endometriosis also showed a trend toward lower AMH levels, but these findings were not statistically significant. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis was associated with 26.8% lower AMH levels (95% confidence interval, -44.6 to -3.4). Stage III to IV disease was associated with 47.8% lower AMH levels (95% confidence interval, -65.8 to -23.2), and all subtypes of endometriosis were statistically significantly associated with lower levels of AMH compared with a postoperative diagnosis of a normal pelvis (ovarian: -60.8%; 95% confidence interval, -74.4 to -39.9; deep: -34.3%; 95% confidence interval, -56.2 to -1.4; superficial: -24.8%; 95% confidence interval, -43.9 to -0.8). Ovarian and moderate to severe (stage III-IV) endometriosis were associated with markedly lower AMH levels compared with no endometriosis. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis and moderate to severe stages (stage III-IV) were associated with statistically significantly lower AMH levels. Additionally, typology (deep, ovarian, or superficial) was associated with statistically significantly lower AMH levels. However, this association was likely driven by the presence of ovarian endometriomas across all subtypes. These findings are consistent with previous studies and demonstrate that endometriosis lesions themselves, independent of surgical intervention, influence AMH levels.
To identify preconception clinical and multi-omics factors associated with conception and early pregnancy loss in women with unexplained recurrent pregnancy loss (URPL). In this prospective cohort study, 149 women with URPL selected from 420 outpatients based on guideline-recommended criteria were enrolled between November 2024 and May 2025 and followed-up for 12 months. Preconception fasting plasma was analyzed for clinical biomarkers, untargeted metabolomics, and data-independent acquisition proteomics. Outcomes included conception, ongoing pregnancy beyond 12 weeks and early pregnancy loss before 12 weeks. Multivariable logistic regression was used to evaluate the associations of clinical and multi-omics factors with reproductive outcomes, adjusting for maternal age, body mass index, number of prior losses, and use of assisted reproductive technology. Of 149 women, 99 conceived (66.4%) during the follow-up. By 12 weeks of gestation, 67 (67.7%) had ongoing pregnancies and 32 (32.3%) experienced early pregnancy loss. Higher testosterone was associated with lower probability of conception (adjusted odds ratio [aOR] 0.50, 95% confidence interval [CI] 0.28-0.89, p = 0.019). Women who conceived showed higher levels of progesterone-related metabolites, including 17-hydroxyprogesterone (fold change, FC = 3.89), pregnanediol 3-O-glucuronide (FC = 2.37), and pregnanetriol 3α-O-β-D-glucuronide (FC = 2.39). Among women who conceived, higher prolactin was associated with higher odds of early pregnancy loss (aOR 1.09, 95% CI 1.01-1.18, p = 0.036), and anti-phosphatidylserine/prothrombin showed a borderline association (aOR 1.07, 95% CI 1.00-1.14, p = 0.052). Early pregnancy loss was characterized by lower bile acid-related metabolites and higher caffeine and methylxanthine metabolites. Proteomic analysis showed enrichment of bile acid biosynthetic process. After adjustment, higher 7α,12α-dihydroxy-3-oxocholest-4-en-27-oic acid was associated with lower odds of early pregnancy loss (aOR 0.64, 95% CI 0.44-0.95, p = 0.025). Higher testosterone was associated with lower odds of conception. Among women who conceived, early pregnancy loss was associated with higher prolactin, borderline higher anti-PS/PT, lower bile acid-related metabolites, and higher caffeine-related metabolites, with 7α,12α-dihydroxy-3-oxocholest-4-en-27-oic acid identified as an exploratory metabolomic candidate. These findings suggest that potential androgen-related biology, prolactin, non-criteria antiphospholipid antibodies, and bile acid metabolism may be associated with reproductive outcomes in URPL, warranting validation in independent cohorts.
Self-reported dietary intake varies across menstrual cycle phases, but objective assessments of dietary intake together with appetite and resting metabolic rate (RMR) are limited. This study aimed to assess differences in dietary intake, appetite, and RMR during two hormonally-distinct menstrual cycle phases in laboratory and free-living settings. Healthy premenopausal females with predictable normal-length menstrual cycles completed two study visits: one in the late-follicular and one in the mid-luteal phase. Menstrual cycle phases were assessed using urinary luteinizing hormone surge and prospective cycle days. Participants consumed a 2-day energyand macronutrient-balanced run-in diet prior to each visit. RMR was measured with indirect calorimetry, followed by appetite ratings before and after a standardized breakfast, and a food cravings questionnaire. Appetite was also tracked for 2.5 days post-visit in a free-living environment. Ad libitum energy and macronutrient intakes were measured using pre-weighed plus weighing of uneaten food at an in-laboratory lunch meal, as well as during the 2.5-day free-living period. Eighteen participants were included (age: 21 ± 4 years; body mass index: 21.2 ± 1.5 kg/m2). There were no differences between in-laboratory ad libitum energy or macronutrient intakes, appetite, or food cravings between phases. RMR did not differ between phases, although the mid-luteal phase RMR tended to be higher (104 ± 218 kcal/day higher; P = 0.074). No main or interaction effects for phase or time were observed for free-living dietary intake nor appetite ratings. Although RMR tended to be increased during the luteal phase, comprehensive appetite and energy intake assessments showed no significant cycle-phase differences in these 18 participants.
Background Reproductive hormones of the fertile window are often referenced to women in regular cycles, but this may not be representative of the hormonal profiles of women in different circumstances like polycystic ovarian syndrome, the postpartum period, and the perimenopause transition. This observational cohort study sought to identify the variability in the hormones of the fertile window in various reproductive categories and to establish potential thresholds for each category based on hormone measurements with the Mira urinary hormone monitor. Results A total of 57 women (ages 22–51) in various circumstances (regular cycles, polycystic ovarian syndrome, postpartum and perimenopause) tracked Mira urine hormone measurements (estrone-3-glucuronide, luteinizing hormone, pregnanediol glucuronide), contributing 444 cycles of data. Using additive mixed models, hormone values were stratified by the four different reproductive categories. The perimenopause and polycystic ovararian syndrome groups demonstrated relative hypoestrogenic states, while the perimenopause group showed low luteal pregnanediol glucuronide and the polycystic ovarian syndrome group showed high luteal pregnanediol glucuronide. The perimenopause group had higher luteinizing hormone values throughout the whole cycle. Conclusion The fertile window hormone thresholds vary depending on a woman’s specific reproductive category. Women in different circumstances should not necessarily use the same hormonal thresholds for the fertile window and ovulation. A larger dataset with ultrasound correlation to ovulation is required to delineate the fertile window with more precision. Hormone differences across the menstrual cycle could be used for targeted treatments in polycystic ovarian syndrome and perimenopause women.
Some medical professional organizations have advocated for including the menstrual cycle as a vital sign in adolescence, but not in adulthood. However, documenting menstrual cycle patterns is not routine clinical or research practice. Vital signs are used to predict health outcomes, indicate needed treatment, and monitor a clinical course. They can help identify pathologies, affirm wellness, and are responsive to exposures. Here we review the scientific evidence showing how the menstrual cycle meets these criteria and should therefore be treated as a vital sign. Using key words and controlled vocabulary terms, we carried out multiple literature searches, prioritizing the inclusion of systematic reviews, meta-analyses, and clinical practice guidelines. This review describes how the menstrual cycle is a health indicator, can cyclically impact health conditions, and its associations with long-term post-menopausal health outcomes. We review exposures influencing the menstrual cycle, evidence underlying its use to optimize wellness, and available tools for documenting cycles. Supplementary materials include patient handouts on menstrual cycle tracking, and an index of related clinical practice guidelines and reviews by subject. The menstrual cycle is a vital sign from menarche through menopause, an underutilized but powerful tool for understanding gynecological and general health.
The use of hormonal treatments for endometriosis has increased in recent years. Their effectiveness lies in creating a stable hormonal environment, reducing peripheral estrogen levels, and suppressing ovulation and menstruation. Although these agents do not cure endometriosis and symptoms often return after discontinuation, they effectively relieve pain in most cases and help prevent disease progression or recurrence. Women are therefore typically managed with long-term hormonal treatments, with or without surgery. However, this approach is unsuitable for those seeking natural pregnancy or undergoing IVF, as all hormonal treatments hinder conception. For women pursuing natural pregnancy, these treatments should be discontinued for about 1 year, the time needed to diagnose infertility. However, this suspension exposes women to the risk of recurrence or progression and is therefore clinically acceptable only if the woman has a reasonable likelihood of achieving pregnancy naturally. In women with endometriosis who are infertile and therefore require IVF, ovarian stimulation significantly raises estrogen levels-up to 10 times those of a natural cycle-potentially boosting the risk of endometriosis relapse. Evidence is reassuring on this issue even if some limited data suggest that ovarian stimulation may promote deep invasive endometriosis progression. Overall, physicians and patients must balance the chances of natural or ART-assisted pregnancy against the risk of disease recurrence or progression during treatment discontinuation or IVF. This choice is also complicated by the increased risk of severe pregnancy complications in women with endometriosis, possibly depending on the conception method. This review discusses the available evidence that can be helpful in guiding the decision-making process.
Bouchard T et al., 2025·J Restorative Reprod Med·
Open Access
There is considerable individual day-to-day variation within the menstrual cycle and between cycles in women. Average hormone curves inadequately describe the individual hormone patterns experienced by women. The present study applies a novel application of a statistical array (heat map) to demonstrate both individual and group menstrual cycle hormone variability.
Using pre-existing datasets, two cohorts of women were analysed using a statistical method to visualise quantitative hormonal variation. In one cohort, 107 women contributed a total of 283 menstrual cycles and in the second cohort, 21 women contributed a total of 62 menstrual cycles. Exposure: Women collected first morning urine samples for analysis of estrone-3-glucuronide (E1G) and luteinizing hormone (LH) in both datasets. In the larger dataset, pregnanediol-3-alpha-glucuronide (PDG) and follicle-stimulating hormone (FSH) were also collected. Serial ultrasounds identified the precise day of ovulation in the larger dataset. In the smaller dataset, peak LH was used to identify the estimated day of ovulation.
The main outcome measure was identifying hormonal variability using hormone array heat maps. Heat maps were able to quickly show clustering of hormone patterns in the fertile window and on the day of ovulation. Individual differences were identified in rows on the heat map relative to the day of ovulation. This new tool to visually represent hormonal changes with heat maps identifies both individual and group variability of menstrual cycle hormones.
Arraztoa JA, 2025·J Restorative Reprod Med·
Open Access
In 1972, a seminal article was published demonstrating that women, adequately trained, could detect the approach of ovulation in the fertile window of their menstrual cycle. It was demonstrated that the symptoms perceived by women at the vulva correlate closely with changes in steroid hormone levels associated with folliculogenesis and the luteal phase. The fertility charting performed by women trained to recognize vulvar symptoms associated with hormonal changes serves as an instrument for detecting potential pathologies and monitoring the effects of treatment These findings established the biological foundations of a tool of fertility awareness tracking that has facilitated the development of restorative reproductive medicine (RRM): an approach that can be applied to identify and treat the underlying causes of infertility/subfertility.
Several core characteristics—or foundational pillars—of the RRM approach to fertility can be identified. These include: a commitment to respecting healthy physiological processes, comprehensive health care for both the couple and the potential embryo, and the provision of education and continuous support throughout the therapeutic process.
This commentary aims to elucidate the interplay of these foundational pillars by drawing upon evidence from peer-reviewed biomedical literature. Finally, the challenges faced by RRM in strengthening its scientific foundations, engaging with the broader scientific community, and promoting the dissemination of this approach are described.
Measurement and Statistics · Instrument Development and Validation
Bouchard TP et al., 2025·Womens Health Rep (New Rochelle)·
Open Access
Measuring quantitative menstrual cycle hormones at home may help women better understand their postpartum and perimenopause fertility transitions, but these quantitative fertility monitors require validation. This study included 16 North American women, aged 28-51, during either the postpartum (n = 8, cycles = 18) or perimenopause (n = 8, cycles = 35) fertility transitions testing daily first-morning urine testing with both the Mira Monitor and ClearBlue Fertility Monitor (CBFM) along with menstrual cycle parameter tracking. The main outcome measures were a rise in estrone-3-glucuronide (E13G) and luteinizing hormone (LH) urine hormone values from the Mira monitor correlated to low, high, or peak values on the CBFM. Both in the postpartum and perimenopause transitions, the identification of the day of ovulation based on the LH surge on the Mira and CBFM monitors was highly correlated (R = 0.94 and 0.83, p < 0.001). The E13G levels on the Mira monitor were significantly higher for a CBFM reading of "High" compared with "Low" for both the postpartum and perimenopausal cycles (all p < 0.001). Similarly, the LH levels on the Mira monitor were significantly higher for a CBFM reading of "Peak" (LH surge) compared with "High" for both the postpartum and perimenopausal cycles (all p < 0.001). The LH surge and levels of E13G in urine identified on the quantitative Mira fertility monitor strongly correlate to the LH surge and the shift from low to high on the CBFM during the postpartum and perimenopause transitions.
Self-reported dietary intake varies across menstrual cycle phases, but objective assessments of dietary intake together with appetite and resting metabolic rate (RMR) are limited. This study aimed to assess differences in appetite, dietary intake, and RMR during two hormonally-distinct menstrual cycle phases in laboratory and free-living settings. Healthy premenopausal females with predictable normal-length menstrual cycles completed two study visits: one in the late-follicular and one in the mid-luteal phase. Menstrual cycle phases were identified using urinary luteinizing hormone surge and cycle days. Participants consumed a 2-day energy- and macronutrient-balanced run-in diet prior to each visit. RMR was measured with indirect calorimetry, followed by appetite ratings before and after a standardized breakfast, and completed a food cravings questionnaire. Appetite was also tracked for 2.5 days post-visit in a free-living environment. Ad libitum energy and macronutrient intake were measured using pre-weighed plus weighing of uneaten food at an in-laboratory lunch meal, as well as during the 2.5-day free-living period. Eighteen participants were included (age: 21±4 years; body mass index: 21.2±1.5 kg/m 2 ). There were no differences between in-laboratory ad libitum energy or macronutrient intakes, appetite, or food cravings between phases. RMR did not differ between phases, although the mid-luteal phase RMR trended toward higher (104±218 kcal/day higher ; P =0.074). No main nor interaction effects for phase and time were observed for free-living dietary intake nor appetite ratings. Accurate measurements show no differences in appetite or energy intake between menstrual cycle phases, though RMR may be slightly elevated in the luteal phase.
Nulianti R et al., 2025·International medical case reports journal
Premature ovarian insufficiency (POI) leads to the early loss of ovarian function before age 40, resulting in infertility and hormonal imbalance. Despite the use of assisted reproductive technologies (ART), success rates remain low in this population. Platelet-rich plasma (PRP) therapy is emerging as a potential adjunct to enhance ovarian reserve. CASE ILLUSTRATIONCASE 1: A 25-year-old nulliparous woman with a history of ectopic pregnancy and an anti-Müllerian hormone (AMH) level below 1 ng/mL received two PRP injections scheduled between days 7 to 12 of her cycle. After the first injection, her AMH level remained <0.5 ng/mL. Following the second PRP injection, her AMH level increased to >0.5 ng/mL. A frozen embryo transfer resulted in a successful term pregnancy and healthy newborn. CASE 2: A 36-year-old nulliparous woman, married for seven years, also presented POI and AMH levels <1 ng/mL followed the same PRP and IVF protocol. After two PRP sessions, her AMH levels improved similarly to Case 1. Despite an initial pregnancy, the patient experienced pregnancy loss. These findings suggest that PRP may improve ovarian response in women with POI undergoing IVF. Further studies are warranted.
Guidelines by Clinical Area · Bone and Endocrine Guidelines
How should premature/primary ovarian insufficiency (POI) be diagnosed and managed, based on the best available evidence from published literature? The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI. POI presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life, on fertility and on bone, cardiovascular and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI. STUDY DESIGN, SIZE, The guideline was developed according to the structured methodology for development of European Society of Human Reproduction and Embryology (ESHRE) guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and healthcare professionals. Literature searches and assessment were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials on POI included in the guideline. PARTICIPANTS/MATERIALS, SETTING, Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. MAIN New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help healthcare professionals apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated follicle stimulating hormone (FSH) >25 IU is required for diagnosis of POI and guidance that AMH testing, repeat FSH measurement and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. LIMITATIONS, The guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. The guideline provides healthcare professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI.
What is the relative length variance of the luteal phase compared to the follicular phase within healthy, non-smoking, normal-weight, proven normally ovulatory, premenopausal women with normal-length menstrual cycles? Prospective 1-year data from 53 premenopausal women with two proven normal-length (21-36 days) and normally ovulatory (≥10 days luteal) menstrual cycles upon enrollment showed that, despite 29% of all cycles having incident ovulatory disturbances, within-woman follicular phase length variances were significantly greater than luteal phase length variances. Many studies report menstrual cycle variability, yet few describe variability in follicular and luteal phase lengths. Luteal lengths are assumed 'fixed' at 13-14 days. Most studies have described follicular and luteal phase variability between-women. STUDY DESIGN, SIZE, Duration: This study was a prospective, 1-year, observational cohort study of relative follicular and luteal phase variability both between and within community-dwelling women with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Eighty-one women enrolled in the study and 66 women completed the 1-year study. This study analyzed data from 53 women with complete data for ≥8 cycles (mean 13). PARTICIPANTS/MATERIALS, SETTING, Participants were healthy, non-smoking, of normal BMI, ages 21-41 with two documented normal-length (21-36 days) and normally ovulatory (≥10 days luteal phase) menstrual cycles prior to enrollment. Participants recorded first morning temperature, exercise durations, and menstrual cycle/life experiences daily in the Menstrual Cycle Diary. We analyzed 694 cycles utilizing a twice-validated least-squares Quantitative Basal Temperature method to determine follicular and luteal phase lengths. Statistical analysis compared relative follicular and luteal phase variance in ovulatory cycles both between-women and within-woman. Normal-length cycles with short luteal phases or anovulation were considered to have subclinical ovulatory disturbances (SOD). Main The 1-year overall 53-woman, 676 ovulatory cycle variances for menstrual cycle, follicular, and luteal phase lengths were 10.3, 11.2, and 4.3 days, respectively. Median variances within-woman for cycle, follicular, and luteal lengths were 3.1, 5.2, and 3.0 days, respectively. Menstrual cycles were largely of normal lengths (98%) with an important prevalence of Sod: 55% of women experienced >1 short luteal phase (<10 days) and 17% experienced at least one anovulatory cycle. Within-woman follicular phase length variances were greater than luteal phase length variances (P < 0.001). However, follicular (P = 0.008) and luteal phase length (P = 0.001) variances, without differences in cycle lengths, were greater in women experiencing any anovulatory cycles (n = 8) than in women with entirely normally ovulatory cycles (n = 6). LIMITATIONS, Limitations of this study include the relatively small cohort, that most women were White, initially had a normal BMI, and the original cohort required two normal-length and normally ovulatory menstrual cycles before enrollment. Thus, this cohort's data underestimated population menstrual cycle phase variances and the prevalence of SOD. Our results reinforce previous findings that the follicular phase is more variable than the luteal phase in premenopausal women with normal-length and ovulatory menstrual cycles. However, our study adds to the growing body of evidence that the luteal phase is not predictably 13-14 days long. STUDY FUNDING/COMPETING INTEREST(S): This medical education project of the University of British Columbia was funded by donations to the Centre for Menstrual Cycle and Ovulation Research. The authors do not have any conflicts of interest to disclose. N/A.
Swann SA et al., 2024·Open Forum Infect Dis·
Open Access
The menstrual cycle is a critical indicator of women's health. Early prolonged secondary amenorrhea increases risks for morbidity and mortality. Menstrual cycle research in women with HIV is inconsistent and often lacks an adequate comparison sample. We aimed to determine whether women with HIV have a higher lifetime prevalence of amenorrhea and whether this is independently associated with HIV and/or other biopsychosocial variables. With data from 2 established HIV cohorts, participants assigned female at birth were eligible if aged ≥16 years, not pregnant/lactating, and without anorexia/bulimia nervosa history. Amenorrhea was defined by self-reported history of (1) no menstrual flow for ≥12 months postmenarche not due to pregnancy/lactation, medications, or surgery or (2) early menopause or premature ovarian insufficiency. Multivariable logistic regression models explored biopsychosocial covariates of amenorrhea. Overall, 317 women with HIV (median age, 47.5 years [IQR, 39.2-56.4]) and 420 women without HIV (46.2 [32.6-57.2]) were included. Lifetime amenorrhea was significantly more prevalent among women with HIV than women without HIV (24.0% vs 13.3%). In the multivariable analysis, independent covariates of amenorrhea included HIV (adjusted odds ratio, 1.70 [95% CI, 1.10-2.64]), older age (1.01 [1.00-1.04]), White ethnicity (1.92 [1.24-3.03]), substance use history (6.41 [3.75-11.1]), and current food insecurity (2.03 [1.13-3.61]). Nearly one-quarter of women with HIV have experienced amenorrhea, and this is associated with modifiable risk factors, including substance use and food insecurity. Care providers should regularly assess women's menstrual health and advocate for actionable sociostructural change to mitigate risks.
The role of minerals in female fertility, particularly in relation to the menstrual cycle, presents a complex area of study that underscores the interplay between nutrition and reproductive health. This narrative review aims to elucidate the impacts of minerals on key aspects of the reproductive system: hormonal regulation, ovarian function and ovulation, endometrial health, and oxidative stress. Despite the attention given to specific micronutrients in relation to reproductive disorders, there is a noticeable absence of a comprehensive review focusing on the impact of minerals throughout the menstrual cycle on female fertility. This narrative review aims to address this gap by examining the influence of minerals on reproductive health. Each mineral's contribution is explored in detail to provide a clearer picture of its importance in supporting female fertility. This comprehensive analysis not only enhances our knowledge of reproductive health but also offers clinicians valuable insights into potential therapeutic strategies and the recommended intake of minerals to promote female reproductive well-being, considering the menstrual cycle. This review stands as the first to offer such a detailed examination of minerals in the context of the menstrual cycle, aiming to elevate the understanding of their critical role in female fertility and reproductive health.
Swann SA et al., 2024·J Acquir Immune Defic Syndr·
Women living with HIV commonly experience low areal bone mineral density (BMD), but whether this is affected by low ovarian hormonal states (prolonged amenorrhea or menopause) is unknown. We compared rates of BMD loss between women living with HIV and HIV-negative control women and investigated its association with low ovarian hormonal states.
Women living with HIV were enrolled from Vancouver Canada and controls from 9 Canadian sites. This longitudinal analysis included age-matched women living with HIV in the Children and Women: AntiRetrovirals and Markers of Aging cohort and controls in the population-based Canadian Multicentre Osteoporosis Study. Rate of change/year in BMD at the total hip and lumbar spine (L1-L4) between 3 and 5 years was compared between groups, adjusting for sociodemographic and clinical variables. Ninety-two women living with HIV (median [interquartile range] age: 49.5 [41.6-54.1] years and body mass index: 24.1 [20.7-30.8] kg/m 2 ) and 278 controls (age: 49.0 [43.0-55.0] years and body mass index: 25.8 [22.9-30.6] kg/m 2 ) were included. Total hip BMD loss was associated with HIV (β: -0.003 [95% CI: -0.006 to -0.0001] g/cm 2 /yr), menopause (β: -0.007 [-0.01 to -0.005] g/cm 2 /yr), and smoking (β: -0.003 [-0.006 to -0.0002] g/cm 2 /yr); BMD gain was linked with higher body mass index (β: 0.0002 [0.0007-0.0004] g/cm 2 /yr). Menopause was associated with losing L1-L4 BMD (β: -0.01 [-0.01 to -0.006] g/cm 2 /yr). Amenorrhea was not associated with BMD loss. HIV and menopause negatively influenced total hip BMD. These data suggest women living with HIV require hip BMD monitoring as they age.
Per- and polyfluoroalkyl substances (PFAS) is persistent endocrine disrupting chemicals. Previous evidence suggests that exposure to PFAS is associated with reproductive hormone levels, but the results of relevant studies are inconsistent. The objective of our study is to determine the association between exposure to PFAS and reproductive hormone levels in gender-specific general population. Based on scientific search strategies, we systematically searched PubMed, Web of Science, Embase, Medline, and Scopus to obtain the eligible studies published before January 21, 2023. The quality of the included articles was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias tool. We combined the β coefficient and 95% confidence intervals (CI) using Stata.17 with random-effect model or fixed-effect model. We also performed subgroup analysis, sensitivity analysis, and Begger's and Egger's tests. Eleven studies involving 7714 participants were included. Meta-analysis showed that PFHxS exposure was positively associated with estradiol (E2) levels in female [β = 0.030, 95% CI: (0.013, 0.046), P = 0.000]. A negative association was found between PFOA [β = -0.012, 95% CI: (-0.023, -0.002), P = 0.017] and PFOS [β = -0.011; 95% CI: (-0.021, -0.000), P = 0.042] exposure with male testosterone (TT) levels. In the subgroup analysis, there were stronger associations in children than in adults. And the high heterogeneity was mainly due to the cross-sectional studies. Publication bias was not found in most of the analyses. Our study showed that PFAS exposure was significantly associated with reproductive hormone levels. Further related studies are needed to identify the association and potential mechanism in the future.
Ecochard R et al., 2024·Fertil Steril·
Open Access
To study whether the menstrual cycle has a circaseptan (7 days) rhythm and whether it is associated with the lunar cycle (also defined as the synodic month, it is the cycle of the phases of the Moon as seen from Earth, averaging 29.5 days in length).
Cross-sectional study. A total of 35,940 European and North American women aged 18-40 years. Exposure: Data were collected in real-life conditions. No intervention was performed. The onset of menstruation was assessed in prospectively measured menstrual cycles (311,064 cycles) over 3 full years (2019-2021). Associations were calculated between the onset of menstruation and the day of the week, and between the onset of menstruation and the lunar phase. In this large data set, a circaseptan (7-day) rhythmicity of menstruation was observed, with a peak (acrophase) of menstrual onset on Thursdays and Fridays. This circaseptan rhythm was observed in every age group, in every phase of the lunar cycle, and in all seasons. This feature was most pronounced for cycle durations between 27 and 29 days. In winter, the circaseptan rhythm was found in cycles of 27-29 days, but not in other cycle lengths. A circalunar rhythm was also statistically significant, but not as clearly defined as the circaseptan rhythm. The peak (acrophase) of the circalunar rhythm of menstrual onset varied according to the season. In addition, there was a small but statistically significant interaction between the circaseptan rhythm and the lunar cycle. Although relatively small in amplitude, the weekly rhythm of menstruation was statistically significant. Menstruation occurs more often on Thursdays and Fridays than on other days of the week. This is particularly true for women whose cycles last between 27 and 29 days. Circalunar rhythmicity was also statistically significant. However, it is less pronounced than the weekly rhythm.
Mengelkoch S et al., 2024·Brain, behavior, and immunity
Women using hormonal contraceptives (HCs) exhibit numerous signs of chronic inflammation, including elevated C-reactive protein levels and greater risk of developing mood and autoimmune disorders. However, users and non-users of HCs often have similar circulating proinflammatory cytokine levels, making the mechanism of association unclear. One possible explanation for this paradox is that HC users exhibit differences in their inflammatory responses to psychosocial stress that, over time, could contribute to chronic inflammation and its pathologies. Here, we tested this possibility by examining women's glucocorticoid, inflammatory, and psychological responses to the Trier Social Stress Test (TSST) in 67 naturally cycling (NC) and 60 oral HC-using women (Mage = 19.31, SDage = 1.95). As hypothesized, HC users and NC women exhibited different glucocorticoid and proinflammatory cytokine responses to the TSST. For NC women, TSST-induced increases in glucocorticoids were uncommon, and increases in glucocorticoids were accompanied by elevations in IL-6. In contrast, for women using HCs, increases in glucocorticoids in response to the TSST were common, and increases in glucocorticoids were accompanied by increases in TNF-α. HC users and NC women also differed in their psychological responses to the TSST, with HC users reporting elevated stress levels compared to NC women. Together, these results suggest that HC use impacts women's glucocorticoid, inflammatory, and psychological responses to psychosocial stress, potentially contributing to observed differences in these women's mental and physical health.
Women are considered to have an irregular menstrual cycle if their cycle length is less than 21 days or more than 35 days, accompanied by less or very severe blood flow. The prevalence of menstrual cycle irregularities varies across countries. Irregular periods can occur due to changes in the body's levels of estrogen and progesterone hormones, which disrupt the normal pattern of the period. Menstrual irregularity has been found to be associated with various diseases and medical conditions, such as metabolic syndrome, coronary heart disease, type 2 diabetes mellitus, and rheumatoid arthritis. Anemia, osteoporosis, psychological problems, impaired quality of life, and infertility have also been recorded. Moreover, a significant correlation between irregular periods and the risk of developing pregnancy-related hypertensive disorders, as well as an increased risk of adverse obstetric and neonatal outcomes, has been proven. Therefore, irregular menstruation is considered an important health indicator among women. Physical, mental, social, psychological, and reproductive problems are often associated with menstrual irregularities. Thus, evaluating the factors associated with irregular menstruation is necessary to determine appropriate preventive and treatment strategies and to decrease the associated health problems. The aim of this review was to define normal and irregular menstruation, their types, and prevalence, to recognize the risk factors and causes of irregular menstruation, and to understand their impact on women's health.
A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.
Hormonal contraception has been linked to mood symptoms and the ability to recognize emotions after short periods of treatment, whereas the mental health of users of long-term hormonal contraceptives has had limited investigation. To evaluate whether short-term hormonal withdrawal, which users of combined oral contraceptives (COCs) undergo once a month (pill pause), was associated with altered mood and emotional recognition in long-term users of COCs. DESIGN, SETTING, This case-control study included a community sample of individuals assigned female sex at birth who identified as women and used COC for 6 months or longer. The control group included women with natural menstrual cycles who otherwise fulfilled the same inclusion criteria. The study was conducted between April 2021 and June 2022 in Salzburg, Austria. COC users and women with natural menstrual cycles were tested twice within a month, once during their active pill phase or luteal phase and once during their pill pause or menses. Negative affect, anxiety, and mental health problems were assessed during each session. The percentage increase in mental health symptoms was calculated during the pill pause compared with that during the active intake phase in COC users. How this change compared with mood fluctuations along the menstrual cycle in women with natural menstrual cycles was assessed. A total of 181 women aged 18 to 35 years (mean [SD] age, 22.7 [3.5] years) were included in the analysis (61 women with androgenic COC use, 59 with antiandrogenic COC use, 60 women with a menstrual cycle not taking COCs). COC users showed a 12.67% increase in negative affect (95% CI, 6.94%-18.39%), 7.42% increase in anxiety (95% CI, 3.43%-11.40%), and 23.61% increase in mental health symptoms (95% CI, 16.49%-30.73%; P < .001) during the pill pause compared with the active intake phase. The effect size of this change did not differ depending on progestin type (negative affect: F1,117 = 0.30, P = .59; state anxiety: F1,117 = 2.15, P = .15; mental health: F1,117 = .16, P = .69) or ethinylestradiol dose (negative affect: F1,57 = .99, P = .32; state anxiety: F1,57 = 2.30, P = .13; mental health: F1,57 = .14, P = .71) was comparable with mood changes along the menstrual cycle in women with natural cycles (negative affect: F2,175 = 0.13, P = .87; state anxiety: F2,175 = 0.14, P = .32; mental health: F2,175 = 0.65, P = .52). Mood worsening during the pill pause was more pronounced in women with higher baseline depression scores (negative affect increase of 17.95% [95% CI, 7.80%-28.10%] in COC users with higher trait depression [BDI >8]). Emotion recognition performance did not differ between active pill phase and pill pause. In this case-control study of long-term COC users, withdrawal from contraceptive steroids during the pill pause was associated with adverse mental health symptoms similar to those experienced by women during menses with withdrawal from endogenous steroids. These results question the use of the pill pause from a mental health perspective. Long-term COC users may benefit more from the mood-stabilizing effects of COCs in cases of continuous intake.
Segarra I et al., 2023·Front Med (Lausanne)·
Open Access
Hormone-based contraception disrupts hormonal balance, creating artificial states of anovulation and threatening women's health. We reviewed its main adverse effects and mechanisms on accelerated ovarian aging, mental health (emotional disruptions, depression, and suicide), sexuality (reduced libido), cardiovascular (brain stroke, myocardial infarction, hypertension, and thrombosis), and oncological (breast, cervical, and endometrial cancers). Other "collateral damage" includes negative effects on communication, scientific mistrust, poor physician-patient relationships, increased patient burden, economic drain on the healthcare system, and environmental pollution. Hormone-sensitive tumors present a dilemma owing to their potential dual effects: preventing some cancers vs. higher risk for others remains controversial, with denial or dismissal as non-relevant adverse effects, information avoidance, and modification of scientific criteria. This lack of clinical assessment poses challenges to women's health and their right to autonomy. Overcoming these challenges requires an anthropological integration of sexuality, as the focus on genital bodily union alone fails to encompass the intimate relational expression of individuals, complete sexual satisfaction, and the intertwined feelings of trust, safety, tenderness, and endorsement of women's femininity.
Wu Q et al., 2023·Reprod Biol Endocrinol·
Open Access
This study aimed to explore the optimal time of laparoscopic cystectomy for unilateral ovarian endometrioma patients and evaluate the influence on ovarian reserve. This prospective randomized controlled study included 88 women with unilateral ovarian endometrioma at a tertiary teaching hospital. All patients received their first identified diagnosis of ovarian endometrioma by ultrasound (> 4 cm and ≤ 10 cm) and were administered an oral contraceptive pill (OC) for one cycle before laparoscopy. They were randomly divided into two groups: laparoscopy at the late luteal phase (group LLP) (n = 44) (termination of OC for two days) and laparoscopy at the early follicular phase (group EFP) (n = 44) (day 3 after menstruation). Basic clinical characteristics were recorded. Serum Anti-Müllerian hormone (AMH) levels were measured at various times to predict ovarian reserve. Serum levels of Anti-Müllerian hormone (AMH) were measured at several time sites to predict the ovarian reserve; AMH and leukocyte esterase (LE) levels of the endometrioma wall were measured. Before surgery, serum AMH levels decreased in both groups from preoperative to one week and six months postoperatively. In contrast, the difference values of group EFP were larger than those of group LLP at postoperative one week and postoperative six months (1.87 ± 0.97 vs. 1.31 ± 0.93, P = 0.07; 1.91 ± 1.06 vs. 1.54 ± 0.93, P = 0.001). The mean rates of postoperative serum AMH decline were 37.92% and 46.34% in group EFP, significantly higher than those in group LLP (25.83% vs. 31.43%, P < 0.001). Ovarian endometrioma wall AMH of group LLP was significantly lower than that of group EFP ([22.86 ± 3.74] vs. [31.02 ± 5.23], P < 0.001). Meanwhile, ovarian endometrioma LE concentration of group LLP was significantly higher than that of group EFP ([482.83 ± 115.88] vs. [371.68 ± 84.49], P<0.001). There was also a significant inverse correlation between leukocyte esterase and AMH concentration in an ovarian endometrioma cyst wall (r=-0.564, P<0.001). CONCLUSION(S): The optimal time for laparoscopic cystectomy for patients with first identified unilateral ovarian endometrioma is the late luteal phase, which reduces ovarian tissue loss and preserves ovarian reserve effectively and safely.
Ovarian rejuvenation is an innovative procedure intended to restore ovarian fertility and development during the climacteric and has been used to enhance fertility in women with premature ovarian insufficiency (POI). This retrospective study was conducted to determine the effects of an intraovarian platelet-rich plasma (PRP) injection on ovarian stimulation outcomes in women referred to an in vitro fertilisation centre. Methods- Population: This was a retrospective observational study, and the inclusion criteria included women of reproductive age with at least one ovary with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure. During the patient's first consultation, a detailed reproductive history was recorded, a pelvic scan for ovarian size was conducted, and hormonal analysis for follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol (E2), and luteinizing hormone (LH) was conducted. In the study, 469 women with a history of infertility, hormonal abnormalities, an absence of a menstrual cycle, and premature ovarian failure had hormonal levels recorded up to four months after treatment, and these were included in the study. The volume of peripheral blood required to prepare 6-8 mL of PRP for administration was 40-60 mL. The initial concentration of platelets in the peripheral blood sample was about 25000/µL, whereas the prepared PRP had a concentration of 900.000/µL. A volume of approximately 2-4 mL per ovary, depending on the ovarian volume, was used for the intraovarian injection. PRP intervention had significant effects on FSH concentration at the α = 0.05 level. Statistically significant increases in normal values of FSH and E2were observed for months three and four after the PRP intervention for all age groups. The results of our observational study revealed that a PRP intraovarian injection is associated with improved ovarian tissue and function. Future randomised clinical trials are needed to shed light on the use of PRP in ovarian rejuvenation before offering it routinely in clinical practice.
This study tested progesterone for perimenopausal hot flush ± night sweat (vasomotor symptom, VMS) treatment. It was a double-blind, randomized trial of 300 mg oral micronized progesterone@bedtime versus placebo for 3-months (m) after a 1-m untreated baseline during 2012/1-2017/4. We randomized untreated, non-depressed, screenand baseline-eligible by VMS, perimenopausal women (with flow within 1-year), ages 35-58 (n = 189). Participants aged 50 (± SD = 4.6) were mostly White, educated, minimally overweight with 63% in late perimenopause; 93% participated remotely. The 1° outcome was 3rd-m VMS Score difference. Participants recorded VMS number and intensity (0-4 scale)/24 h on a VMS Calendar. Randomization required VMS (intensity 2-4/4) of sufficient frequency and/or ≥ 2/week night sweat awakenings. Baseline total VMS Score (SD) was 12.2 (11.3) without assignment difference. Third-m VMS Score did not differ by therapy (Rate Difference - 1.51). However, the 95% CI [- 3.97, 0.95] P = 0.222, did not exclude 3, a minimal clinically important difference. Women perceived progesterone caused decreased night sweats (P = 0.023) and improved sleep quality (P = 0.005); it decreased perimenopause-related life interference (P = 0.017) without increased depression. No serious adverse events occurred. Perimenopausal night sweats ± hot flushes are variable; this RCT was underpowered but could not exclude a minimal clinically important VMS benefit. Perceived night sweats and sleep quality significantly improved.
Prior JC et al., 2023·Expert Rev Endocrinol Metab·
Bone health in those with Polycystic Ovary Syndrome (PCOS) is complex, but the general consensus is that cortical areal bone mineral density (aBMD) sites will be higher in PCOS than in ageand BMI-similar controls. However, spine aBMD sites may be lower, especially in non-obese PCOS. Whether or not incident fracture risk is increased in PCOS is currently controversial; no meta-analysis has yet assessed prevalent fractures. We assessed the bone effects of PCOS-related ovarian hormone alterations, e.g. androgen excess, tonically normal/higher estradiol, and lower-than-normal progesterone levels. We also highlighted evidence that common PCOS medications (e.g. combined hormonal contraceptives [CHC], metformin, and spironolactone) have important bone effects. In adolescents, meta-analysis of CHC showed significant negative aBMD changes. Inflammation has negative PCOS bone effects and is linked with CHC use. EXPERT Opinion: Is fracture risk altered by PCOS? Our meta-analysis showed a 25% increased risk of prevalent fracture in PCOS versus controls; this did not reach statistical significance. Future prospective research needs to collect and evaluate ovulation characteristics, progesterone exposure, and adolescent CHC use, in addition to the complex variables that may influence risks for prevalent or incident fragility fractures and/or for cortical and cancellous aBMD values in PCOS.
This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.
Early menopause (<45 years) has significant impacts on bone, cardiovascular, and cognitive health. Several studies have suggested earlier menopause for women living with HIV; however, the current literature is limited by reliance on self-report data. We determined age at menopause in women living with HIV and socio-demographically similar HIV-negative women based on both self-report of menopause status (no menses for ≥12 months) and biochemical confirmation (defined as above plus follicle-stimulating hormone level ≥ 25 IU/mL). Multivariable median regression models assessed factors associated with menopause age, controlling for relevant confounders. Overall, 91 women living with HIV and 98 HIV-negative women were categorized as menopausal by self-report, compared to 83 and 92 by biochemical confirmation. Age at menopause did not differ significantly between groups, whether based on self-report (median [IQR]: 49.0 [45.3 to 53.0] vs. 50.0 [46.0 to 53.0] years; p = 0.28) or biochemical confirmation (50.0 [46.0 to 53.0] vs. 51.0 [46.0 to 53.0] years; p = 0.54). In the multivariable model, no HIV-related or psychosocial variables were associated with earlier age at menopause (all p > 0.05). Overall, HIV status per se was not statistically associated with an earlier age at menopause, emphasizing the importance of comparing socio-demographically similar women in reproductive health and HIV research.
Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, typically characterized by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Lifestyle or diet, environmental pollutants, genetics, gut dysbiosis, neuroendocrine alterations, and obesity are among the risk factors that predispose females to PCOS. These factors might contribute to upsurging metabolic syndrome by causing hyperinsulinemia, oxidative stress, hyperandrogenism, impaired folliculogenesis, and irregular menstrual cycles. Dysbiosis of gut microbiota may play a pathogenic role in the development of PCOS. The restoration of gut microbiota by probiotics, prebiotics, or a fecal microbiota transplant (FMT) might serve as an innovative, efficient, and noninvasive way to prevent and mitigate PCOS. This review deliberates on the variety of risk factors potentially involved in the etiology, prevalence, and modulation of PCOS, in addition to plausible therapeutic interventions, including miRNA therapy and the eubiosis of gut microbiota, that may help treat and manage PCOS.
Rzewuska AM et al., 2023·Journal of clinical medicine
Endometriosis is a chronic disease, in which endometrial-like tissue is found outside the uterine cavity. Lesions are typically located in the true pelvis but can be found, in addition to extragenital endometriosis, in the respiratory system, the diaphragm, the pleura or the pericardium. As the extrauterine endometrial lesions undergo the menstrual cycle, they cause many symptoms, including pain, and besides infertility, they all mostly affect the quality of the patient's life. Pharmacological management of endometriosis significantly increases in importance either as a first-line treatment or as a complementary therapy after surgery. Yet, current research on antagonists of the gonadotropin-releasing hormone (GnRH) has revealed their potential benefits in endometriosis treatment. Their mechanism of action is to down-regulate the hypothalamic-pituitary-gonadal axis and therefore induce a hypoestrogenic state. The resulting reduction of estrogen levels prevents disease progression and diminishes the recurrence rate after surgical removal of endometriosis. The present review summarizes recent reports of the role oral GnRH antagonists have as a significant treatment option for pain reduction in endometriosis patients.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Greff D et al., 2023·Reprod Biol Endocrinol·
Open Access
Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. PROSPERO registration number: CRD42021283275.
Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological complex series of disorders that impacts a woman throughout her lifespan. PCOS is a disorder of hormonal imbalance occurring in women of reproductive age. This disorder is characterized by high levels of male androgens like testosterone. This can lead to symptoms like irregular periods, amenorrhea (absence of menstruation), anovulation (absence of ovulation), hirsutism, acne, and obesity. PCOS also causes metabolic impairment. Multiple peripherally arranged immature follicles of about 2-5mm in diameter are present in the ovary. These follicles do not mature due to hormonal imbalances leading to an irregular menstrual cycle. PCOS is a metabolic, reproductive, and psychological complex series of disorders that impacts a woman throughout her lifespan. Polycystic ovarian syndrome is not a fatal or life-threatening disorder as its main complication is infertility. PCOS can be a root cause of serious medical conditions like obesity, hypertension, type-2 diabetes mellitus due to insulin resistance, endometrial cancers, ovarian cancer, etc. Stress may cause the hormone levels in the pituitary to fluctuate. Since the menstrual cycle is hormone-based, there are apparent irregularities.
Endometriosis is characterized by the presence of endometrial tissues outside the uterine lining, typically on the external surface of the uterus, the ovaries, fallopian tubes, abdominal wall, or intestines. The prevalence of endometriosis in North America, Australia, and Europe is \~1-5% in women of reproductive age. Treatment options for endometriosis are limited. While over-the-counter medications may be used to reduce acute pain, hormonal treatments are common and may interfere with fertility. In more severe cases, laparoscopic excision procedures and even hysterectomies are used to treat the pain associated with endometriosis. Nutritional interventions may be helpful in the prevention and treatment of endometriosis and associated pain. Reducing dietary fat and increasing dietary fiber have been shown to reduce circulating estrogen concentrations, suggesting a potential benefit for individuals with endometriosis, as it is an estrogen-dependent disease. Meat consumption is associated with greater risk of developing endometriosis. Anti-inflammatory properties of plant-based diets may benefit women with endometriosis. Additionally, seaweed holds estrogen-modulating properties that have benefitted postmenopausal women and offers potential to reduce estradiol concentrations in pre-menopausal women. Furthermore, consumption of vitamin D has been shown to reduce endometrial pain via increased antioxidant capacity and supplementation with vitamins C and E significantly reduced endometriosis symptoms, compared with placebo. More randomized clinical trials are needed to elucidate the role of diet in endometriosis.
Endometriosis is a complex chronic disease that affects approximately 10% of women of reproductive age worldwide and commonly presents with pelvic pain and infertility. METHOD & A systematic review of the literature was carried out using the databases Pubmed, Scopus, Cochrane and ClinicalTrials.gov in women with a confirmed laparoscopic diagnosis of endometriosis receiving progestins to determine a reduction in pain symptoms and the occurrence of adverse effects. Eighteen studies were included in the meta-analysis. Progestins improved painful symptoms compared to placebo (SMD = -0.61, 95% CI (-0.77, -0.45), P < 0.00001) with no comparable differences between the type of progestin. After median study durations of 6-12 months, the median discontinuation rate due to adverse effects was 0.3% (range: 0 - 37.1%) with mild adverse effects reported. The meta-analysis revealed that pain improvement significantly increased with the use of progestins with low adverse effects. PROSPERO CRD42021285026.
Opportunistic salpingectomy (OS) is an attractive method for primary prevention of ovarian cancer. Although OS has not been associated with a higher complication rate, it may be associated with earlier onset of menopause. To provide a systematic review and meta-analysis of the effect of OS on both age at menopause and ovarian reserve. A search was conducted in the Cochrane Library, Embase and MEDLINE databases from inception until March 2022. We included randomized clinical trials and cohort studies investigating the effect of OS on onset of menopause and/or ovarian reserve through change in anti-Müllerian hormone (AMH), antral follicle count (AFC), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH). Data was extracted independently by two researchers. Random-effects meta-analyses were conducted to estimate the pooled effect of OS on ovarian reserve. The initial search yielded 1047 studies. No studies were found investigating the effect of OS on age of menopause. Fifteen studies were included in the meta-analysis on ovarian reserve. Meta-analyses did not result in statistically significant differences in mean change in AMH (MD -0.07 ng/ml, 95%CI -0.18;0.05), AFC (MD 0.20 n, 95 % CI -4.91;5.30), E2 (MD 3.97 pg/ml, 95%CI -0.92;8.86), FSH (MD 0.33mIU/ml, 95%CI -0.15;0.81) and LH (MD 0.03mIU/ml; 95%CI -0.47;0.53). Our study shows that OS does not result in a significant reduction of ovarian reserve in the short term. Further research is essential to confirm the absence of major effects of OS on menopausal onset since clear evidence on this subject is lacking. Registration number PROSPERO CRD42021260966.
The possession of two X chromosomes may come with the risk of various illnesses, females are more likely to be affected by osteoarthritis, heart disease, and anxiety. Given the reported correlations between gut microbiome dysbiosis and various illnesses, the female gut microbiome is worthy of exploration. Herein, we discuss the composition of the female gut microbiota and its dysbiosis in pathologies affecting the female population. Using PubMed, we performed a literature search, using key terms, namely: "gut microbiome", "estrogen", "menopause", "polycystic ovarian syndrome", "pregnancy", and "menstruation". In polycystic ovarian syndrome (PCOS), the abundance of Bacteroides vulgatus, Firmicutes, Streptococcus, and the ratio of Escherichia/Shigella was found to be increased while that of Tenericutes ML615J-28, Tenericutes 124-7, Akkermansia, Ruminococcaceae, and Bacteroidetes S24-7 was reduced. In breast cancer, the abundance of Clostridiales was enhanced, while in cervical cancer, Prevotella, Porphyromonas, and Dialister were enhanced but Bacteroides, Alistipes, and members of Lachnospiracea, were decreased. In ovarian cancer, Prevotella abundance was increased. Interestingly, the administration of Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum ameliorated PCOS symptoms while that of a mix of Bifidobacterium lactis W51, Bifidobacterium bifidum W23, Lactobacillus brevis W63, Bifidobacterium lactis W52, Lactobacillus salivarius W24, Lactobacillus acidophilus W37, Lactococcus lactis W19, Lactobacillus casei W56, and Lactococcus lactis W58 alleviated vascular malfunction and arterial stiffness in obese postmenopausal women, and finally, while further research is needed, Prevotella maybe protective against postmenopausal bone mass loss. As several studies report the therapeutic potential of probiotics and since the gut microbiota of certain female pathological states has been relatively characterized, we speculate that the administration of certain bacterial species as probiotics is warranted, as novel independent or adjunct therapies for various female pathologies.
González-Rodríguez A et al., 2022·Brain Sci·
Open Access
It has been hypothesized that, whenever estrogen levels decline, psychosis symptoms in women increase. At menopause, this can happen in two main ways: (a) the loss of estrogen (mainly estradiol) can directly affect central neurotransmission, leading to increase in schizophrenia-related symptoms, and (b) the loss of estrogen can decrease the synthesis of enzymes that metabolize antipsychotic drugs, thus weakening their efficacy. Aims and The aim of this narrative review was to investigate the second possibility by searching PubMed and ClinicalTrials.gov for studies over the last two decades that investigated the metabolism of antipsychotics and their efficacy before and after menopause in women or that studied systemic and local estrogen level effects on the pharmacokinetics and pharmacodynamics of individual antipsychotic drugs. The evidence suggests that symptom level in women with schizophrenia rises after menopause for many reasons beyond hormones but, importantly, there is an estrogen-dependent loss of efficacy related to antipsychotic treatment. Effective clinical intervention is challenging; nevertheless, several promising routes forward are suggested.
Casto KV et al., 2022·Frontiers in neuroendocrinology
Oral contraceptives (OCs) are widely used yet understudied given their potential for public health consequences. Emerging investigations scaling from single-subject, dense-sampling neuroimaging studies to population-level metrics have linked OCs to altered brain structure and function. Modeling the hypogonadal, hypergonadal, or mixed state effects of OCs in terms of their impact on hormone action in the brain is a valuable approach to synthesizing results across neuroimaging studies and comparing OC effects to companion findings from research on menstrual cycle phase effects on brain anatomy and function. Resting-state functional connectivity studies provide a powerful tool to evaluate the role of OCs on the intrinsic network connectivity that underlies multiple behavioral domains. The preponderance (but not consensus) of the current literature indicates that (1) as the menstrual cycle proceeds from a low to high progesterone state, prefrontal connectivity increases and parietal connectivity decreases; (2) OCs tend to mimic this connectivity pattern; therefore (3) OCs may produce a hyperprogestogenic state in the brain, in spite of overall reductions in endogenous steroid hormone levels. Alternative models are also considered.
Investigate the impact of sex, menstrual cycle phase and oral contraceptive use on intestinal permeability and ex-vivo tumour necrosis factor alpha (TNFα) release following treatment with lipopolysaccharide (LPS) and hyperthermia. Twenty-seven participants (9 men, 9 eumenorrheic women (MC) and 9 women taking an oral contraceptive pill (OC)) completed three trials. Men were tested on 3 occasions over 6 weeks; MC during early-follicular, ovulation, and mid-luteal phases; OC during the pill and pill-free phase. Intestinal permeability was assessed following a 4-hour dual sugar absorption test (lactulose: rhamnose). Venous blood was collected each trial and stimulated with 100 μg·mL-1 LPS before incubation at 37 °C and 40 °C and analysed for TNFα via ELISA. L:R ratio was higher in OC than MC (+0.003, p = 0.061) and men (+0.005, p = 0.007). Men had higher TNFα responses than both MC (+53 %, p = 0.004) and OC (+61 %, p = 0.003). TNFα release was greater at 40 °C than 37 °C (+23 %, p < 0.001). Men present with lower resting intestinal barrier permeability relative to women regardless of OC use and displayed greater monocyte TNFα release following whole blood treatment with LPS and hyperthermia. Oral contraceptive users had highest intestinal permeability however, neither permeability or TNFα release were impacted by the pill cycle. Although no statistical effect was seen in the menstrual cycle, intestinal permeability and TNFα release were more variable across the phases.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
Dave SC et al., 2022·Current problems in pediatric and adolescent health care
Relative Energy Deficiency in Sport (RED-S) refers to a condition in which energy imbalance leads to impaired physiological function of multiple organ systems and expands on the diagnosis previously known as the Female Athlete Triad. Researchers attribute the medical complications of RED-S to low energy availability, in which energy availability is defined as dietary energy intake minus exercise energy expenditure divided by fat-free mass. This article reviews the history of this diagnosis, the changing terminology, and the reasons for the expansion. Accepted definitions of each part of the energy availability equation are considered and the difficulties that exist using these equations in practice or comparatively in the literature are assessed. The review analyzes the broad spectrum of health consequences of RED-S, especially as it relates to hypoestrogenemia and menstrual function, gives guidance to those caring for athletes on the identification and management of RED-S, and sheds lights on the important role of coaches, athletic trainers, and families in recognizing this diagnosis and in helping getting patients to care.
Duane M et al., 2022·Front Med (Lausanne)·
Open Access
Fertility awareness-based methods (FABMs) educate about reproductive health and enable tracking and interpretation of physical signs, such as cervical fluid secretions and basal body temperature, which reflect the hormonal changes women experience on a cyclical basis during the years of ovarian activity. Some methods measure relevant hormone levels directly. Most FABMs allow women to identify ovulation and track this "vital sign" of the menstrual or female reproductive cycle, through daily observations recorded on cycle charts (paper or electronic). Physicians can use the information from FABM charts to guide the diagnosis and management of medical conditions and to support or restore healthy function of the reproductive and endocrine systems, using a restorative reproductive medical (RRM) approach. FABMs can also be used by couples to achieve or avoid pregnancy and may be most effective when taught by a trained instructor. Information about individual FABMs is rarely provided in medical education. Outdated information is widespread both in training programs and in the public sphere. Obtaining accurate information about FABMs is further complicated by the numerous period tracking or fertility apps available, because very few of these apps have evidence to support their effectiveness for identifying the fertile window, for achieving or preventing pregnancy. This article provides an overview of different types of FABMs with a published evidence base, apps and resources for learning and using FABMs, the role FABMs can play in medical evaluation and management, and the effectiveness of FABMs for family planning, both to achieve or to avoid pregnancy.
Hua X et al., 2022·Journal of medical microbiology·
Open Access
Introduction. Evidence has linked exogenous and endogenous sex hormones with the human microbiome.Hypothesis/Gap statement. The longitudinal effects of oral contraceptives (OC) on the human gut microbiome have not previously been studied.Aim. We sought to examine the longitudinal impact of OC use on the taxonomic composition and metabolic functions of the gut microbiota and endogenous sex steroid hormones after initiation of OC use.Methodology. We recruited ten healthy women who provided blood and stool samples prior to OC use, 1 month and 6 months after starting OC. We measured serum levels of sex hormones, including estradiol, progesterone, sex hormone-binding globulin (SHBG), and total testosterone. Shotgun metagenomic sequencing was performed on DNA extracted from faecal samples. Species and metabolic pathway abundances were determined using MetaPhlAn2 and HUMAnN2. Multivariate association with linear models was used to identify microbial species and metabolic pathways associated with OC use and endogenous levels of sex hormones.Results. The percentage variance of the microbial community explained by individual factors ranged from 9.9 % for age to 2.7 % for time since initiation of OC use. We observed no changes in the diversity or composition of the gut microbiome following OC initiation. However, the relative abundance of the biosynthesis pathways of peptidoglycan, amino acids (lysine, threonine, methionine, and tryptophan), and the NAD salvage pathway increased after OC initiation. In addition, serum levels of estradiol and SHBG were positively associated with Eubacterium ramulus, a flavonoid-degrading bacterium. Similarly, microbes involving biosynthesis of l-lysine, l-threonine, and l-methionine were significantly associated with lower estradiol, SHBG, and higher levels of total testosterone.Conclusion. Our study provides the first piece of evidence supporting the association between exogenous and endogenous sex hormones and gut microbiome composition and function.
Cakiroglu Y et al., 2022·Aging (Albany NY)·
Open Access
The aim of the current study was to characterize ovarian reserve parameters and IVF outcomes in women with a history of poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Reproductive age women (N=510; age range 30-45yo) diagnosed with POR based on Poseidon criteria were included in the study. PRP treatment resulted in higher AFC, higher serum AMH, lower serum FSH, and a higher number of mature oocytes and cleavage and blastocyst stage embryos. After PRP injection, 22 women (4.3%) conceived spontaneously, 14 (2.7%) were lost to follow up, and 474 (92.9%) attempted IVF. Among women who attempted IVF, 312 (65.8%) generated embryos and underwent embryo transfer, 83 (17.5%) achieved a pregnancy, and 54 (11.4%) achieved sustained implantation/live birth (SI/LB). In total, of the 510 women with POR and mean age of 40.3, PRP resulted in improvement of ovarian reserve parameters, a pregnancy rate of 20.5% and SI/LB rate of 12.9%. Our findings suggest that PRP treatment may be considered in women with POR. For wider clinical application, its clinical efficacy will need to be demonstrated in prospective randomized clinical trials.
Mei M et al., 2022·Proceedings. Biological sciences
Odour cues associated with shifts in ovarian hormones indicate ovulatory timing in females of many nonhuman species. Although prior evidence supports women's body odours smelling more attractive on days when conception is possible, that research has left ambiguous how diagnostic of ovulatory timing odour cues are, as well as whether shifts in odour attractiveness are correlated with shifts in ovarian hormones. Here, 46 women each provided six overnight scent and corresponding day saliva samples spaced five days apart, and completed luteinizing hormone tests to determine ovulatory timing. Scent samples collected near ovulation were rated more attractive, on average, relative to samples from the same women collected on other days. Importantly, however, signal detection analyses showed that rater discrimination of fertile window timing from odour attractiveness ratings was very poor. Within-women shifts in salivary oestradiol and progesterone were not significantly associated with within-women shifts in odour attractiveness. Between-women, mean oestradiol was positively associated with mean odour attractiveness. Our findings suggest that raters cannot reliably detect women's ovulatory timing from their scent attractiveness. The between-women effect of oestradiol raises the possibility that women's scents provide information about overall cycle fecundity, though further research is necessary to rigorously investigate this possibility.
Reproductive Immunology · Autoimmune Conditions and Fertility
Tańska K et al., 2022·Frontiers in endocrinology·
Open Access
Thyroid autoimmunity (TAI) is commonly defined as the presence of thyroperoxidase antibodies (TPOAbs) and/or thyroglobulin antibodies (TgAbs), which predisposes an individual to hypothyroidism. TAI affects nearly 10% of women of reproductive age and evokes great interest from clinicians because of its potentially negative impact on female fertility and pregnancy course. In this mini-review, we review the current literature concerning the influence of TPOAb or TPOAb/TgAb positivity without thyroid dysfunction on reproduction. TAI may negatively affect female fertility; several studies have found an increased prevalence of TAI in infertile women, especially in those with unexplained infertility and polycystic ovary syndrome. According to some observations, TAI might also be connected with premature ovarian insufficiency and endometriosis. The relationship between TAI and an increased risk of pregnancy loss is well documented. The pathophysiological background of these observations remains unclear, and researchers hypothesize on the direct infiltration of reproductive organs by thyroid antibodies, co-existence of TAI with other autoimmune diseases (either organ specific or systemic), immunological dysfunction leading to inhibition of immune tolerance, and relative thyroid hormone deficiency. Interestingly, in the current literature, better outcomes of assisted reproductive technology in women with TAI have been reported compared with those reported in earlier publications. One plausible explanation is the more widespread use of the intracytoplasmic sperm injection method. The results of randomized clinical trials have shown that levothyroxine supplementation is ineffective in preventing adverse pregnancy outcomes in women with TAI, and future research should probably be directed toward immunotherapy.
A new fertility monitor is now available that provides quantitative measurement of urinary hormones, but clinical use requires validation against an established fertility monitor that provides only qualitative results. Two fertility monitors were compared using daily first morning urine samples over 3 cycles of use in 21 women users with experience using a fertility monitor with the Marquette Method of Natural Family Planning. Women were aged 33.4 ± 5.5 years and had menstrual cycles ranging between 23 and 41 days. The quantitative Mira Monitor estimates of ovulation were highly correlated with the qualitative ClearBlue Fertility Monitor (CBFM) estimates of ovulation. Both monitors provided an accurate estimate of the fertile window. In this preliminary trial, the Mira monitor was shown to be effective at delineating the fertile window and ovulation. We demonstrated the feasibility of applying the Marquette Method algorithm with the use of the Mira monitor. Satisfaction differences between the two monitors did not reach statistical significance. We anticipate that quantitative fertility monitoring will give couples and health-care providers new and unprecedented insights into the menstrual cycle and fertility.
Couple infertility is a pathology with an absolute number of cases growing markedly over the last decade in connection mainly with the increased age of couples wishing to conceive. Platelet-rich plasma (PRP) is an alternative treatment used for several years for experimental purposes. Yet, this method is not yet defined as a standard therapeutic option in the infertility protocol for poor responders in assisted human reproduction procedures. Thus, the present study is a retrospective study conducted between February 2019 and February 2020 to evaluate the effect of ovarian PRP injection in patients with a poor ovarian response (POR) to ovarian stimulation. Women (n=20; age 31-44 years) diagnosed with POR based on the European Society of Human Reproduction and Embryology criteria underwent ovarian injection with autologous PRP injection. Markers of ovarian reserve before, during the following two menstrual cycles, and at six months after treatment were followed as well as stimulation and fertilisation parameters before and post-treatment. PRP treatment resulted in increased antral follicle count and serum anti-Mullerian hormone, while levels of serum follicle-stimulating hormone and luteinising hormone were decreased. These changes were more pronounced during the 2nd menstrual cycle following treatment. By six months following the injection, their values return to pre-treatment levels and any small differences were not considered statistically significant. The average dose of gonadotropin used and duration remained statistically unchanged, but a significant increase in estradiol achieved by the day of the human chorionic gonadotropin trigger day was achieved. The cancellation rate decreased following PRP treatment while the number of collected oocytes, number of oocytes in metaphase II rose. The number of embryos (of A and B quality) resulting also increased but fell short of the significance level set (α=0.073). Following the PRP injection, two singleton pregnancies were achieved, resulting in live births at term without complications during pregnancy. Another pregnancy was achieved spontaneously 45 months following the PRP and a failed assisted human reproduction procedure. Although the group included a small number of women, the results indicate the potential benefits of an ovarian autologous PRP injection in women with POR. Positive results appear to be short-term for 2-6 months after the procedure.
Functional hypothalamic amenorrhoea (FHA) is a common cause of amenorrhoea, but diagnosis can be challenging. The aim of this study was to investigate the clinical and biochemical features of FHA, compared to that of polycystic ovarian syndrome (PCOS) and assess the diagnostic performance of the different parameters for differentiating the two conditions. This was a retrospective observational study. We analysed clinical and biochemical parameters of women diagnosed with FHA and PCOS following specialist assessment at the reproductive endocrine gynaecology clinic, St Mary's Hospital. Compared with PCOS, women with FHA had significantly lower body mass index (BMI; 20.1 ± 2.9 vs. 31.1 ± 7.8 kg/m2 ; p< .0001) and a thinner endometrium (3.75 ± 2.23 vs. 6.82 ± 3.32 mm; p< .0001). Women with FHA had significantly lower luteinising hormone (LH; 3.46 ± 7.31 vs. 8.79 ± 4.98 IU/L; p< .0001), and lower LH to follicle-stimulating hormone (FSH) ratio, estradiol, thyroid-stimulating hormone, free thyroxine and prolactin levels; there was no significant difference in FSH levels. BMI had the greatest predictive performance for FHA (area under the curve [AUC]: 0.93; p< .001), followed by estradiol (AUC: 0.89; p< .001), LH (AUC: 0.88; p< .001) and LH:FSH ratio (AUC: 0.86; p< .001). Our data provides quantification for diagnostic accuracy of clinical parameters to differentiate FHA from PCOS, namely low BMI, estradiol, LH and LH:FSH ratio. These data could help clinicians more reliably diagnose FHA in women with secondary amenorrhoea.
Stanford JB et al., 2021·BMC Pregnancy Childbirth·
Open Access
Restorative reproductive medicine (RRM) seeks to identify and correct underlying causes and factors contributing to infertility and reproductive dysfunction. Many components of RRM are highly suitable for primary care practice. We studied the outcomes amongst couples who received restorative reproductive medicine treatment for infertility in a primary care setting. Two family physicians in Massachusetts trained in a systematic approach to RRM (natural procreative technology, or NaProTechnology) treated couples with infertility. We retrospectively reviewed the characteristics, diagnoses, treatments, and outcomes for all couples treated during the years 1989 to 2014. We compared pregnancy and live birth by clinical characteristics using Kaplan-Meier analysis. We employed the Fleming-Harrington weighted Renyi test or the logrank test to compare the cumulative proportion with pregnancy or with live birth. Among 370 couples beginning treatment for infertility, the mean age was 34.8 years, the mean prior time trying to conceive was 2.7 years, and 27% had a prior live birth. The mean number of diagnoses per couple was 4.9. Treatment components included fertility tracking with the Creighton Model FertilityCare System (80%); medications to enhance cervical mucus production (81%), to stimulate ovulation (62%), or to support the luteal phase (75%); and referral to female laparoscopy by a surgeon specializing in endometriosis (46%). The cumulative live birth rate at 2 years was 29% overall; this was significantly higher for women under age 35 (34%), and for women with body mass index < 25 (40%). There were 2 sets of twins and no higher-order multiple gestations. Of the 63 births with data available, 58 (92%) occurred at term. Family physicians can provide a RRM approach for infertility to identify underlying causes and promote healthy term live births. Younger women and women with body mass index < 25 are more likely to have a live birth.
Evaluation of vitamin D supplementation on ovarian reserve in women with diminished ovarian reserve and vitamin D deficiency. The study is a before-and-after intervention study that was performed on women with diminished ovarian reserve referred to Shahid Mofteh Clinic in Yasuj, Iran. Eligible women were prescribed vitamin D tablets at a dose of 50,000 units weekly for up to 3 months. Serum levels of vitamin D and AMH were evaluated at the end of 3 months. Significance level was also considered P ≤ 0.05. Our results have been showed there was a statistically significant difference in vitamin D levels of participants before [12.1(6.5)] and after [26(9.15)] the intervention (P < 0.001). Moreover, there was a statistically significant difference in serum AMH levels of participants before [0.50(0.44)] and after [0.79(0.15)] the intervention (P=0.02 ). In conclusion, the results of the current study support a possible favorable effect of vitamin D on increase AMH expression by acting on the AMH gene promoter. Therefore, it is possible that vitamin D increases AMH levels without changing the antral follicle count/ovarian reserve.
What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. STUDY DESIGN, SIZE, This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. PARTICIPANTS/MATERIALS, SETTING, Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. MAIN The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. LIMITATIONS, We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. STUDY FUNDING/COMPETING INTEREST(S): Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. N/A.
Macbeth AB et al., 2021·Women's Reproductive Health·
Women's interest in sex is asserted to increase at the mid-cycle pre-ovulatory estradiol peak. We explored this belief in healthy, spontaneously normally menstruating/ovulating women. Women recorded "interest in sex" in a daily diary; validated Quantitative Basal Temperature analysis documented ovulation. Interest in sex showed no mid-cycle peak in 61 normal-weight, nonsmoking women, ages 33.7 ± 5.6 years, over a mean of 311 consecutive days. The cycle-plotted diary "self-worth" factor (including feelings of energy, interest in sex) also showed no mid-cycle peak. Thus, interest in sex is related more strongly to women's feelings/experiences than to hormones, challenging deterministic or sex-hormone-dependent cultural and sociobiological understandings.
Carmichael MA et al., 2021·International journal of environmental research and public health
The effect of the menstrual cycle on physical performance is being increasingly recognised as a key consideration for women's sport and a critical field for further research. This narrative review explores the findings of studies investigating the effects of menstrual cycle phase on perceived and objectively measured performance in an athletic population. Studies examining perceived performance consistently report that female athletes identify their performance to be relatively worse during the early follicular and late luteal phases. Studies examining objective performance (using anaerobic, aerobic or strength-related tests) do not report clear, consistent effects of the impact of menstrual cycle phase on physical performance. Overall sport performance can be influenced by both perceived and physical factors. Hence, to optimise performance and management of eumenorrheic female athletes, there is a need for further research to quantify the impact of menstrual cycle phase on perceived and physical performance outcomes and to identify factors affecting variability in objective performance outcomes between studies.
Mathews DM et al., 2021·Human reproduction (Oxford, England)
Iodine is a vital micronutrient and its importance in thyroid function is well established. However, abnormalities in iodine intake may also have other effects. In particular, iodine is taken up avidly by the ovary and endometrium. Iodine deficiency is associated with reduced fertility. The use of high iodine concentration contrast media has recently been shown to improve conception rates in couples with unexplained infertility (UI). We hypothesize that this improvement could be related to the iodine excess and mechanisms independent of its action on thyroid. In this article, the metabolism of iodine and its potential role in fertility will be discussed, including the impact of both iodine deficiency and excess states and the importance of iodine in normal fetal development. This will include insights from animal studies on the effect of iodine in the uterine and ovarian structural environment, hormonal milieu and immunological factors affecting implantation. We speculate that iodine may well have a role as a potential therapy for UI.
Catamenial epilepsy (CE) is exacerbated by hormonal fluctuations during the menstrual cycle. Approximately 1.7 million women have epilepsy in the United States. CE affects more than 40% of women with epilepsy. There is a paucity of literature addressing this condition from a clinical standpoint, and the literature that does exist is limited to the neurological community. This article reviews the diagnosis and management of CE for the non-neurologist. Women with CE have early touch points in their care with numerous health care providers before ever consulting with a specialist, including OB/GYNs, pediatricians, emergency department physicians, and family medicine providers. In addition, women affected by CE have seizures that are more recalcitrant to traditional epilepsy treatment regimens. To optimize management in patients affected by CE, menstrual physiology must be understood, individualized hormonal contraception treatment considered, and adjustments and interactions with antiepileptic drugs addressed.
Observations: CE is a unique subset of seizure disorders affected by menstrual fluctuations of progesterone and estrogen. The diagnosis of CE has been refined and clarified. There is an ever-increasing understanding of the importance and variety of options of hormonal contraception available to help manage CE. Furthermore, antiepileptic drugs and contraception can interact, so attention must be directed to optimizing both regimens to prevent uncontrolled seizures and pregnancy. CE can be diagnosed with charting of menstrual cycles and seizure activity. Hormonal treatments that induce amenorrhea have been shown to reduce CE. Optimizing antiepileptic drug dosing and contraceptive methods also can minimize unplanned pregnancies in women affected by CE.
To determine whether serum anti-Müllerian hormone (AMH) level is a predictor of clinical pregnancy in women trying to achieve a natural conception. Eleven studies (4,388 women) were ultimately included in this meta-analysis. The AUC and Cochran Q indices were 0.5932 and 0.5702, respectively. Serum AMH levels have poor predictive value for natural pregnancy. Our findings suggest that low serum AMH levels are not associated with reduced fertility.
Li Y et al., 2021·Journal of clinical laboratory analysis
Spontaneous abortion occurs in 15% ~ 25% of clinical pregnancy. β-human chorionic gonadotropin (β-HCG) and progesterone (P) have been widely used in early pregnancy assessment, but their clinical significances are still controversial. Estradiol (E2) has not been used as widely as β-HCG and P, and its value in predicting pregnancy outcome is unclear. In this retrospective study, two hundred early pregnancy women were divided into two groups according to their early pregnancy outcomes: the ongoing pregnancy group and inevitable abortion group. Serum E2 and β-HCG levels and their growth rates were compared weekly. Estradiol and β-HCG of the ongoing pregnancy group were significantly higher than that of the inevitable abortion group from the 5th to 10th week of pregnancy. Taking 489.5 pg/mL in the 5th and 6th week, 590.5 pg/mL in the 7th week, and 614.5 pg/mL in the 8th week as cutoff levels of E2, the sensitivity and specificity for E2 to predict bad pregnancy outcome were 91.7% and 41.5%, 82.9% and 71.1%, 84.8% and 84.7%, 75.0% and 95.7%, respectively (P < .05). Both E2 and β-HCG increased much more rapidly in the ongoing pregnancy group. 80% of the normal pregnancy women showed continuously increasing E2 level. Meanwhile, the inevitable abortion group presented E2 variation types as slow increase or fluctuation, continuous decline, and sudden drop, which account for 54.0%, 34.0%, and 12.0%, respectively. Low values and low growth rates of E2 and β-HCG probably indicate bad pregnancy outcomes.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
Areta JL et al., 2021·European journal of applied physiology
Energy availability (EA) is defined as the amount of dietary energy available to sustain physiological function after subtracting the energetic cost of exercise. Insufficient EA due to increased exercise, reduced energy intake, or a combination of both, is a potent disruptor of the endocrine milieu. As such, EA is conceived as a key etiological factor underlying a plethora of physiological dysregulations described in the female athlete triad, its male counterpart and the Relative Energy Deficiency in Sport models. Originally developed upon female-specific physiological responses, this concept has recently been extended to males, where experimental evidence is limited. The majority of data for all these models are from cross-sectional or observational studies where hypothesized chronic low energy availability (LEA) is linked to physiological maladaptation. However, the body of evidence determining causal effects of LEA on endocrine, and physiological function through prospective studies manipulating EA is comparatively small, with interventions typically lasting ≤ 5 days. Extending laboratory-based findings to the field requires recognition of the strengths and limitations of current knowledge. To aid this, this review will: (1) provide a brief historical overview of the origin of the concept in mammalian ecology through its evolution of algebraic calculations used in humans today, (2) Outline key differences from the 'energy balance' concept, (3) summarise and critically evaluate the effects of LEA on tissues/systems for which we now have evidence, namely: hormonal milieu, reproductive system endocrinology, bone metabolism and skeletal muscle; and finally (4) provide perspectives and suggestions for research upon identified knowledge gaps.
The neuropeptide oxytocin acts as a hormone and a neuromodulator, influencing a multitude of human social behaviors, including reproduction. During childbirth and the postpartum period, it plays a key role in regulating and controlling processes that ensure a safe birth and the health of mother and child. Especially the onset of labor, the progress of labor and initial breastfeeding are mediated by oxytocin. In the maternal brain it controls the initiation of the mother-infant bond and the mother's emotional responses towards her child. In this review we summarize the current state of knowledge about the role of oxytocin during the different aspects and mechanisms of human childbirth, combining research from human and animal studies. Physiological and psychological stress during childbirth and lactation can have negative effects on the progress of labor, breastfeeding and bonding. We discuss how maternity caregivers can support the positive effects of oxytocin and minimize the effects of stress. Furthermore, we highlight aspects of the basic neurobiological principles and connections where further research is needed to improve our understanding of the regulation and the effects of oxytocin to support maternal and infant health.
In elite athletes, training individualization is widely recommended to optimize competitive performance. Previous studies have evidenced the impact of hormonal fluctuations on different performance parameters among female athletes. While consideration of menstrual cycle (MC) phases as a parameter in training individualization strategies is necessary, systematic evidence identifying such impacts in elite athletes should be evaluated. Systematically review publications that have investigated the link between MC phases and performance in elite female athletes. The overarching aim is to identify whether a consensus across studies exists enabling evidence-based recommendations for training individualization depending on menstrual cycle phases. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three major scientific publication databases were searched from inception until November 3, 2020. Studies included focused on the influence of physiological or psychological parameters throughout at least one phase of the menstrual cycle of elite athletes. A total of 780 search results were yielded and 26 references from a past bibliography were added manually. About 662 papers were reviewed of which 218 studies were assessed for eligibility. Of these, only seven (1%) precisely investigated the influence of a performance or physical parameter during at least one menstrual cycle phase. These seven studies included a total of 314 elite female participants (20.58 ± 1.91 years). Three used interviews, questionnaires or prospective analyses of reports. Four conducted several performance tests or included physical measures although only two performed tests during training or before/during competition. Among the seven studies, five performed hormonal testing through sampling of blood, saliva, or urine. The remaining relied on athletes' menstruation diaries. The current evidence suggests a variable association between menstrual cycle and a few performance-related outcomes, such as endurance or power resistance, ligament stiffness, decision making skills, psychology, or competitiveness. Different sports performance-related parameters are affected during the menstrual cycle among elite athletes, but the parameters themselves and the magnitude and the direction of the effects are inconclusive. Additional longitudinal and prospective studies to systematically monitor on-field performance parameters are urgently required in order to enable recommendations and training individualization in female elite athletes.
Early and Premature Transition · Premature Ovarian Insufficiency
Petryk N et al., 2020·Reproductive sciences (Thousand Oaks, Calif.)
Due to the fact that modern American and European women postpone childbirth until later in life, they are more likely to face the problem of ovarian insufficiency by the time they are ready to have children. So, the ability to restore the ovarian function safely is crucially important. Our study involved 38 women 31-45 years of age with low ovarian reserves and at least two unsuccessful attempts to receive their oocytes through IVF. The blood from the patients was collected into two BD vacutainers for PRP preparation. The platelet concentration in the PRP was 1 × 106 μl. PRP injections into the ovaries were performed by a gynecologist with a special 25G needle, 20 cm in length, as an ultrasound-guided procedure or a laparoscopic-assisted approach. After PRP treatment, women were tested with several criteria for 12 months. We saw a significant improvement in hormone levels; six healthy babies were born, ten pregnancies were achieved, and four out of the ten were from natural conception. The PRP injections into the ovaries are safe, productive, and a natural treatment that may help women with premature ovarian insufficiency to give birth to their own child. The difference and novelty with our method of ovarian rejuvenation is in obtaining a higher platelet concentration (about 1 × 106 μl), which allows us to achieve long-lasting results, within 12 months, after a single procedure. Additionally, for the first time, we proposed and successfully performed a laparoscopically assisted technique for administering PRP into the ovary.
McNulty KL et al., 2020·Sports medicine (Auckland, N.Z.)
Concentrations of endogenous sex hormones fluctuate across the menstrual cycle (MC), which could have implications for exercise performance in women. At present, data are conflicting, with no consensus on whether exercise performance is affected by MC phase. To determine the effects of the MC on exercise performance and provide evidence-based, practical, performance recommendations to eumenorrheic women. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four databases were searched for published experimental studies that investigated the effects of the MC on exercise performance, which included at least one outcome measure taken in two or more defined MC phases. All data were meta-analysed using multilevel models grounded in Bayesian principles. The initial meta-analysis pooled pairwise effect sizes comparing exercise performance during the early follicular phase with all other phases (late follicular, ovulation, early luteal, mid-luteal and late luteal) amalgamated. A more comprehensive analysis was then conducted, comparing exercise performance between all phases with direct and indirect pairwise effect sizes through a network meta-analysis. Results from the network meta-analysis were summarised by calculating the Surface Under the Cumulative Ranking curve (SUCRA). Study quality was assessed using a modified Downs and Black checklist and a strategy based on the recommendations of the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group. Of the 78 included studies, data from 51 studies were eligible for inclusion in the initial pairwise meta-analysis. The three-level hierarchical model indicated a trivial effect for both endurance- and strength-based outcomes, with reduced exercise performance observed in the early follicular phase of the MC, based on the median pooled effect size (ES0.5 = - 0.06 [95% credible interval (CrI): - 0.16 to 0.04]). Seventy-three studies had enough data to be included in the network meta-analysis. The largest effect was identified between the early follicular and the late follicular phases of the MC (ES0.5 = - 0.14 [95% CrI: - 0.26 to - 0.03]). The lowest SUCRA value, which represents the likelihood that exercise performance is poor, or among the poorest, relative to other MC phases, was obtained for the early follicular phase (30%), with values for all other phases ranging between 53 and 55%. The quality of evidence for this review was classified as "low" (42%). The results from this systematic review and meta-analysis indicate that exercise performance might be trivially reduced during the early follicular phase of the MC, compared to all other phases. Due to the trivial effect size, the large between-study variation and the number of poor-quality studies included in this review, general guidelines on exercise performance across the MC cannot be formed; rather, it is recommended that a personalised approach should be taken based on each individual's response to exercise performance across the MC.
Environmental Exposures · Pesticides and Agricultural Chemicals
Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or "environmentally relevant" doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed.
It has been well documented that female sex is a significant risk factor for the development of various autoimmune diseases. While the reason for this has been debated, one well-regarded theory is that increased estrogen and decreased testosterone play a role in this predisposition. Interstitial cystitis (IC), also known as painful bladder syndrome (PBS), is an autoimmune disorder that affects over nine million women in the United States. It presents with pelvic and bladder pain and urinary symptoms, both of which significantly and negatively affect the quality of life. Even so, very few studies have examined the pathophysiologic relationship between autoimmune disorders and hormonal contraceptives. In this report, we present a case of IC likely precipitated by oral contraceptives (OCPs) in a premenopausal female. Shortly after beginning OCPs, this patient developed symptoms of severe pelvic pain and increased urinary frequency. Over the course of a year, the patient was diagnosed and treated for a variety of conditions, such as urinary tract infection (UTI), fungal vaginitis, and nephrolithiasis. After consultation with a gynecologist, a normal abdominal CT scan, and unsuccessful cystoscopy due to pain, she was finally diagnosed with IC. The patient independently learned of a potential link between hormonal contraceptive pills and IC and decided to discontinue this method of birth control. Following this, her symptoms completely resolved within several months. The timing of her initiation and discontinuation of OCPs, alongside her symptomatology, suggest a connection to the development of IC. A literature review was performed, which supports this association. We, therefore, highlight this case as an important example of IC precipitated by OCPs.
Sclerostin, a natural hormone made in bone, suppresses bone formation. Sclerostin is also decreased by estrogen. Progesterone, estrogen's menstrual partner, stimulates bone formation. It is unclear whether progesterone influences sclerostin. This study showed that progesterone did not change sclerostin using serum remaining from a randomized progesterone hot flush therapy trial.
Progesterone and sclerostin are both endogenous hormones acting through osteoblast-origin cells and promote or suppress bone formation, respectively. Estradiol suppresses sclerostin, but progesterone, its menstrual cycle partner hormone, has unclear sclerostin relationships. We postulated that progesterone therapy would influence serum sclerostin levels. We obtained sclerostin levels for an ethics-approved post hoc analysis. Fasting sclerostin was measured in all remaining sera from a previous 12-week randomized controlled trial (RCT) of oral micronized progesterone (progesterone) for menopausal (> 1 year after last flow) vasomotor symptoms (VMS). Women in the RCT took 300 mg progesterone at bedtime or placebo (1:1) in a trial showing progesterone significantly decreased VMS. Participants were healthy menopausal, primarily Caucasian (91.2%) community-dwelling women (± SD), 55.2 ± 4.6 years old with BMI 24.9 ± 2.9 kg/m(2). The baseline sclerostin level in 60 women was 28.41 ± 10.47 pmol/L. Baseline sclerostin was not correlated with the run-in VMS score (r = 0.143, P = 0.294). Paired baseline and 12-week RCT data for 52 women showed serum sclerostin levels did not change related to experimental therapy (P = 0.504). Changes in final sclerostin values adjusted for baseline were progesterone (- 1.07 ± 7.96 pmol/L) and placebo (- 2.64 ± 8.70 pmol/L). In observational data (n = 60), baseline sclerostin levels correlated with the General Framingham Cardiovascular (CVD) Risk score (r = - 0.398, P = 0.003) and self-reported health by SF-36 quality of life instrument (QoL, r = - 0.331, P = 0.016). Physiological oral micronized progesterone did not stimulate nor suppress serum sclerostin levels based on post hoc analysis of RCT data. Exploratory results, however, showed sclerostin negatively correlated with CVD risk and QoL. ClinicalTrials.gov #NCT0146469.
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the proinflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
Oral contraception (OC) is used by approximately fifty-five million women in the USA alone and is listed as an essential medicine by the World Health Organisation. Altered mood is a common reason for OC cessation. Here we investigate the effects of OC on hormones that are linked to mood. We obtained blood samples from 185 young women (average age 21.2) in two cohorts and tested the effects of OC on plasma levels of oxytocin, adrenocorticotropic hormone (ACTH), estradiol, progesterone and testosterone. We related plasma hormone levels with self-reported measures of mood, well-being and depression. OC-users in both cohorts showed elevated basal oxytocin, lower ACTH, estradiol, progesterone and testosterone compared with non-OC users. Satisfaction With Life Score (SWLS) was higher in OC -users compared to non-OC users, with no differences in the Beck Depression Score (BDI) and Positive And Negative Affect Schedule (PANES). In conclusion, our data show alterations in hormone levels and SWLS in response to OC.
Nose-Ogura S et al., 2020·Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine
To determine whether secondary amenorrhea during teenage years influences bone mineral density (BMD) in female athletes in their 20s. Original research. Japan Institute of Sports Sciences. Two hundred ten elite female athletes older than 20 years were included in the study. Information on the participants' past (ie, during their teenage years) and current menstrual cycle, training time, history of stress fractures, and blood tests for hormones received was obtained. Bone mineral density of the lumbar spine was evaluated by dual-energy x-ray absorptiometry; low BMD was defined as a Z-score ≤-1. We investigated the correlation factors for low BMD in athletes in their 20s by univariable and multivariable logistic regression analysis. A total of 39 (18.6%) female athletes had low BMD. Secondary amenorrhea in their teens [odds ratio (OR), 7.11, 95% confidence interval (CI), 2.38-21.24; P < 0.001] and present body mass index (BMI) (OR, 0.56, 95% CI, 0.42-0.73; P < 0.001) were independent correlation factors for low BMD in the multivariable logistic regression analysis. The average Z-score for those with secondary amenorrhea in their teens and 20s, secondary amenorrhea in their 20s only, and regular menstruation was -1.56 ± 1.00, -0.45 ± 1.21, and 0.82 ± 1.11 g/cm, respectively. Secondary amenorrhea for at least 1 year during teenage years in female athletes and BMI at present was strongly associated with low BMD in their 20s.
Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with core symptoms (affective lability, irritability, depressed mood, anxiety) and increased sensitivity to stress occurring in the luteal phase of the menstrual cycle. PMDD can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs). In this review, we describe the role of the NAS allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor (GABAA-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABAA-Rs in terms of affective symptom expression, with evidence from rodent and human studies. We discuss evidence of increased luteal phase stress sensitivity as a result of poor ALLO-GABA control of the HPA axis. Finally, we describe how treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABAA-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABAA-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.
Najmabadi S et al., 2020·Paediatr Perinat Epidemiol·
There is variability between women for days of menstrual bleeding, cycle lengths, follicular phase lengths, and luteal phase lengths, related to age and parity. To describe total cycle length; anovulatory cycles; follicular and luteal phase lengths; and days and intensity of menstrual and non-menstrual bleeding in women without known subfertility over the course of 1 year. 581 women (3,324 cycles) with no known subfertility (18-40 years of age) were followed for up to 1 year. Women recorded vaginal bleeding and mucus discharge daily. We used the peak day of cervical mucus as the estimated day of ovulation and the last day of the follicular phase. We used generalised linear mixed models stratified by age and parity to describe menstrual cycle parameters. The majority of women were <30 years of age (74.5%), non-Hispanic White (88.6%), and nulliparous (70.4%). The mean menses length was 6.2 (1.5) days, median 6; cycle length 30.3 (6.7) days, median 29; follicular phase length 18.5 (6.5) days, median 17; and luteal phase length 11.7 (2.8) days, median 12. Nulliparous women aged ≥30 years vs nulliparous women aged <30 had shorter cycles (29.2 days, 95% confidence interval (CI) 27.8, 30.7 vs 31.5 days, 95% CI 30.8, 32.2) and shorter follicular phases (17.6 days, 95% CI 16.2, 18.9 vs 19.6 days, 95% CI 18.9, 20.2). Among all women, within-woman differences between the longest and shortest menses length >3 days, total cycle length >7 days, follicular phase >7 days, and luteal phase >3 days were found in 11.6%, 43.0%, 41.7%, and 58.8% of women, respectively. Our findings confirm variability between women of menstrual cycle parameters related to age and parity, and also highlight within-woman variability in the follicular and luteal phases.
Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). Outcomes: Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.
Coomarasamy A et al., 2020·Am J Obstet Gynecol·
Open Access
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.
Michels KA et al., 2020·Chronobiol Int·
Open Access
Despite research indicating that sleep disorders influence reproductive health, the effects of sleep on reproductive hormone concentrations are poorly characterized. We prospectively followed 259 regularly menstruating women across one to two menstrual cycles (the BioCycle Study, 2005-2007), measuring fasting serum hormone concentrations up to eight times per cycle. Women provided information about daily sleep in diaries and chronotype and night/shift work on a baseline questionnaire. We evaluated percent differences in mean hormone concentrations, the magnitude of shifts in the timing and amplitude of hormone peaks, and the risk for sporadic anovulation associated with self-reported sleep patterns and night/shift work. We estimated chronotype scores - categorizing women below and above the interquartile range (IQR) as "morning" and "evening" chronotypes, respectively. For every hour increase in daily sleep duration, mean estradiol concentrations increased by 3.9% (95% confidence interval [CI] 2.0, 5.9%) and luteal phase progesterone by 9.4% (CI 4.0, 15.2%). Receiving less than 7 hours of sleep per day was associated with slightly earlier rises in peak levels for several hormones. Women reporting night/shift work (n = 77) had lower testosterone relative to women employed without night/shift work (percent difference: -9.9%, CI -18.4, -0.4%). Women with morning chronotypes (n = 47) had earlier rises in estradiol during their cycles and potentially an earlier rise in luteinizing hormone. Compared to those who had intermediate chronotypes, women with evening chronotypes (n = 42) had a later luteinizing hormone peak of borderline statistical significance. A reduced risk for sporadic anovulation was suggested, but imprecise, for increasing hours of daily sleep leading up to ovulation (risk ratio 0.79, CI 0.59, 1.06), while an imprecise increased risk was observed for women with morning chronotypes (risk ratio 2.50, CI 0.93, 6.77). Sleep-related hormonal changes may not greatly alter ovarian function in healthy women, but have the potential to influence gynecologic health.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Xie L et al., 2020·Evid Based Complement Alternat Med·
Open Access
To assess the efficacy and safety of berberine on reproductive endocrine and metabolic outcomes in women with polycystic ovary syndrome (PCOS). PubMed (from 1950), the Cochrane Library, the CNKI (from 1979), the VIP (from 1989), and the Wanfang Data (from 1990) and the reference lists of the retrieved articles were searched for randomized controlled trials in human beings with the search terms including "polycystic ovary syndrome/PCOS" and "berberine/BBR/Huangliansu (in Chinese)/Xiao bojian (in Chinese)" till 30 May 2019. Relevant indicators were collected and the data were analyzed by using RevMan 5.3 software. Eventually, a total of 12 randomized controlled trials were included in this systematic review. Our study suggested that berberine had similar live birth rates compared with placebo or metformin and lower live birth rates (RR: 0.61, 95% CI: 0.44 to 0.82) compared with letrozole. There was a significant difference between berberine and placebo and between berberine and no treatment in terms of decreasing total testosterone and luteinizing hormone to follicle-stimulating hormone (LH/FSH) ratio (8 RCTs, 577 participants, MD: -0.34, 95% CI: -0.47 to -0.20; 3 RCTs, 179 participants, MD: -0.44, 95% CI: -0.68 to -0.21, respectively). Berberine was associated with decreasing total cholesterol (3 RCTs, 201 participants; MD: -0.44, 95% CI: -0.60 to -0.29), waist circumference (3 RCTs, 197 participants, MD: -2.74, 95% CI: -4.55 to -0.93), and waist-to-hip ratio (4 RCTs, 258 participants, MD: -0.04, 95% CI: -0.05 to -0.03) compared with metformin, but not with improved BMI (4 RCTs, 262 participants, MD: -0.03, 95% CI: -0.46 to 0.39). Berberine did not increase the incidence of gastrointestinal adverse events (3 RCTs, 567 participants, RR: 1.01, 95% CI: 0.76 to 1.35) or serious events during pregnancy (RR: 0.98, 95% CI: 0.70 to 1.37) compared with placebo. This review found no solid evidence that berberine could improve live birth or other clinical outcomes in women with PCOS. However, berberine appeared to be more efficacious for improving insulin resistance and dyslipidemia and decreasing androgen levels and LH/FSH ratio in women with PCOS when compared with metformin.
Female fecundity is finely regulated by hormonal signaling, representing a potential target for endocrine-disrupting chemicals. Among the chemicals of most concern are the perfluoroalkyl substances (PFAS), widely used in consumer goods, that are associated with adverse effects on reproductive health. In this context, the endometrium clearly represents an important fertility determining factor. The aim of this study was to investigate PFAS interference on hormonal endometrial regulation. This study was performed within a screening protocol to evaluate reproductive health in high schools. We studied a cohort of 146 exposed females aged 18-21 from the Veneto region in Italy, one of the four areas worldwide heavily polluted with PFAS, and 1080 non-exposed controls. In experiments on Ishikawa cells included UV-Vis spectroscopy, microarray analysis and qPCR. We report a significant dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity. The most differentially-expressed genes upon PFOA coincubation were ITGB8, KLF5, WNT11, SULT1E1, ALPPL2 and G0S2 (all p < 0.01). By qPCR, we confirmed an antagonistic effect of PFOA on all these genes, which was reversed at higher progesterone levels. Molecular interference of PFOA on progesterone was confirmed by an increase in the intensity of absorption spectra at 250 nm in a dose-dependent manner, but not in the presence of β-estradiol. Age at menarche (+164 days, p = 0.006) and the frequency of girls with irregular periods (29.5% vs 21.5%, p = 0.022) were significantly higher in the exposed group. Our results are indicative of endocrine-disrupting activity of PFAS on progesterone-mediated endometrial function.
This study investigated the association between synthetic ovarian hormone use [i.e., the oral contraceptive (OC) pill] and basal C-reactive protein (CRP), peripheral blood immune cell subsets, and circulating pro- and anti-inflammatory cytokine concentrations in elite female athletes. Elite female athletes (n = 53) selected in Rio Summer Olympic squads participated in this study; 25 were taking an OC (AthletesOC) and 28 were naturally hormonally cycling (AthletesNC). Venous blood samples were collected at rest for the determination of sex hormones, cortisol, CRP, peripheral blood mononuclear memory and naïve CD4+ T-cells, CD8+ T-cells and natural killer cells, as well as pro- and anti-inflammatory cytokine concentrations. C-reactive protein concentrations were elevated (p < 0.001) in AthletesOC (median = 2.02, IQR = 3.15) compared to AthletesNC (median = 0.57, IQR = 1.07). No differences were reported for cortisol, cytokines, or PBMC immune cell subsets, although there was a trend (p = 0.062) for higher IL-6 concentrations in AthletesNC. Female Olympians had substantially higher CRP concentrations, a marker of inflammation and tissue damage, before the Rio Olympic Games if they used an OC. Future research should examine the potential consequences for athlete performance/recovery so that, if necessary, practitioners can implement prevention programs.
In 2006-2008, 610 premenopausal, spontaneously menstruating women in the Metro Vancouver region participated in a Canadian Institutes of Health Research (CIHR)-funded singlecycle in which they collected first morning urine specimens for estrogen and progesterone metabolites1. Following that study, after analyses, we retrieved the remaining urine specimens from the analyzing laboratory (University of Washington). We sorted data so that samples from all those women who were anovulatory by the two combined urinary steroid evaluation methods2,3, plus from those who were ovulatory with the highest and the lowest urinary hormone values were shipped to Health Canada (HC) via Dr. Warren Foster’s laboratory at McMaster University. Those data on flame retardant contaminants in women’s urine have been published4, but the cycle-phase specific data are still in analysis (personal communication, S Kalyan, 2019). In 2017, HC basic scientists launched applications to HC to fund a similar study to assess flame retardant excretory changes in the same population/locale 10 years later. This application was funded in 2018 at Health Canada with Dr. JC Prior as a collaborator. Extensive negotiations by CeMCOR and HC scientists ensued about funding the process of obtaining these follow-up specimens. CeMCOR managed to obtain a HC agreement to fund the minimal cost of recruiting, training and obtaining two menstrual phase-specific urine specimens from 250 Metro Vancouver women. Because of the lack of a progesterone threshold for ovulation, we will collect one follicular and one luteal/premenstrual urine sample per woman. However, this time we will better characterize the ovulatory cycle using a validated quantitative basal temperature method5,6 that can assess luteal phase length as well as the presence/absence of evidence for ovulation. In addition we will collect serial salivary progesterone and estradiol values measured by the state-of-the-art sensitive and specific tandem mass spectrometry (LC-MS/MS) methods7 to use as the gold standard for an ovulatory cycle. There is increasing evidence that many variables differ across women’s two main menstrual cycle phases: follicular and luteal7-10. These real and potential differences in metabolism may alter the susceptibility of women to environment exposures, and also could change their urinary elimination. Those are the root reasons for doing this study.
Cyclic hormonal stimulation of the breast tissue plays a significant role in breast carcinogenesis. Current risk factor models do not include direct measures of cycle characteristics although the effects of possible surrogates of cycle activity such as age at menarche and menopause, parity, and nursing time have been investigated. Future risk models should also include menstrual cycle length, regularity, number of cycles before first full-term pregnancy, and life-time number of cycles. New risk factor models for pre- and postmenopausal breast cancer are proposed here. Furthermore, there is a need for more long-term, prospective studies investigating menstrual cycle characteristics as data currently available are primarily retrospective and collected at one time-point only.
Endometrial BCL6 protein levels are significantly elevated in women with unexplained recurrent pregnancy loss and unexplained infertility compared with fertile controls, with 79% of subfertile women displaying elevated BCL6. Among those with abnormal BCL6 who underwent laparoscopy, most were found to have endometriosis, suggesting a continuum of progesterone resistance and inflammatory/endometriosis-related endometrial dysfunction.
Women who experience pregnancy loss are especially prone to high stress, though the effects of stress on reproductive outcomes in this vulnerable population are unknown. We assessed relationships between perceived stress and hormones, anovulation, and fecundability among women with prior loss. One thousand two hundred fourteen women with 1-2 prior losses were followed for ≤6 cycles while attempting pregnancy and completed end-of-cycle stress assessments. For cycles 1 and 2, women also collected daily urine and completed daily perceived stress assessments. We assessed anovulation via. an algorithm based on human chorionic gonadotropin (hCG), pregnanediol-3-glucuronide (PdG), luteinizing hormone (LH), and fertility monitor readings. Pregnancy was determined via. hCG. Adjusted weighted linear mixed models estimated the effect of prospective phase-varying (menses, follicular, periovulatory, and luteal) perceived stress quartiles on estrone-1-glucuronide (E1G), PdG, and LH concentrations. Marginal structural models accounted for time-varying confounding by hormones and lifestyle factors affected by prior stress. Poisson and Cox regression estimated risk ratios and fecundability odds ratios of cycle-varying stress quartiles on anovulation and fecundability. Models were adjusted for age, race, body mass index (BMI), parity, and time-varying caffeine, alcohol, smoking, intercourse, and pelvic pain. Women in the highest versus lowest stress quartile had lower E1G and PdG concentrations, a marginally higher risk of anovulation [1.28; 95% confidence interval (CI) = 1.00, 1.63], and lower fecundability (0.71; 95% CI = 0.55, 0.90). Preconception perceived stress appears to adversely affect sex steroid synthesis and time to pregnancy. Mechanisms likely include the effects of stress on ovulatory function, but additional mechanisms, potentially during implantation, may also exist.
Roomruangwong C et al., 2019·Frontiers in Psychology·
Open Access
It is unknown whether lowered steady state levels of sex hormones coupled with changes in those hormones during the menstrual cycle are associated with premenstrual syndrome (PMS). To examine associations between levels of progesterone and oestradiol during the menstrual cycle and PMS considering different diagnostic criteria for PMS. Forty-one women aged 18-45 years with a regular menstrual cycle completed the Daily Record of Severity of Problems (DRSP) for all 28 consecutive days of the menstrual cycle. Blood was sampled at days 7, 14, 21, and 28 to assay oestradiol and progesterone. We developed a new diagnosis of peri-menstrual syndrome, which is characterized by increased DRSP severity in pre and post-menstrual periods and increased scores on the major DRSP dimensions, i.e., depression, physio-somatic symptoms, breast tenderness and appetite, and anxiety. This new diagnosis performed better than classical diagnoses of PMS, including that of the American College of Obstetricians and Gynecologists (ACOG). Lowered steady state levels of progesterone, when averaged over the menstrual cycle, together with declining progesterone levels during the luteal phase predict severity of peri-menstrual symptoms. Steady state levels of oestradiol and declining oestradiol levels during the cycle are also related to DRSP severity although most of these effects appeared to be mediated by progesterone. A significant increase in menstrual-cycle related symptoms can best be conceptualized as "peri-menstrual syndrome" and may result from insufficient progesterone production (relative corpus luteum insufficiency), which, in part may result from lowered oestradiol production indicating suboptimal pre-ovulatory follicular development.
King EM et al., 2019·Open forum infectious diseases·
Open Access
Background Women living with HIV (WLWH) have higher rates of long-term amenorrhea (no flow for ≥12 months) than HIV-negative women. However, little is known about the consequences of amenorrhea for WLWH. Both amenorrhea and HIV are associated with lower areal bone mineral density (BMD); though the combined effect of both on BMD remains unclear. In this cross-sectional study we investigated whether prolonged amenorrhea adversely affects BMD among WLWH. Methods We investigated BMD (using a Hologic bone densitometer) and prolonged amenorrhea among WLWH and HIV-negative control women of similar socioeconomic backgrounds aged 19–68 in the CARMA cohort. Participants were stratified by HIV status and history of prolonged secondary amenorrhea defined as a self-reported absence of menses for at least one year in the past or present, occurring at age <45 years and not due to surgery, breastfeeding, pregnancy or hormonal contraception. Hip and spine Z-scores (ageand racestandardized BMD values) were compared between groups using linear models, followed by multivariable analysis of BMD-related factors. Results WLWH (N = 129) had significantly lower hip (mean±SD −0.4 ± 0.9 vs. 0.3 ± 1.1; P < 0.001) and spine (−0.5 ± 1.3 vs. 0.2 ± 1.3; P = 0.001) Z-scores vs. controls (N = 129). Multivariable linear regression found prolonged amenorrhea was independently related to lower hip (P = 0.01), but not spine (P = 0.94) BMD. Within WLWH, the effect of amenorrhea was also additive to that of HIV, with hip Z-scores of -0.8±0.9for those with amenorrhea vs. -0.3±0.8for those normally cycling (P = 0.01). Amongst WLWH, those with prolonged amenorrhea had higher rates of illicit substance use, smoking, chronic opioid therapy, hepatitis C viral infection, and poorer HIV viral control than those with normal menstruation. Conclusion These data suggest that WLWH having prolonged amenorrhea of ≥1 year’s duration are at increased risk for hip bone loss, a finding influenced by comorbid, HIV-associated conditions. Screening WLWH for menstrual history will allow early discovery of osteoporosis risk, and stimulate preventative measures to mitigate bone loss. Disclosures All authors: No reported disclosures.
Metabolic and Endocrine Agents · Thyroid Replacement
Dhillon-Smith RK et al., 2019·Efficacy Mech Eval·
Open Access
Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy. The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. This was a randomised, double-blind, placebo-controlled, multicentre study conducted in 49 hospitals across the UK between 2011 and 2016. Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible. Participants were randomised to levothyroxine at a dose of 50 mcg daily or placebo. The primary outcome was live birth at >= 34 completed weeks of gestation. Of the 19,556 women screened, 1420 were eligible and 952 were randomised. The live birth rate was 37% in the levothyroxine group and 38% in the placebo group (relative risk 0.97, 95% CI 0.83 to 1.14; p = 0.74). Levothyroxine therapy in a dose of 50 mcg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies.
Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.
Oral contraceptive (OC) effects on the brain have gained increasing interest, but are highly controversial. Previous studies suggest that OC users have larger hippocampi, parahippocampi, fusiform gyri and Cerebelli. Preliminary evidence from one of those studies even suggests an effect of previous contraceptive use on the hippocampi of women who are not current users of OCs. Furthermore, more recent studies postulate an involvement of previous OC treatment in later development of mood disorders. To address the question whether previous OC treatment affects women's brain structure later in life, high resolution structural images were obtained from 131 naturally cycling women. Among them, 52 women had never used OC before, 52 had previously used one OC for a continuous time period and 27 had previously used multiple contraceptives. The groups did not differ in gray matter volumes. Since endogenous sex hormones modulate gray matter volumes of the hippocampus and basal ganglia along the menstrual cycle, we hypothesize effects of OC use on these areas. Specifically, we hypothesize that a longer duration of previous OC treatment is related to larger hippocampi and larger basal ganglia. Indeed we found the duration of previous OC use to be positively correlated to hippocampal and basal ganglia volumes bilaterally. For the hippocampus, but not for the basal ganglia, this association disappeared after controlling for the time since discontinuation. These results suggest that for the hippocampus, but not for the basal ganglia, effects of previous contraceptive treatment are reversed after a time period comparable to treatment duration. These data question the immediate reversibility of OC effects on brain structure. Accordingly, some changes in the brain due to long-term contraceptive use, while subtle, may be long-lasting.
Pantos K et al., 2019·Cell Transplant·
Open Access
Since the introduction of autologous platelet-rich plasma (PRP) in medical practice, various studies have documented that implementing PRP can enhance healing and the anti-aging process, employing angiogenesis regeneration due to the multiple growth factors and cytokines involved. Numerous reports have shown promising results with the use of PRP in ovarian treatment, regarding ovarian regeneration and reactivation of folliculogenesis. This case series reports on two women with premature ovarian failure (POF) aged 40 and 27 years, respectively, and one menopausal woman aged 46 years. All patients presented with lack of menstrual cycle for over a year. The women reported previous failed in vitro fertilization (IVF) attempts, and, after rejecting the option of oocyte donation, they opted for the approach of autologous ovarian PRP treatment. Following PRP treatment, the three patients were invited to conceive naturally. The primary outcome was the restoration of menstruation following autologous ovarian PRP treatment, as well as an improvement in hormonal profile, a decrease in follicle-stimulating hormone (FSH) levels, and a concurrent increase in anti-Müllerian hormone (AMH) levels. Further to that, our patients achieved pregnancy through natural conception within 2-6 months following PRP treatment, resulting in currently ongoing complication-free clinical pregnancies - a first report in the literature for menopausal and POF patients. Implementation of PRP should be further investigated through randomized controlled trials (RCTs), as it may hold the key to successful treatment for a certain cohort of patients exploring reproductive treatment options following menopause.
Bouchard TP et al., 2019·Front Public Health·
Open Access
Progesterone rises \~24-36 h after ovulation. Past studies using ultrasound-confirmed ovulation have shown that three consecutive tests with a threshold of 5μg/mL of urine progesterone (pregnanediol-3-glucuronide, PDG), taken after the luteinizing hormone (LH) surge, confirmed ovulation with 100% specificity. The purpose of this study was to a evaluate a new urine PDG self-test to retrospectively confirm ovulation in women who were monitoring ovulation using a hormonal fertility monitor. Thirteen women of reproductive age were recruited to test urine PDG while using their home hormonal fertility monitor. The monitor measured the rise in estrogen (estrone-3-glucuronide, E3G) and LH to estimate the fertile phase of the menstrual cycle. The women used an online menstrual cycle charting system to track E3G, LH and PDG levels for four menstrual cycles. The participants (Mean age 33.6) produced 34 menstrual cycles of data (Mean length 28.4 days), 17 of which used a PDG test with a threshold of 7μg/mL and 17 with a threshold of 5μg/mL. In the cycles that used the 7μg/mL test strips, 59% had a positive confirmation of ovulation, and with the 5μg/mL test strips, 82% of them had a positive confirmation of ovulation. The 5μg/mL PDG test confirmed ovulation in 82% of cycles and could assist women in the evaluation of the luteal progesterone rise of their menstrual cycle.
Metabolic and Endocrine Agents · Thyroid Replacement
Akhtar MA et al., 2019·Cochrane Database Syst Rev·
Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction. To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction. We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist. We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri-iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment. We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage. The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies.In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%.In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I(2) = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I(2) = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%.Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. AUTHORS' We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.
Guideline Appraisal · Evidence Base and Strength of Recommendation
A recent cross-sectional national USA registry of surgery to repair anterior cruciate ligament tears found that fewer adolescent women who reported using combined hormonal contraceptives (CHC) had the surgery. They reviewed a complex literature on ovarian steroidal relationships with connective tissues biology, physiology and clinical issues. They concluded, based on their data and that evidence shows the greatest gender imbalance for women's ACL injury during adolescence, that all adolescent athletic women should be treated with CHC to prevent ACL injury. We caution that this admonition is using association to imply causation, implies we understand the ovarian hormonal relationships with connective tissues while that remains unclear, the directive to use CHC in adolescent ignores the recent meta-analytic evidence that its use is associated with failure to achieve peak bone mass and that these authors have used erroneous inferential reasoning and ignored the other variables besides sex and age related to ACL injury and the convincing evidence that training strategies can prevent tears.
Coomarasamy A et al., 2019·N Engl J Med·
Open Access
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
The menstrual cycle is known to impact mood and cognitive function and has been shown to lead to variability in symptoms of obsessive-compulsive disorders and anxiety. Using a within-subject design, the present study examined ovarian hormones, the error-related negativity (ERN), and self-reported checking symptoms in both the mid-follicular and mid-luteal phases of the menstrual cycle. ERN amplitude and checking symptom severity did not vary between the follicular and luteal phases. However, a more negative ERN was associated with greater checking symptoms in the luteal phase of the menstrual cycle, even when controlling for ERN amplitude in the follicular phase. Moreover, changes in checking symptoms between phases were associated with phase-related changes in the ERN. Finally, a significant mediation model was found such that the ERN measured in the luteal phase mediated the association between progesterone in the luteal phase and checking symptoms in the luteal phase. Collectively, the present findings suggest that levels of progesterone in the luteal phase could impact checking symptoms by modulating response monitoring and sensitivity to errors, and that fluctuation in the ERN between menstrual cycle phases may play an important role in the expression of anxious and obsessive-compulsive symptoms.
Anti-Müllerian hormone (AMH) levels are used worldwide as a screening tool for the duration of the female reproductive lifespan. Although AMH levels are associated with age at menopause, individual predictions of menopause with a single AMH measurement are unreliable. This study investigated whether individual AMH decline patterns can improve the prediction of menopause compared with a single measurement.
The study population comprised 2434 premenopausal women from the population-based Doetinchem Cohort Study. Participants were followed up every 5 years for a total of 20 years, and AMH was measured in 6699 plasma samples with the picoAMH assay. Longitudinal statistical modeling was combined with time varying Cox modeling, to integrate multiple AMH measurements per woman. The mean age at menopause was 50 years, and 7.4% of the women who reached menopause during follow-up did so before age 45 years. For a 25-year-old, the AMH decline rate between ages 20 and 25 years increased the C-statistic of menopause prediction from 0.64 to 0.69. Beyond that age, the AMH decline rate did not improve predictions of menopause or early menopause. For women younger than age 30 years, for whom menopause prediction is arguably most relevant, the models underestimated the risk of early menopause. These results suggest that knowledge of the AMH decline rate does not improve the prediction of menopause. Based on the low discriminative ability and underestimation of the risk of early menopause, the use of AMH as a screening method for the timing of menopause cannot currently be advocated.
Goodale BM et al., 2019·J Med Internet Res·
Open Access
Previous research examining physiological changes across the menstrual cycle has considered biological responses to shifting hormones in isolation. Clinical studies, for example, have shown that women's nightly basal body temperature increases from 0.28 to 0.56 ˚C following postovulation progesterone production. Women's resting pulse rate, respiratory rate, and heart rate variability (HRV) are similarly elevated in the luteal phase, whereas skin perfusion decreases significantly following the fertile window's closing. Past research probed only 1 or 2 of these physiological features in a given study, requiring participants to come to a laboratory or hospital clinic multiple times throughout their cycle. Although initially designed for recreational purposes, wearable technology could enable more ambulatory studies of physiological changes across the menstrual cycle. Early research suggests that wearables can detect phase-based shifts in pulse rate and wrist skin temperature (WST). To date, previous work has studied these features separately, with the ability of wearables to accurately pinpoint the fertile window using multiple physiological parameters simultaneously yet unknown. In this study, we probed what phase-based differences a wearable bracelet could detect in users' WST, heart rate, HRV, respiratory rate, and skin perfusion. Drawing on insight from artificial intelligence and machine learning, we then sought to develop an algorithm that could identify the fertile window in real time. We conducted a prospective longitudinal study, recruiting 237 conception-seeking Swiss women. Participants wore the Ava bracelet (Ava AG) nightly while sleeping for up to a year or until they became pregnant. In addition to syncing the device to the corresponding smartphone app daily, women also completed an electronic diary about their activities in the past 24 hours. Finally, women took a urinary luteinizing hormone test at several points in a given cycle to determine the close of the fertile window. We assessed phase-based changes in physiological parameters using cross-classified mixed-effects models with random intercepts and random slopes. We then trained a machine learning algorithm to recognize the fertile window. We have demonstrated that wearable technology can detect significant, concurrent phase-based shifts in WST, heart rate, and respiratory rate (all P<.001). HRV and skin perfusion similarly varied across the menstrual cycle (all P<.05), although these effects only trended toward significance following a Bonferroni correction to maintain a family-wise alpha level. Our findings were robust to daily, individual, and cycle-level covariates. Furthermore, we developed a machine learning algorithm that can detect the fertile window with 90% accuracy (95% CI 0.89 to 0.92). Our contributions highlight the impact of artificial intelligence and machine learning's integration into health care. By monitoring numerous physiological parameters simultaneously, wearable technology uniquely improves upon retrospective methods for fertility awareness and enables the first real-time predictive model of ovulation.
Yang Y et al., 2019·Journal of the Endocrine Society·
Open Access
Sclerostin is an osteocyte-produced glycoprotein that inhibits the WNT/β-catenin pathway essential for bone formation. Sclerostin was postulated to relate to normal bone metabolism in 2001; we still have an incomplete understanding of its regulation. Estradiol, a bone antiresorptive ovarian steroid, inhibits sclerostin. Estrogen and progesterone act together in menstrual cycles and bone remodelling with progesterone exerting an anabolic effect. We hypothesized a relationship between progesterone and sclerostin because progesterone and estrogen are “partner” hormones in most tissues, and because progesterone and sclerostin modulate bone formation in opposite directions. Two observational menstrual cycle studies have reported sclerostin levels; neither documented changes across cycles nor in luteal phases during which progesterone levels are high(1)(,2). Some reports have also shown positive correlations between sclerostin and age and BMI. In this study, sclerostin was measured using an assay (MSD) of high sensitivity (LOD ± 1pg/mL), broad detection range (1-10 000 pg/mL), and intra/inter-assay precisions of 6% and 10% respectively(3). We collected fasting serum during a 3-month double blind randomized controlled trial (RCT) of 300 mg oral micronized progesterone vs placebo in symptomatic menopausal women; progesterone significantly decreased hot flushes/night sweats (vasomotor symptoms, VMS)(4). Statistical analysis showed sclerostin was not related to the 28-day baseline VMS Score (r=.18, p=.22). Pearson correlation coefficients were used to evaluate sclerostin vs baseline data and ANCOVA to analyze RCT results (alpha=0.05 significant, [SD]). The study’s purpose was to determine if sclerostin levels changed during a 3-month RCT of progesterone for VMS in healthy menopausal women(3). The primary outcome was sclerostin level in the 3(rd) month adjusted for baseline and randomization. Results showed the 52 participating women had a mean age of 55.2 (4.6) years, height 1.60 (0.07) m, weight 66.4 (8.6) kg, BMI 24.9 (2.9) kg/m(2) and were primarily Caucasian (91.2%). Baseline variables did not correlate with the baseline mean serum sclerostin level of 27.9 (10.2) pmol/L. Sclerostin had no statistically significant relationship with progesterone or placebo therapy during this RCT; mean changes were -1.07 and -2.60 pmol/L respectively. These data are the first evidence that progesterone neither increases nor decreases serum sclerostin levels. These data fit with the lack of menstrual cycle changes in sclerostin levels(1)(,2). That sclerostin did not correlate with age and BMI in this RCT is likely due to their low trial variance. A limitation of this study is the small sample size. However, it has considerable strength in its RCT design that can document causation. (1)Cidem M Gyn Obstetric Invest. 2012; (2)Liakou CG Endocrine 2016; (3)Van Lierop AH J Bone Miner Res 2011; (4)Hitchcock CL Menopause 2012.
von Versen-Höynck F et al., 2019·Hypertension (Dallas, Tex. : 1979)
In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.
Although the 2017 Endocrine Society Guidelines for gender dysphoria stipulated that cross-sex hormone therapy (CHT) achieve gonadal steroid levels equivalent to those of a cisperson of the chosen sex, for transgender women (male-to-female gender dysphoria), current gonadal therapy is usually estradiol. Accumulated evidence indicates that normally ovulatory menstrual cycles are necessary for ciswomen's current fertility, as well as for later-life bone and cardiovascular health and the prevention of breast and endometrial cancers.
Evidence Acquisition: Extensive past clinical experience with transgender women's CHT using estradiol/estrogen combined with progesterone/medroxyprogesterone and pioneering the addition of spironolactone. Comprehensive progesterone physiology research plus a brief review of transgender women's literature to assess current therapy and clinical outcomes, including morbidity and mortality. To emphasize that both ovarian hormones, progesterone as well as estradiol, are theoretically and clinically important for optimal transgender women's CHT.
Evidence Synthesis: It is important to add progesterone to estradiol and an antiandrogen in transgender women's CHT. Progesterone may add the following: (i) more rapid feminization, (ii) decreased endogenous testosterone production, (iii) optimal breast maturation to Tanner stages 4/5, (iv) increased bone formation, (v) improved sleep and vasomotor symptom control, and (vi) cardiovascular health benefits. Evidence has accrued that normal progesterone (and ovulation), as well as physiological estradiol levels, is necessary during ciswomen's premenopausal menstrual cycles for current fertility and long-term health; transgender women deserve progesterone therapy and similar potential physiological benefits.
Early and Premature Transition · Premature Ovarian Insufficiency
Sfakianoudis K et al., 2018·J Clin Med·
Open Access
This report presents the case of a woman aged 40 who has experienced premature menopause from the age of 35. Having rejected oocyte donation, she opted for intraovarian injection of autologous platelet-rich plasma with the aim to rejuvenate the ovarian tissue and enable the employment of her own gametes through in-vitro fertilization. Six weeks following the autologous platelet-rich plasma treatment, a significant reduction in the patient's follicle-stimulating hormone (FSH) levels were noted. A natural in-vitro fertilization cycle led to a biochemical pregnancy, resulting in a spontaneous abortion at the 5th week of pregnancy. This is the first report of a successful autologous platelet-rich plasma application leading to pregnancy in menopause. This report uniquely contributes to the medical knowledge and challenges current practice in the context of infertility. The efficiency and safety of this treatment with regard to the reproductive system merits further investigation.
Identifying the return of fertility with cervical mucus observations is challenging during the postpartum period. Use of urinary measurements of estrogen and progesterone can assist in understanding the return to fertility during this period. The purposes of this study were to describe the postpartum return of fertility by an analysis of total estrogen (TE) and pregnanediol glucuronide (PDG) profiles and to correlate these profiles with cervical mucus observations. Twenty-six participants collected urine samples during the postpartum period and recorded mucus scores. TE and PDG hormones were analyzed and compared with mucus scores. During amenorrhea, mucus reflected TE changes in only 35 percent of women; after amenorrhea, typical mucus patterns were seen in 33 percent of cycles. We concluded that postpartum mucus and hormone profiles are significantly dissociated but that monitoring urinary hormones may assist in identifying the return of fertility. We also identified different hormonal patterns in the return to fertility. The postpartum period is a challenging time for identifying the return of fertility. The purposes of this study were to describe the hormonal patterns during the return of fertility and to correlate these patterns with cervical mucus observations. Twenty-six postpartum women collected urine samples and recorded mucus scores. Urinary estrogen and progesterone hormones were analyzed and compared with mucus scores. Before the return of menses, mucus reflected hormonal changes in only 35 percent women and after first menses in 33 percent of cycles. We found that hormone profiles do not correlate well with mucus observations during the postpartum return of fertility.
Natural family planning (NFP) methods have served many generations well, and in particular, the symptothermal or symptohormonal methods. The comparison of daily mucus and temperature records for individual cycles with daily hormone measurements, which is now possible, shows that some of the assumptions underlying NFP may not be completely accurate. The various methods are inadvertently depending on an element of chance, which, of course, cannot be known by the NFP user. However, it is statistically inevitable that such errors will result eventually in an unexpected pregnancy, and these discrepancies are the likely reason for the method failures. Further research and integration of home hormone measurements with NFP symptoms are needed.
Traditional NFP methods, based on the observations of temperature, mucus, and luteinizing hormone, can work well. However, these data are sometimes difficult to interpret, and significant changes in the variables are sometimes "missing" from some cycles. Changes in these variables are elicited by the estrogen and progesterone released from the ovaries. It follows that the direct measures of events in the ovaries are the levels of estrogen and progesterone or their derivatives in blood or urine. Measurements of urinary derivatives of estrogen and progesterone can be used to monitor the ovaries directly and are clearer indicators than traditional NFP methods.
Estradiol (E2) is women's dominant 'bone hormone' since it is essential for development of adolescent peak bone mineral density (BMD) and physiological levels prevent the rapid (3-week) bone resorption that causes most adult BMD loss. However, deceasing E2 levels trigger bone resorption/loss. Progesterone (P4) is E2's physiological partner, collaborating with E2 in every cell/tissue; its bone 'job' is to increase P4-receptor-mediated, slow (3-4 months) osteoblastic new bone formation. When menstrual cycles are normal length and normally ovulatory, E2 and P4 are balanced and BMD is stable. However, clinically normal cycles commonly have ovulatory disturbances (anovulation, short luteal phases) and low P4 levels; these are more frequent in teen and perimenopausal women and increased by everyday stressors: energy insufficiency, emotional/social/economic threats and illness. Meta-analysis shows that almost 1%/year spinal BMD loss occurs in those with greater than median (∼31%) of ovulatory disturbed cycles. Prevention of osteoporosis and fragility fractures requires the reversal of stressors, detection and treatment of teen-to-perimenopausal recurrent cycle/ovulatory disturbances with cyclic oral micronized progesterone. Low 'Peak Perimenopausal BMD' is likely the primary risk for fragility fractures in later life. Progesterone plus estradiol or other antiresorptive therapies adds 0.68%/year and may be a highly effective osteoporosis treatment. Randomized controlled trials are still needed to confirm progesterone's important role in women's bone formation.
Although minerals are linked to several reproductive outcomes, it is unknown whether dietary minerals are associated with ovulatory function. We hypothesised that low intakes of minerals would be associated with an increased risk of anovulation. We investigated associations between dietary mineral intake and both reproductive hormones and anovulation in healthy women in the BioCycle Study, which prospectively followed up 259 regularly menstruating women aged 18-44 years who were not taking mineral supplements for two menstrual cycles. Intakes of ten selected minerals were assessed through 24-h dietary recalls at up to four times per cycle in each participant. Oestradiol, progesterone, luteinising hormone (LH), follicle-stimulating hormone (FSH), sex-hormone-binding globulin and testosterone were measured in serum up to eight times per cycle. We used weighted linear mixed models to evaluate associations between minerals and hormones and generalised linear models for risk of anovulation. Compared with Na intake ≥1500 mg, Na intake <1500 mg was associated with higher levels of FSH (21·3 %; 95 % CI 7·5, 36·9) and LH (36·8 %; 95 % CI 16·5, 60·5) and lower levels of progesterone (-36·9 %; 95 % CI -56·5, -8·5). Na intake <1500 mg (risk ratio (RR) 2·70; 95 % CI 1·00, 7·31) and Mn intake <1·8 mg (RR 2·00; 95 % CI 1·02, 3·94) were associated with an increased risk of anovulation, compared with higher intakes, respectively. Other measured dietary minerals were not associated with ovulatory function. As essential minerals are mostly obtained via diet, our results comparing insufficient levels with sufficient levels highlight the need for future research on dietary nutrients and their associations with ovulatory cycles.
Ferrero S et al., 2018·Expert opinion on pharmacotherapy
Pharmacotherapy has a pivotal role in the management of endometriosis with long-term treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors including age and patient preference, reproductive plans, intensity of pain, severity of disease and incidence of adverse effects. The aim of this review is to provide the reader with a complete overview of drugs that are currently available or are under investigation for the treatment of endometriosis highlighting on-going clinical trials. Almost all of the available treatment options for endometriosis suppress ovarian function and are not curative. Combined oral contraceptives and progestins are commonly administered to these patients in order to ameliorate pain symptoms. Gonadotropin-releasing hormone-agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary.
Abdulla SH et al., 2018·Front Public Health·
Open Access
Explore potential relationships between preovulatory, periovulatory, and luteal-phase characteristics in normally cycling women.
Observational study.
Eight European natural family planning clinics. Patient(s): Ninety-nine women contributing 266 menstrual cycles. Intervention(s): The participants collected first morning urine samples that were analyzed for estrone-3 glucuronide (E1G), pregnanediol-3alpha-glucuronide (PDG), follicle stimulating hormone (FSH), and luteinizing hormone (LH). The participants underwent serial ovarian ultrasound examinations. Main Outcome Measure(s): Four outcome measures were analyzed: short luteal phase, low mid-luteal phase PDG level (mPDG), normal then low luteal PDG level, low then normal luteal PDG level. A long preovulatory phase was a predictor of short luteal phase, with or without adjustment for other variables. A high periovulatory PDG level was a predictor for short luteal phase as well as normal then low luteal PDG level. A low periovulatory PDG level predicted low mPDG and low then normal luteal PDG level, with or without adjustment for other variables. A small maximum follicle predicted normal then low luteal PDG level, with or without adjustment for other variables. The relationship between small maximum follicle size and short luteal phase or small maximum follicle size and low mPDG was no longer present when the regression was adjusted for certain characteristics. A younger age at menarche and a high body mass index were both predictors of low mPDG. Luteal phase abnormalities exist over a spectrum where some ovulation disorders may exist as deviations from the normal ovulatory process.This study confirms the negative impact of a small follicle size on the quality of the luteal phase. The occurrence of normal then low luteal PDG level is confirmed as a potential sign of luteal phase abnormality.
Animal models and a few human investigations suggest progesterone may be associated with anxiety. Progesterone naturally fluctuates across the menstrual cycle, offering an opportunity to understand how within-person increases in progesterone and average progesterone levels across the cycle correspond to women's anxiety. Across two longitudinal studies, we simultaneously modeled the between- and within-person associations between progesterone and anxiety using multilevel modeling. In Study 1, 100 Polish women provided saliva samples and reported their anxiety at three phases of the menstrual cycle: follicular, peri-ovulatory, and luteal. A significant between-person effect emerged, revealing that women with higher average progesterone levels across their cycles reported higher levels of anxiety than women with lower progesterone cycles. This effect held controlling for estradiol. In Study 2, 61 American women provided saliva samples and reported their attachment anxiety during laboratory sessions during the same three cycle phases. A significant between-person and within-person association emerged: women with higher average progesterone levels reported higher levels of attachment anxiety, and as women's progesterone levels increased across their cycles, so too did their attachment anxiety. These effects held controlling for cortisol. In sum, both studies provide support for a link between menstrual cycle progesterone levels and subjective anxiety.
Goshtasebi A et al., 2018·Int J Environ Res Public Health·
Open Access
Amenorrhea is important for women's bone health. However, few have reported reproductive, anthropometric (body mass index [BMI], height) and bone health (areal bone mineral density [BMD], prevalent fractures) in a population-based study. The purposes of this cross-sectional study of women in the randomly-selected Canadian Multicentre Osteoporosis Study (CaMos) population were: (1) to describe reproductive, demographic, anthropometric and lifestyle variables; and (2) in menstruating women, to relate reproductive and other variables to BMD at the lumbar spine (L1-4, LS), femoral neck (FN) and total hip (TH) sites and to prevalent fragility fractures. This study describes the reproductive characteristics of 1532 women aged 30⁻60 years. BMD relationships with reproductive and other variables were described in the 499 menstruating women. Mean menarche age was 12.8 years, 96% of women were parous and 95% had used combined hormonal contraceptives (CHC). Infertility was reported by 9%, androgen excess by 13%, amenorrhea by 8% and nulliparity by 4%. LS BMD was negatively associated with amenorrhea and androgen excess and positively related to current BMI and height. A later age at menarche negatively related to FN BMD. BMI and height were strongly related to BMD at all sites. Prevalent fragility fractures were significantly associated with quartiles of both LS and TH BMD.
Prior JC et al., 2018·Int J Environ Res Public Health·
Open Access
Approximately 33% of normal-length (21⁻35 days) cycles have subclinical ovulatory disturbances and lack sufficient progesterone, although their normal length ensures enough estrogen. Subclinical ovulatory disturbances are related to significant premenopausal spine bone loss (-0.86%/year). Molimina, non-distressing premenstrual experiences, may detect ovulation within normal-length cycles. This prospective study assessed the relationship between molimina and ovulation. After 1-cycle of daily diary and first morning urine collections, women answered the Molimina Question (MQ): "Can you tell by the way you feel that your period is coming?" and were invited to share (a) predictive premenstrual experience(s). A 3-fold increase in follicular-luteal pregnanediol levels confirmed ovulation. In 610 spontaneously menstruating women (not on hormonal contraception, mean age 31.5 ± 5.3, menarche age 12.7 ± 1.5, cycle length [CL] 29 days, MQ positive in 89%), reported premenstrual experiences which included negative moods (62%), cramps (48%), bloating (39%), and front (26%) or axillary (25%) breast tenderness. Of 432 women with pregnanediol-documented cycles, 398 (92%) were ovulatory (CL: 29 ± 5) and 34 (8%) had ovulatory disturbances (CL: 32 ± 14). Women with/without ovulatory cycles were similar in parity, body mass index, smoking, dietary restraint and the MQ; ovulatory-disturbed cycles were longer. Molimina did not confirm ovulation. A non-invasive, inexpensive ovulation indicator is needed to prevent osteoporosis.
Priest SE et al., 2018·Am J Physiol Heart Circ Physiol·
Open Access
Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, β-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants were tested three times: men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. β-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). β-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (β-stiffness: r = 0.003, P = 0.99; cfPWV: r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence β-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.
Schmidt K et al., 2018·Clin Nutr ESPEN·
Open Access
BACKGROUND & Many women experience emotional and physical symptoms around the time of ovulation and more so before menstruation interfering with their daily normal life also known as premenstrual syndrome (PMS). Recent observational data suggest that supplementation with Lipogen's phosphatidylserine (PS) and phosphatidic acid (PA) complex (PAS) alleviates these PMS symptoms. The aim of this study was to confirm these observations on the effects of PAS on PMS symptom severity within a controlled clinical trial setting. Forty women aged 18-45 years with a diagnosis of PMS were assigned to either take PAS (containing 400 mg PS & 400 mg PA per day) or a matching placebo. The study comprised 5 on-site visits including 1 baseline menstrual cycle followed by 3 treatment cycles. Treatment intake was controlled for by using an electronic device, the Medication Event Monitoring System (MEMS(®)). Primary outcome of the study was the PMS symptoms severity as assessed by using the Daily Record of Severity of Problems (DRSP). Further, SIPS questionnaire (a German version of the Premenstrual Symptoms Screening Tool (PSST)), salivary hormone levels (cortisol awakening response (CAR) and evening cortisol levels) as well as serum levels (cortisol, estradiol, progesterone and corticosteroid binding globulin (CBG)) were assessed. PMS symptoms as assessed by the DRSP Total score showed a significantly better improvement (p = 0.001) over a 3 cycles PAS intake as compared to placebo. In addition, PAS treated women reported a greater improvement in physical (p = 0.002) and depressive symptoms (p = 0.068). They also reported a lower reduction of productivity (p = 0.052) and a stronger decrease in interference with relationships with others (p = 0.099) compared to the placebo group. No other DRSP scale or item showed significant results. Likewise, the reduction in the number of subjects fulfilling PMS or premenstrual dysphoric disorder (PMDD) criteria as classified by the SIPS did not differ between the PAS and the placebo group. For the biomarkers, the salivary cortisol percentage increase of the CAR was significantly less pronounced in the follicular phase of cycle 4 than in the follicular phase of cycle 1 for subjects taking PAS when compared to subjects taking placebo (p = 0.018). Furthermore, the change of serum cortisol levels between visit 1 and visit 5 differed significantly between groups (p = 0.043). While serum cortisol levels of PAS treated females slightly decreased between visit 1 and visit 5, cortisol levels of females treated with placebo increased. For all other biomarkers, no treatment effects were observed over the 4 cycles study period. Overall, this study confirms that a daily intake of PAS, containing 400 mg PS and 400 mg PA, can be considered as safe. Results substantiate the efficacy of PAS in reducing symptoms of PMS. In view of the recent inclusion of severe PMS symptoms (PMDD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the positive results of this clinical study merits consideration of developing the PAS complex as a botanical drug for treatment of PMDD. CLINICAL The study is registered at Deutsches Register Klinischer Studien with the registration number DRKS00009005.
Sills ES et al., 2018·Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
Platelets modulate clinically relevant yet incompletely understood tissue regeneration processes, and platelet rich plasma (PRP) has been previously used with some success in various non-reproductive medical contexts. Here, we extended PRP application to ovarian tissue with a view to document impact on ovarian reserve among women attending for infertility treatment. PRP was freshly isolated from patients (n= 4) with diminished ovarian reserve as determined by at least one prior IVF cycle canceled for poor follicular recruitment response or estimated by serum AMH and/or FSH, no menses for ≥1 year. Immediately following substrate isolation and activation with calcium gluconate, approximately 5 mL of autologous PRP was injected into each ovary under direct transvaginal sonogram guidance. For each study subject, AMH, FSH, and serum estradiol data were recorded at two-week intervals post-PRP and compared to baseline (pre-PRP) values. In this pilot group, mean (±SD) patient age was 42 ± 4 years with infertility duration reported as 60 ± 25 months. Following this protocol of intraovarian PRP administration, increases in serum AMH (p = .17), decreases in FSH (p < .01), or both, were observed in all cases, sufficient to permit retrieval of 5.3 ± 1.3 MII oocytes. IVF occurred 78 ± 22 (range = 59-110) days after activated PRP injection, and results appeared independent of patient age, infertility duration, baseline platelet concentration or pretreatment antral follicle count. Each patient had at least one blastocyst suitable for cryopreservation. While autologous PRP has been successfully applied therapeutically to various tissues to accelerate healing and wound repair, this is the first description of direct injection of activated PRP into the human ovary of poor prognosis IVF patients. Evidence of improved ovarian function was noted in all who received intraovarian PRP, possibly as early as two months after treatment. Additional research is needed to clarify (and enhance) which PRP components are responsible for altered ovarian function, and to identify predictive characteristics for patients most likely to benefit from this intervention.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
The long-term effects of metformin in women with polycystic ovarian syndrome (PCOS) are inadequately studied. The effects of metformin on women with PCOS during 24 months with respect to menses, hormones, and metabolic profiles are assessed. Prospective cohort. A reproductive endocrinology clinic in a university-affiliated medical center. One hundred nineteen women with PCOS, defined by the Rotterdam criteria, were enrolled. Metformin was given daily for 24 months. The primary outcome was the proportion of patients with regular menstruation during treatment. Changes in anthropometric, hormonal, and metabolic parameters were also assessed. Analyses were performed using segmented regression analysis with a generalized estimating equation methodology. Outcomes are expressed as magnitude of change from the baseline. Both overweight (OW) and normal-weight (NW) women with PCOS had increased menstrual frequency and decreased body mass index (BMI), testosterone, and luteinizing hormone levels in the first 6 months. Further stratification showed that NW women exhibiting elevated testosterone at baseline had the largest magnitude of improvement at 6 months [odds ratio (OR), 7.21; 95% confidence interval (CI), 2.35 to 22.17], whereas OW patients with normal testosterone were most likely to achieve normal menses at 12 months (OR, 0.63; 95% CI, 0.47 to 0.77). Metformin was associated with improvements in the menstrual cycle and most hormonal profiles in OW and NW women with PCOS during 24 months of treatment. Most parameters reached maximal response and steady-state after 6 months. Phenotypic differences in baseline BMI and testosterone level can be used as patient selection criteria or treatment prognostics.
Orouji Jokar T et al., 2017·J Clin Endocrinol Metab·
Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. DESIGN, SETTING, Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and ≤5 mIU/L) and normal prolactin levels (≤20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). TSH and prolactin. Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, interquartile range: (1.54, 2.61); severe male factor: TSH 1.66 mIU/L, interquartile range: (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH ≥2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI.
The concept of the ovarian continuum can be understood as a process that occurs during a woman's lifetime and begins during intrauterine life with fertilization. Women start their reproductive years with approximately five hundred thousand follicles containing oocytes, of which only around five hundred will be released during ovulation. Ovulation has been recognized as an event linked with reproduction; however, recent evidence supports the role of ovulation as a sign of health. The use of biomarkers that help women recognize ovulation enables them to identify their health status. This knowledge helps medical healthcare providers in the prevention, diagnosis, and treatment of different pathologies related with endocrine disorders, gynecological abnormalities, autoimmune, genetic, and neoplastic diseases, as well as pregnancy-related issues. The knowledge of the ovarian continuum and the use of biomarkers to recognize ovulation should be considered a powerful tool for women and medical professionals.
The ovarian continuum is a process that occurs during a woman's lifetime. It begins during intrauterine life with fertilization and ends with menopause. This process can be greatly affected by different conditions such as changes in hormonal levels and illnesses. Therefore, understanding and promoting the knowledge and use of biomarkers of ovulation in women is a key aspect to consider when evaluating their health status. The knowledge and education about the ovarian continuum should be taken into account as a powerful tool for women and medical professionals.
Sohda S et al., 2017·J Med Internet Res·
Open Access
There are many mobile phone apps aimed at helping women map their ovulation and menstrual cycles and facilitating successful conception (or avoiding pregnancy). These apps usually ask users to input various biological features and have accumulated the menstrual cycle data of a vast number of women. The purpose of our study was to clarify how the data obtained from a self-tracking health app for female mobile phone users can be used to improve the accuracy of prediction of the date of next ovulation. Using the data of 7043 women who had reliable menstrual and ovulation records out of 8,000,000 users of a mobile phone app of a health care service, we analyzed the relationship between the menstrual cycle length, follicular phase length, and luteal phase length. Then we fitted a linear function to the relationship between the length of the menstrual cycle and timing of ovulation and compared it with the existing calendar-based methods. The correlation between the length of the menstrual cycle and the length of the follicular phase was stronger than the correlation between the length of the menstrual cycle and the length of the luteal phase, and there was a positive correlation between the lengths of past and future menstrual cycles. A strong positive correlation was also found between the mean length of past cycles and the length of the follicular phase. The correlation between the mean cycle length and the luteal phase length was also statistically significant. In most of the subjects, our method (ie, the calendar-based method based on the optimized function) outperformed the Ogino method of predicting the next ovulation date. Our method also outperformed the ovulation date prediction method that assumes the middle day of a mean menstrual cycle as the date of the next ovulation. The large number of subjects allowed us to capture the relationships between the lengths of the menstrual cycle, follicular phase, and luteal phase in more detail than previous studies. We then demonstrated how the present calendar methods could be improved by the better grouping of women. This study suggested that even without integrating various biological metrics, the dataset collected by a self-tracking app can be used to develop formulas that predict the ovulation day when the data are aggregated. Because the method that we developed requires data only on the first day of menstruation, it would be the best option for couples during the early stages of their attempt to have a baby or for those who want to avoid the cost associated with other methods. Moreover, the result will be the baseline for more advanced methods that integrate other biological metrics.
Stress and Allostatic Load · Cortisol and the Adrenal Axis
Joseph DN et al., 2017·International journal of molecular sciences
An organism's reproductive fitness is sensitive to the environment, integrating cues of resource availability, ecological factors, and hazards within its habitat. Events that challenge the environment of an organism activate the central stress response system, which is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The regulatory functions of the HPA axis govern the cardiovascular and metabolic system, immune functions, behavior, and reproduction. Activation of the HPA axis by various stressors primarily inhibits reproductive function and is able to alter fetal development, imparting a biological record of stress experienced in utero. Clinical studies and experimental data indicate that stress signaling can mediate these effects through direct actions in the brain, gonads, and embryonic tissues. This review focuses on the mechanisms by which stress activation of the HPA axis impacts fertility and fetal development.
Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. DESIGN, SETTING, Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Exposures: Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Conclusions and Relevance: Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.
Low levels of gonadal circulating estrogen observed in post-menopausal women can adversely impact a diverse range of physiological factors, with clinical implications for brain cognition, gut health, the female reproductive tract and other aspects of women's health. One of the principal regulators of circulating estrogens is the gut microbiome. This review aims to shed light on the role of the gut microbiota in estrogen-modulated disease. The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms. When this process is impaired through dysbiosis of gut microbiota, characterized by lower microbial diversity, the decrease in deconjugation results in a reduction of circulating estrogens. The alteration in circulating estrogens may contribute to the development of conditions discussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function. The bi-directional relationship between the metabolic profile (including estrogen levels) and gut microbiota in estrogen-driven disease will also be discussed. Promising therapeutic interventions manipulating the gut microbiome and the metabolic profile of estrogen-driven disease, such as bariatric surgery and metformin, will be detailed. Modulation of the microbiome composition subsequently impacts the metabolic profile, and vice versa, and has been shown to alleviate many of the estrogen-modulated disease states. Last, we highlight promising research interventions in the field, such as dietary therapeutics, and discuss areas that provide exciting unexplored topics of study.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Laganà AS et al., 2017·Int J Endocrinol Metab·
Open Access
Polycystic ovary syndrome (PCOS)’s rate is about 6% to10% among the reproductive aged women; it is characterized by menstrual cycle irregularity with oligo-anovulation, hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. Despite the fact that the last two elements are present in a large percentage of PCOS women, they are not mandatory for the diagnosis; in order to explain the pathogenesis in these patients, it was supposed that ovarian theca cells got higher insulin sensitivity probably related to the mechanism of intracellular signalling transduction (1). Corroborating this view, it was previously demonstrated that diazoxid, which has the well-known effect of decreasing insulin levels, reduced hyperandrogenism in lean women affected by PCOS, even in the cases of normal insulin level and insulin sensitivity (2). Based on the detrimental role of insulin resistance, several insulin sensitizer drugs have been used to ameliorate PCOS symptoms and signs. Although metformin has represented the landmark of PCOS therapy in the recent past, to date several studies have tested the efficacy of Inositols, a carbocyclic polyols. Two stereoisomers, in particular Myo-inositol (MI) and D-Dhiro-inositol (DCI) showed a clinical efficacy and safety during PCOS. MI is converted in DCI by epimerase, an enzyme regulated also by insulin action. In the form of inositol-phosphoglycans (IPGs), they are involved in a non-classical insulin signalling cascade: insulin receptor is coupled by G-protein which can activate phospholipase, allowing the release of second messengers (DCI-glycan), which is able to stimulate pyruvate dehydrogenase and glycogen synthase activities, the enzyme involved in the oxidative and the non-oxidative glucose metabolism (3). On one hand, MI-IPG is able to inhibit cyclic adenosine monophosphate (cAMP) kinase and adenylyl cyclase, both involved in free fatty acid metabolism. On the other hand, DCI-IPG play a pivotal role during the binding of insulin to its receptor on cell membrane where it stimulates IPG release and starts signalling cascade. In addition, Inositols are incorporated in membrane phospholipids as phosphoinositides. Phosphatidylinositol 4, 5 bisphosphate (PtdIns-4, 5P) and phosphatidylinositol 4P (PtdIns-4P), in particular, are involved in the regulation of the cytoskeleton structure and in the regulation of cellular motility, which account also the beneficial effects of Inositol administration on sperm parameters. PtdIns-4, 5P plays a key role in controlling calcium-mediated intracellular signalling which is mandatory to address the oocytes maturation and fecundation (4).
How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, Duration: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. Main Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.
Rattan S et al., 2017·Journal of Endocrinology·
Open Access
Endocrine disrupting chemicals are ubiquitous chemicals that exhibit endocrine disrupting properties in both humans and animals. Female reproduction is an important process, which is regulated by hormones and is susceptible to the effects of exposure to endocrine disrupting chemicals. Disruptions in female reproductive functions by endocrine disrupting chemicals may result in subfertility, infertility, improper hormone production, estrous and menstrual cycle abnormalities, anovulation, and early reproductive senescence. This review summarizes the effects of a variety of synthetic endocrine disrupting chemicals on fertility during adult life. The chemicals covered in this review are pesticides (organochlorines, organophosphates, carbamates, pyrethroids, and triazines), heavy metals (arsenic, lead, and mercury), diethylstilbesterol, plasticizer alternatives (di-(2-ethylhexyl) phthalate and bisphenol A alternatives), 2,3,7,8-tetrachlorodibenzo-p-dioxin, nonylphenol, polychlorinated biphenyls, triclosan, and parabens. This review focuses on the hypothalamus, pituitary, ovary, and uterus because together they regulate normal female fertility and the onset of reproductive senescence. The literature shows that several endocrine disrupting chemicals have endocrine disrupting abilities in females during adult life, causing fertility abnormalities in both humans and animals.
An affordable, user-friendly fertility-monitoring tool remains an unmet need. We examine in this study the correlation between pulse rate (PR) and the menstrual phases using wrist-worn PR sensors. 91 healthy, non-pregnant women, between 22-42 years old, were recruited for a prospective-observational clinical trial. Participants measured PR during sleep using wrist-worn bracelets with photoplethysmographic sensors. Ovulation day was estimated with "Clearblue Digital-Ovulation-urine test". Potential behavioral and nutritional confounders were collected daily. 274 ovulatory cycles were recorded from 91 eligible women, with a mean cycle length of 27.3 days (±2.7). We observed a significant increase in PR during the fertile window compared to the menstrual phase (2.1 beat-per-minute, p < 0.01). Moreover, PR during the mid-luteal phase was also significantly elevated compared to the fertile window (1.8 beat-per-minute, p < 0.01), and the menstrual phase (3.8 beat-per-minute, p < 0.01). PR increase in the ovulatory and mid-luteal phase was robust to adjustment for the collected confounders. There is a significant increase of the fertile-window PR (collected during sleep) compared to the menstrual phase. The aforementioned association was robust to the inter- and intra-person variability of menstrual-cycle length, behavioral, and nutritional profiles. Hence, PR monitoring using wearable sensors could be used as one parameter within a multi-parameter fertility awareness-based method.
Bani Mohammad M et al., 2017·Asian Pac J Cancer Prev·
The polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and a notable proportion of women of reproductive age are affected. It may constitute a risk factor for cancer development. Different factors could result in different manifestations and many of these are related to predispositions. It is essential to establish criteria to achieve an exact diagnosis of PCOS, especially among adolescent patients because of the overlap between features of PCO syndrome and physiological findings in puberty. Day by day the technology of ultrasonography is improving and accuracy is increasing, but remains dependent on the specific equipment available. Some factors are inter-related in determining PCOS prognosis. Serum AMH is synthesized by small antral follicles, which are precisely those seen on ultrasound and could help us to diagnose PCOS but there are many aspects that still require elucidation. In this minireview we have attempted to identify some of these correlations.
Lovett JL et al., 2017·Evolution, medicine, and public health
In the evolutionary past, women spent most of their reproductive lives either pregnant or in lactational amenorrhea, and rarely menstruated. The current pattern of frequent menses, and the associated increase in endogenous hormonal exposure, has been implicated in the current breast cancer epidemic. It is not known, however, whether oral contraceptives further increase, or actually decrease, hormonal exposure over one menstrual cycle. Here, we examined variation in hormonal exposure across seven oral contraceptive (OC) formulations, and produced the first quantitative comparison of exogenous versus endogenous hormone exposure. Methodology: Data from 12 studies of serum estradiol (E2) and progesterone (P4) were aggregated to create a composite graph of endogenous hormone levels over one menstrual cycle in European or American women (age 19-40 years). Pharmacokinetic package insert data, also from Western women, were used to calculate exposures for hormones in seven different OC formulations. Endogenous and exogenous hormone levels were compared after adjusting for the relative binding affinity (RBA) of progestin to the progesterone receptor and ethinyl estradiol (EE) to the estrogen receptor. After adjusting for RBA, median ethinyl estradiol exposure across 28 days in the OCs was 11.4 nmol/l, similar to median E2 exposure. One formulation, however, was 40% higher in ethinyl estradiol exposure relative to median endogenous estradiol. Median exposure from progestins in OCs (1496 nmol/l) was 4-fold higher than the median endogenous exposure from P4 (364 nmol/l). Exposure from OC progestins ranged from one sixtieth to 8-fold median endogenous P4 over 28 days. Conclusions and Given that breast cancer risk increases with hormonal exposure, our finding that four widely prescribed formulations more than quadruple progestin exposure relative to endogenous progesterone exposure is cause for concern. As not all formulations produce the same exposures, these findings are pertinent to contraceptive choice. We also identify critical gaps in the provision of relevant data on pharmacokinetics and carcinogenicity by drug manufacturers.
This population-based cohort study examined preconception TSH levels and their association with pregnancy outcomes in 184,611 Chinese women planning to conceive. Women were classified into reference (0.48-2.49 mIU/L), upper limit (2.5-4.28 mIU/L), and high TSH (4.29-10 mIU/L) groups. The high normal TSH group showed higher rates of spontaneous abortion, preterm birth, and operative vaginal delivery compared to reference. The high TSH group had higher rates of spontaneous abortion, stillbirth, and preterm births.
Endometriosis is characterized by frequent recurrences of symptoms and lesions even after extirpative surgery. Because medical therapies control but do not cure the disease, long periods of pharmacologic management may be needed until pregnancy desire or, sometimes, physiologic menopause. Hormonal drugs suppress ovulation and menstruation and have similar beneficial effects against pain. However, only estrogen-progestins and progestins have safety/tolerability/cost profiles that allow long-term use. These compounds induce atrophy of eutopic and ectopic endometrium, have antiinflammatory and proapoptotic properties, and can be delivered via different modalities, including oral, transdermal, subcutaneous, intramuscular, vaginal, and intrauterine routes. At least two-thirds of symptomatic women are relieved from pain and achieve appreciable improvements in health-related quality of life. Progesterone resistance may cause nonresponse in the remaining one-third. When using estrogen-progestins continuously, individualized, tailored cycling should be explained to improve compliance. All combinations demonstrated a similar effect on dysmenorrhea, independently from progestin type. Estrogen-progestins with the lowest possible estrogen dose should be chosen to combine optimal lesion suppression and thrombotic risk limitation. Progestins should be suggested in women who do not respond or manifest intolerance to estrogen-progestins and in those with dyspareunia and/or deep lesions. Progestins do not increase significantly the thrombotic risk and generally may be used when estrogens are contraindicated. Estrogen-progestins and progestins reduce the incidence of postoperative endometrioma recurrence and show a protective effect against endometriosis-associated epithelial ovarian cancer risk.
Sleep and Circadian Health · Shift Work and Light Exposure
Goldstein CA et al., 2016·Current Sleep Medicine Reports
Adequate sleep is crucial for general health and wellbeing. Although the neuronal control of the reproductive axis and sleep-generating neurons share an anatomical location, little is known regarding the impact of sleep and circadian disruption on fertility in women. Animal models have established clear circadian control of the pre-ovulatory luteinizing hormone surge. Additionally, disruption of the circadian timing system by exposure to abnormal light-dark cycles or mutations of core clock genes results in diminished reproductive capacity in animals. Abnormalities in menstruation, fertility, and early pregnancy maintenance in female shift workers provide evidence for a role of circadian rhythms in the reproductive health of women. Reproductive hormones may modify sleep, and the relationship is bidirectional such that sleep disruption may alter the profile of reproductive hormone secretion. Therefore, sleep, apart from its circadian timing, may also have relevance in attaining pregnancy. Additionally, infertility is associated with psychological distress which may result in poor quality sleep. The interaction between psychological distress and disturbed sleep in reproduction has garnered minimal attention and may be a crucial factor to consider during the evaluation and treatment of infertility. This work reviews animal models and evidence in women that suggest a role for sleep and circadian rhythms in reproductive health and reveals areas that require future investigation.
Rosenfield RL et al., 2016·Endocrine reviews·
Open Access
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
Schliep KC et al., 2016·Am J Clin Nutr·
Open Access
Clinicians often recommend limiting caffeine intake while attempting to conceive; however, few studies have evaluated the associations between caffeine exposure and menstrual cycle function, and we are aware of no previous studies assessing biological dose via well-timed serum measurements. We assessed the relation between caffeine and its metabolites and reproductive hormones in a healthy premenopausal cohort and evaluated potential effect modification by race. Participants (n = 259) were followed for ≤2 menstrual cycles and provided fasting blood specimens ≤8 times/cycle. Linear mixed models were used to estimate associations between serum caffeine biomarkers and geometric mean reproductive hormones, whereas Poisson regression was used to assess risk of sporadic anovulation. The highest compared with the lowest serum caffeine tertile was associated with lower total testosterone [27.9 ng/dL (95% CI: 26.7, 29.0 ng/dL) compared with 29.1 ng/dL (95% CI: 27.9, 30.3 ng/dL), respectively] and free testosterone [0.178 ng/mL (95% CI: 0.171, 0.185 ng/dL) compared with 0.186 ng/mL (95% CI: 0.179, 0.194 ng/dL), respectively] after adjustment for age, race, percentage of body fat, daily vigorous exercise, perceived stress, depression, dietary factors, and alcohol intake. The highest tertiles compared with the lowest tertiles of caffeine and paraxanthine were also associated with reduced risk of anovulation [adjusted RRs (aRRs): 0.39 (95% CI: 0.18, 0.87) and 0.40 (95% CI: 0.18, 0.87), respectively]. Additional adjustment for self-reported coffee intake did not alter the reproductive hormone findings and only slightly attenuated the results for serum caffeine and paraxanthine and anovulation. Although reductions in the concentrations of total testosterone and free testosterone and decreased risk of anovulation were greatest in Asian women, there was no indication of effect modification by race. Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.
Johnson KA et al., 2016·Pharmacoepidemiol Drug Saf·
Open Access
The purpose of this study is to characterize the patterns of medication intake in healthy, reproductive-age women not using hormonal contraception. Two hundered fifty-nine healthy, premenopausal women (18-44 years of age) enrolled in the BioCycle Study (2005-2007) were followed over two menstrual cycles. Women were excluded if they were currently using oral contraceptives or other chronic medications. Over-the-counter and prescription medication use among participants was evaluated daily throughout the study via a diary assessing type of medication, dosage, units, and frequency. Medications were categorized as allergy, antibiotics, central nervous system (CNS), cold and cough, gastrointestinal, musculoskeletal, and pain medication based on primary active ingredient. Medication use within each category was assessed across standardized 28-day cycles to evaluate differences in use across cycle phases (i.e., early, middle, and late). Medication use was reported by 73% of participants. The most and least frequently used medications, respectively, were pain (69%) and musculoskeletal medications (1%). Pain, CNS, and antibiotic medication use varied significantly across the cycle, with pain and CNS medication more frequently reported during menses and antibiotics more frequently during the luteal phase. Allergy, cold and cough, gastrointestinal, and musculoskeletal medication use did not vary across the cycle. Patterns of medication use among reproductive age women vary across the menstrual cycle for certain types of medications, particularly in pain (e.g., Ibuprofen), antibiotics (e,g, Amoxicillin), and CNS (e.g., Adderall) medications. Future studies involving use of these types of medication in premenopausal women may need to consider the relationship of their use to the menstrual cycle.
Non-sexually active adolescents are currently treated with combined hormonal contraception (CHC) for common experiences (e.g., cramps, acne) and serious problems (e.g., hypothalamic amenorrhea, heavy menstrual flow) for which it is not indicated, is ineffective, and is likely to cause negative long-term reproductive and bone effects. The importance to a woman's health of adolescent reproductive/bone maturation is described. Evidence is also provided to show the association of CHC use by adolescents with subfertility and inadequate bone growth. Ibuprofen is safer and more effective for cramps and heavy flow; cyclic progesterone builds bone in amenorrhea. In summary, a common, unscientific medical "habit" is compromising long-term reproductive and bone health in adolescents.
Vitamin D is associated with markers of ovarian reserve in women of advanced reproductive age and
in vitro
studies suggest that vitamin D may influence anti‐mullerian hormone (AMH). Higher vitamin D levels are also associated with improved IVF outcomes in some studies. However, less is understood regarding associations with ovarian reserve or time to pregnancy among younger women or women without a history of infertility. Our purpose was to assess the relationships between vitamin D and AMH and fecundability among women with proven fecundity.
Secondary analysis of the EAGeR Trial, a multicenter, block‐randomized, double‐blind, placebo‐controlled clinical trial to evaluate the effect of preconception‐initiated daily low dose aspirin on reproductive outcomes in women with a history of pregnancy loss and normal fecundity. Participants were attempting pregnancy, aged 18–40 years, with 1–2 prior pregnancy losses and no history of infertility. We assessed 25‐OH vitamin D and AMH in serum at baseline (not pregnant) among 1185 women. AMH levels were log‐transformed for normality. Linear regression was used to estimate associations between vitamin D and AMH concentrations adjusting for age, body mass index, race, season, physical activity, and number of prior losses. Time to hCG detected pregnancy was assessed using Cox proportional hazard regression models for discrete survival time, accounting for left truncation and right censoring, to estimate fecundability odds ratios (FOR), adjusting for the same factors. A total of 163 women (13.8%) had deficient vitamin D levels (<20 ng/mL). Overall, vitamin D levels were not associated with AMH (percent change −1.6, 95% confidence interval [CI] −5.3%, 2.3% per 10 ng/mL). Vitamin D deficiency was also not associated with AMH (deficient: adjusted geometric mean AMH 2.51, 95% CI 2.20, 2.85 vs. inadequate/sufficient: 2.74, 95% CI 2.60, 2.89). There also were no significant associations observed between overall vitamin D levels or deficiency and fecundability (FOR 1.09, 95% CI 0.84, 1.42 comparing deficient vs. inadequate/sufficient) after adjustment. Vitamin D was not associated with AMH, time to pregnancy, or fecundability among women with proven fecundity. These results suggest that vitamin D is not associated with ovarian reserve or fecundability and that vitamin D supplementation may offer little clinical benefit for improving markers of ovarian reserve and fecundity.
Support or Funding Information
Intramural Research Program, DIPHR, NICHD, NIH
To evaluate if antimüllerian hormone (AMH) is associated with pregnancy loss.
Prospective cohort study within a block-randomized, double-blind, placebo-controlled trial of low-dose aspirin.
Not applicable. PATIENT(S): Women (n = 1,228) were of ages 18-40 years with a history of one to two pregnancy losses and were actively attempting pregnancy without fertility treatment. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Pregnancy loss. RESULT(S): Relative risks (and 95% confidence interval [CIs]) of human chorionic gonadotropin (hCG)-detected and clinical pregnancy loss were assessed with the use of log binomial models with robust variance and inverse probability weights adjusted for age, race, body mass index, income, trial treatment assignment, parity, number of previous losses, and time since most recent loss. AMH levels were defined as: low (<1.00 ng/mL; n = 124), normal (referent; 1.00-3.5 ng/mL; n = 595), and high (>3.5 ng/mL; n = 483). Of the 1,202 women with baseline AMH data, 19 (17.3%) with low AMH experienced a clinical loss, compared with 61 (11.4%) with normal AMH and 50 (11.8%) with high AMH levels. Low or high AMH levels, compared with normal AMH, were not associated with clinical loss. Results for hCG-detected pregnancy loss mirrored those of clinical loss. CONCLUSION(S): AMH values were not associated with hCG-detected or clinical pregnancy loss in unassisted conceptions in women with a history of one to two previous losses. Our data do not support routine AMH testing for prediction of pregnancy loss. Clinical NCT00467363.
Petousis S et al., 2016·J Matern Fetal Neonatal Med·
To compare the expression of progesterone receptors (A + B) and type-B progesterone receptors in the epithelial and stromal cells of fertile and infertile women. Women were divided into two groups, the group of fertile controls (group 1) and the group of infertile women (group 2) and were set on regular ultrasound imaging in order to detect ovulation. An endometrial biopsy was obtained on the seventh or eighth post-ovulatory day. Immunohistochemistry was performed to measure percentage of positive nuclei, intensity of staining and h-score for progesterone receptors (PgR) (A + B) as well as type-B progesterone receptors in epithelial and stromal cells. Secondary outcomes included endometrial tissue dating, the rate of tissues being out-of-phase and endometrial thickness. Endometrial issue was obtained from 15 fertile and 30 infertile women. Expression of PgR (A + B) and PgR type-B was significantly lower in the epithelial cells of infertile women. PgR (A + B) h-score was 220.0 ± 18.5 for fertile versus 147.3 ± 18.0 for infertile women (p = 0.02). PgR type-B h-score in epithelial cells was 166.8 ± 30.7 for fertile versus 90.8 ± 20.6 for infertile (p = 0.04). No significant difference was observed in stromal cells. Expression levels of PgR (A + B) as well as type-B receptors are significantly lower in the epithelial cells of infertile women during implantation window.
Vissenberg R et al., 2016·Eur J Obstet Gynecol Reprod Biol·
Thyroid dysfunction has been described as a possible risk factor for having an abnormal fetal position at birth. In this study we aim to determine the association between thyroid function in early pregnancy and breech presentation at term. We used data from the Amsterdam Born Children and their Development (ABCD) cohort. 3347 pregnant women were included between January 2003 and March 2004 in Amsterdam, the Netherlands. Thyroid function tests were performed between 5 and 37 weeks gestational age (median 12.9 weeks). The main outcome measure was the association between thyroid function in early pregnancy and breech presentation at term. Univariate and multivariate analysis were performed to determine the association between thyroid function and breech presentation. Increased TSH in pregnancy, defined as thyroid stimulating hormone (TSH) >97.5th percentile (>3.53mIU/L), was associated with a higher risk for breech presentation at term (aOR 2.32, CI 1.1-4.8, p=0.02) compared to euthyroidism (TSH between 2.5th and 97.5th percentile). After exclusion of overt hypothyroidism and hyperthyroidism the aOR was 2.34 (CI 1.1-5.0, p=0.03). Trimester specific analysis showed a significant association of increased TSH levels (>3.68mIU/L) in the second trimester with breech presentation (aOR 3.7, CI 1.7-7.8, p=0.001). In the second trimester low free thyroxine (FT4) <2.5th percentile (<6.7pmol/L) was also associated with breech presentation (aOR 2.5, CI 1.0-6.3, p=0.04). Increased TSH and decreased FT4 in the second trimester of pregnancy are associated with an increased risk for breech presentation at term. The association of abnormal thyroid parameters in the first of third trimester is still unclear.
To identify factors associated with cancer treatment-induced amenorrhea and time to return of menses. Population-based cohort study. Not applicable. PATIENT(S): Female cancer survivors who were diagnosed with cancer between the ages of 20 and 35 and were at least 2 years postdiagnosis at the time of recruitment (median = 7 years; interquartile range, 5-11). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Amenorrhea (≥6 months without menses) and resumption of menses. RESULT(S): After excluding women with hysterectomies before cancer diagnosis, 1,043 women were eligible for analysis. Amenorrhea occurred in 31.6% of women. Among women treated with chemotherapy (n = 596), older age at diagnosis (30-35 vs. 20-24 years: adjusted odds ratio [aOR] = 2.37; 95% confidence interval [CI], 1.30, 4.30) and nulligravidity (vs. gravid: aOR = 1.50; 95% CI, 1.02, 2.21) were risk factors for amenorrhea. Among amenorrheic women, menses resumed in most (70.0%), and resumption occurred within 2 years of treatment for 90.0% of women. Survivors of breast cancer were more likely to resume menses at times greater than 1 year compared with lymphoma and pelvic-area cancers. Women diagnosed at older ages, those exposed to chemotherapy, and those exposed to any radiation experienced longer times to return of menses. Women who were older at diagnosis were more likely to have irregular cycles when menses returned. CONCLUSION(S): Treatment-induced amenorrhea is common in cancer survivors, although most women resume menses within 2 years. However, once resumed, older women are more likely to have irregular cycles. Age at diagnosis and pregnancy history affect the risk of amenorrhea.
Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (α-tocopherol, γ-tocopherol, retinol, lutein, lycopene, and β-carotene), ascorbic acid, and reproductive hormone concentrations were measured 5-8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. Serum antioxidant concentrations varied across the menstrual cycle. Retinol and α-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, -0.03 mIU/mL). The ratio of αto γ-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress.
Progesterone support in pregnancy has been in use for over 60 years, having received its start in the 1940s. Its initial use was in patients who had habitual spontaneous abortion caused by luteal phase deficiency. More recently, the administration of progesterone later in pregnancy has been considered to be justified because of an observed decrease in circulating progesterone with the onset of labor, an association of premature labor with decreased progesterone concentrations, and the observation that progesterone has a tocolytic effect. A considerable boost to the use of progestational agents to reduce preterm delivery was received with the publication of two papers which showed a significant reduction in preterm delivery rates with the prophylactic administration of either progesterone or 17-a hydroxyprogesterone caproate. Recently it has been shown, however, that its use is not universal. This may be related to the significant late sequelae that were documented following the in utero exposure of the fetus to the potent steroid diethylstilbestrol (DES) and that this bad experience cast “a long shadow,” In spite of this, the use of progesterone, at least in early pregnancy, is widespread in the various artificial reproductive programs and is growing in its use as an agent to reduce prematurity. Over the years, there has been an extraordinary amount of confusion related to the use of progesterone support in pregnancy. The Food & Drug Administration (FDA) created some of this confusion. In various labeling of progesterone products by the FDA, one of the contraindications to the use of oral progesterone is listed as “known or suspected pregnancy.” And, yet, no such contraindication is identified for the use of progesterone gel. In fact, progesterone gel is indicated for progesterone supplementation or replacement as a part of an assisted reproductive technology (ART) treatment program for infertile women with a progesterone deficiency. To make this even more confusing, oral progesterone, while it was contraindicated in “known or suspected pregnancy,” its official labeling stated that it “should be used during pregnancy only if indicated (see contraindications).” Also, up until very recently, there was a dire “warning” contained in the labeling for USP progesterone injection in sesame seed oil regarding an increased possibility of birth defects. An analysis of the fetal safety of isomolecular progesterone (Pregn-4-ene-3,20-dione) administration during the course of 1,310 pregnancies over a 35-year period of time (1979-2014) was undertaken to address this confusion.
Do the basal body temperature (BBT) shift and the cervical mucus markers for the beginning of the post-ovulatory infertile phase (POIP) of a menstrual cycle agree with the corresponding urinary pregnanediol glucuronide (PdG) threshold value? Perfect agreement between the cervical mucus markers and BBT shift and the hormonal definition of the start of post-ovulatory infertility occurred for only 7-17% of the cycles. The PdG threshold of 7.0 µmol/24 h is an objective and accurate marker for the beginning of the POIP. The rise in serum progesterone also produces the BBT shift and changes in cervical mucus which determine the mucus peak. Serum progesterone and urinary PdG are closely correlated when variations in urine volume are taken into account. STUDY DESIGN, SIZE, Individual menstrual cycle profiles of urinary PdG excretion rates for 91 fertile cycles from normally cycling women were analysed to identify the day of the beginning of the POIP. These days were compared with those determined by the day of the BBT shift +2 days, the day of the mucus peak +4 days and the later of these two indicators. The study lasted 3 years. PARTICIPANTS/MATERIALS, SETTING, A total of 62 women with normal menstrual cycles were recruited from three centres: Palmerston North, New Zealand; Sydney, Australia and Santiago, Chile. The cycles were displayed individually in a proprietary database program which recorded the PdG excretion rates, the BBT shift day and the cervical mucus peak day. A group of 15 women from a separate Chilean study had PdG urinary data measured as well as their day of ovulation determined by ultrasound. MAIN The BBT and cervical mucus markers differed significantly in their identification of the beginning of the POIP when compared with the PdG excretion rate of 7.0 µmol/24 h. The observation that the BBT shift day and the mucus peak day could be identified even though the PdG excretion rates were still at baseline levels in some cycles could lead to an unexpected pregnancy for women using these natural family planning (NFP) indicators. LIMITATIONS, The study consisted only of fertile cycles from women with regular cycles of 20-40 days duration. All the women were intending to avoid a pregnancy during the study, thus the limits of the fertile window were not tested. The NFP signals occurring earlier than the PdG threshold day could lead to an unexpected pregnancy. The signals occurring on the same day or later than the PdG threshold would not lead to unexpected pregnancies, but would require extra abstinence that could lead to non-compliance with the NFP method. A possible improvement in reliability of NFP methods is suggested. This study (project #90905) was funded by the NDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP). D.G.C. currently works for a diagnostic development company, Science Haven Ltd. The other authors have nothing to declare.
Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).
Brown SA et al., 2015·Journal of diabetes science and technology·
Open Access
Factors influencing glycemic variability in type 1 diabetes (T1D) may play a significant role in the refinement of closed loop insulin administration. Phase of menstrual cycle is one such factor that has been inadequately investigated. We propose that unique individual patterns can be constructed and used as parameters of closed loop systems. Women with T1D on continuous subcutaneous insulin infusion and continuous glucose monitoring were studied for 3 consecutive menstrual cycles. Ovulation prediction kits and labs were used to confirm phase of menstrual cycle. Glycemic risks were assessed using the low- and high blood glucose indices (LBGI and HBGI). Insulin sensitivity (SI) was estimated using a Kalman filtering method from meal and insulin data. Overall change significance for glycemic risks was assessed by repeated measures ANOVA, with specific phases emphasized using contrasts. Ovulation was confirmed in 33/36 cycles studied in 12 subjects (age = 33.1 ± 7.0 years, BMI = 25.7 ± 2.9 kg/m(2), A1c = 6.8 ± 0.7%). Risk for hyperglycemia changed significantly during the cycle (P = .023), with HBGI increasing until early luteal phase and returning to initial levels thereafter. LBGI was steady in the follicular phase, decreasing thereafter but not significantly. SI was depressed during the luteal phase when compared to the early follicular phase (P ≤ .05). Total daily insulin, carbohydrates, or calories did not show any significant fluctuations. Women with T1D have glycemic variability changes that are specific to the individual and are linked to phase of cycle. An increased risk of hyperglycemia was observed during periovulation and early luteal phases compared to the early follicular phase; these changes appear to be associated with decreased insulin sensitivity during the luteal phase.
To what extent does oral contraception (OC) impair ovarian reserve parameters in women who seek fertility assessment and counselling to get advice on whether their remaining reproductive lifespan is reduced? Ovarian reserve parameters defined by anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume were found to be significantly decreased by 19% (95% CI 9.1-29.3%), 18% (95% CI 11.2-24.8%) and 50% (95% CI 45.1-53.7%) among OC users compared with non-users. AMH and AFC have proved to be reliable predictors of ovarian ageing. In women, AMH declines with age and data suggest a relationship with remaining reproductive lifespan and age at menopause. OC may alter parameters related to ovarian reserve assessment but the extent of the reduction is uncertain. STUDY DESIGN, SIZE, A cross-sectional study of 887 women aged 19-46 attending the Fertility Assessment and Counselling Clinic (FACC) from 2011 to 2014 comparing ovarian reserve parameters in OC users with non-OC users. PARTICIPANTS/MATERIALS, SETTING, The FAC Clinic was initiated to provide individual fertility assessment and counselling. All women were examined on a random cycle day by a fertility specialist. Consultation included; transvaginal ultrasound (AFC, ovarian volume, pathology), a full reproductive history and AMH measurement. Women were grouped into non-users and users of OC (all combinations of estrogen-progestin products and the contraceptive vaginal ring). Non-users included women with an intrauterine device (IUD) or no hormonal contraception. MAIN Of the 887 women, 244 (27.5%) used OC. In a linear regression analyses adjusted for age, ovarian volume was 50% lower (95% CI 45.1-53.7%), AMH was 19% lower (95% CI 9.1-29.3%), and AFC was 18% lower (95% CI 11.2-24.8%) in OC users compared with non-users. Comparison of AMH at values of <10 pmol/l OC was found to have a significant negative influence on AMH (OR 1.6, 95% CI 1.1; 2.4, P = 0.03). Furthermore, we found a significant decrease in antral follicles sized 5-7 mm (P < 0.001) and antral follicles sized 8-10 mm (P < 0.001) but an increase in antral follicles sized 2-4 mm (P = 0.008) among OC users. The two groups (OC users versus non-users) were comparable regarding age, BMI, smoking and maternal age at menopause. LIMITATIONS, The study population comprised women attending the FAC Clinic. Recruitment was based on self-referral, which could imply a potential selection bias. Ovarian reserve was examined at a random cycle day. However, both AMH and AFC can be assessed independently of the menstrual cycle. The accuracy in predicting residual reproductive lifespan is still needed in both users and non-users of OC. OC has a major impact on the ovarian volume, and a moderate impact on AFC and AMH with a shift towards the smaller sized antral follicle subclasses. The most evident reduction occurs in the antral follicles of 5-7 and 8-10 mm with the highest number of AMH secreting granulosa cells. It is essential to be aware of the impact of OC use on ovarian reserve parameters when guiding OC users on their fertility status and reproductive lifespan. The FAC Clinic was established in 2011 as part of the ReproHigh collaboration. This study received funding through the Capital Region Research Fund and by EU-regional funding. There are no competing interests. The biobank connected to FAC Clinic is approved by the Scientific Ethical Committee (H-1-2011-081).
Ovulatory menstrual cycles are essential for women's fertility and needed to prevent bone loss. There is a medical/cultural expectation that clinically normal menstrual cycles are inevitably ovulatory. Currently within the general population it is unknown the proportion of regular, normal-length menstrual cycles that are ovulatory. Thus, the objective of this study was to determine the population point prevalence of ovulation in premenopausal, normally menstruating women. The null hypothesis was that such cycles are ovulatory. This is a single-cycle, cross-sectional, population-based study-a sub-study of the HUNT3 health study in the semi-rural county (Nord Trøndelag) in mid-Norway. Participants included >3,700 spontaneously (no hormonal contraception) menstruating women, primarily Caucasian, ages 20-49.9 from that county. Participation rate was 51.9%. All reported the date previous flow started. A single, random serum progesterone level was considered ovulatory if ≥9.54 nmol/L on cycle days 14 to -3 days before usual cycle length (CL). Ovulation was assessed in 3,168 women mean age 41.7 (interquartile range, [IQR] 36.8 to 45.5), cycle length 28 days (d) (IQR 28 to 28) and body mass index (BMI) 26.3 kg/m2 (95% CI 26.1 to 26.4). Parity was 95.6%, 30% smoked, 61.3% exercised regularly and 18% were obese. 1,545 women with a serum progesterone level on cycle days 14 to -3 were presumed to be in the luteal phase. Of these, 63.3% of women had an ovulatory cycle (n = 978) and 37% (n = 567) were anovulatory. Women with/ without ovulation did not differ in age, BMI, cycle day, menarche age, cigarette use, physical activity, % obesity or self-reported health. There were minimal differences in parity (96.7% vs. 94.5%, P = 0.04) and major differences in progesterone level (24.5 vs. 3.8 nmol/L, P = 0.001). Anovulation in a random population occurs in over a third of clinically normal menstrual cycles.
The aim of the study was to evaluate the effect of Trigonella foenum-graecum (fenugreek) seed extract on sex hormones and sexual function in healthy menstruating women who reported low sexual drive. This short term, single site, double blind, randomised, placebo-controlled study was conducted on 80 women, aged 20 to 49 years. Participants were randomised to either an oral dose of a standardised T. foenum-graecum seed extract (libifem) at a dose of 600 mg/day or placebo over two menstrual cycles. Dehydroepiandrosterone sulfate, progesterone, androstenedione, total and free testosterone, estradiol (E2), luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and cholesterol were measured at baseline and 8 weeks. The individual aspects of sexual function were measured using the Derogatis interview for sexual functioning and female sexual function index self-administered questionnaires. Stress, fatigue and quality of the relationship with partner were also measured using the PSS (Perceived Stress Scale), MFI-20 (Multidimensional Fatigue Inventory) and DAS (Dyadic Adjustment Scale) quality of life measures, respectively. There was a significant increase in free testosterone and E2 in the active group as well as sexual desire and arousal compared with the placebo group. The results indicate that this extract of T. foenum-graecum may be a useful treatment for increasing sexual arousal and desire in women.
Buckley SJ, 2015·The Journal of perinatal education·
Open Access
This report synthesizes evidence about innate hormonally mediated physiologic processes in women and fetuses/newborns during childbearing, and possible impacts of common maternity care practices and interventions on these processes, focusing on four hormone systems that are consequential for childbearing. Core hormonal physiology principles reveal profound interconnections between mothers and babies, among hormone systems, and from pregnancy through to the postpartum and newborn periods. Overall, consistent and coherent evidence from physiologic understandings and human and animal studies finds that the innate hormonal physiology of childbearing has significant benefits for mothers and babies. Such hormonally-mediated benefits may extend into the future through optimization of breastfeeding and maternal-infant attachment. A growing body of research finds that common maternity care interventions may disturb hormonal processes, reduce their benefits, and create new challenges. Developmental and epigenetic effects are biologically plausible but poorly studied. The perspective of hormonal physiology adds new considerations for benefit-harm assessments in maternity care, and suggests new research priorities, including consistently measuring crucial hormonally mediated outcomes that are frequently overlooked. Current understanding suggests that safely avoiding unneeded maternity care interventions would be wise, as supported by the Precautionary Principle. Promoting, supporting, and protecting physiologic childbearing, as far as safely possible in each situation, is a low-technology health and wellness approach to the care of childbearing women and their fetuses/newborns that is applicable in almost all maternity care settings.
Male Endocrine and Genetic Factors · Male Hormonal Axis
Sumigama S et al., 2015·Biology of reproduction·
Open Access
During transit through the female reproductive tract, mammalian spermatozoa are exposed to increasing concentrations of progesterone (P4) released by the cumulus oophorus. P4 triggers massive calcium influx into human sperm through activation of the sperm-specific calcium channel CatSper. These properties of human spermatozoa are thought to be unique since CatSper is not progesterone sensitive in rodent sperm. Here, by performing patch clamp recording from spermatozoa from rhesus macaque for the first time, we report that they express P4-sensitive CatSper channel identically to human sperm and react to P4 by inducing responsiveness to zona pellucida, unlike human sperm, which respond directly to P4. We have also determined the physiologic levels of P4 capable of inducing capacitation-associated changes in macaque sperm. Progesterone (1 μM) induced up to a 3-fold increase in the percentage of sperm undergoing the zona pellucida-induced acrosome reaction with the lowest threshold as low as 10 nM of P4. Submicromolar levels of P4 induced a dose-dependent increase in curvilinear velocity and lateral head displacement, while sperm protein tyrosine phosphorylation was not altered. Macaque spermatozoa exposed to 10 μM of P4 developed fully hyperactivated motility. Similar to human sperm, on approaching cumulus mass and binding to zona pellucida, macaque spermatozoa display hyperactivation and undergo an acrosome reaction that coincides with the rise in the sperm intracellular calcium. Taken together, these data indicate that P4 accelerates the completion of capacitation and provides evidence of spermatozoa "priming" as they move into a gradient of progesterone in search for the oocyte.
Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women? Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women. Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation. STUDY DESIGN, SIZE, Duration: We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007. PARTICIPANTS/MATERIALS, SETTING, Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle. Main Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03). LIMITATIONS, Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential. This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare.
Infertility remains a common and often unresolved condition afflicting certain couples. Numerous animal studies have demonstrated that alterations in the light-dark cycle can affect reproduction as mediated by the pineal gland and its hormone, melatonin. To examine whether a similar disruption could affect human fertility, a pilot study was conducted with infertile women enrolled in a Natural Family Planning program.
Leiva R et al., 2014·J Am Board Fam Med·
Open Access
Difficult clinical signs such as confusing cervical mucus or erratic basal body temperature can make the use of fertility awareness methods (FAMs) difficult in some cases. The goal of this study was to assess the feasibility of using a cheap urinary luteinizing hormone (LH)-surge identification kit as an adjunct to identify the infertile phase after ovulation when facing these scenarios. The study used a block-allocation, crossover, 2-arm methodology (LH kit/FAM vs FAM only). Comparison of the 2 arms was done with regard to the accuracy of identification (yes/no) of the luteal phase in each cycle as confirmed by serum progesterone concentrations. We recruited 23 Canadian women currently using FAM, aged 18 to 48 years, who have had menstrual cycles 25 to 35 days long for the past 3 months and perceive themselves to have difficulty with identifying the infertile phase after ovulation. LH kits identified 100% of the luteal phases, whereas FAM indentified 87% (statistically significant). In those identified cycles, LH kits provided a mean of 10.3 days of infertility, and FAM only provided 10 days of infertility (not statistically significant). Among this population, LH kits may offer an adjunct for women who may wish to have an additional double-check. However, there are still clinical circumstances when even an LH kit does not provide confirmation. More research in this area is encouraged.
To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function. The BioCycle Study (2005-2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake. High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, -10.6 to -2.5) and luteal phase progesterone (-22.1%; -36.2 to -4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4). High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women.
Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo. Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change). ClinicalTrials.gov NCT00152438.
Algars M et al., 2014·Journal of psychosomatic research
The relation between eating disorders and menstrual function has been widely studied, but it is unknown whether the behavior of binge eating itself is related to menstrual dysfunction. The 11,503 women included in this study were from the Swedish Twin study of Adults: Genes and Environment. The associations between menstrual dysfunction and binge eating were analyzed using logistic regression or multiple linear regression models with generalized estimation equations. Women who reported lifetime binge eating were more likely to report either amenorrhea or oligomenorrhea than women who reported no binge eating. These results persisted when controlling for compensatory behaviors including self-induced vomiting, laxative use, and diuretic use. No differences between women with and without a history of binge eating were observed for age at menarche. Even when controlling for the effect of compensatory behaviors, the behavior of binge eating is associated with menstrual dysfunction. Metabolic and endocrinological factors could underlie this association. Careful evaluation of menstrual status is warranted for women with all eating disorders, not just anorexia nervosa.
Filiberto AC et al., 2013·Fertil Steril·
Open Access
To assess the association of total isoflavone intake with ovulatory function, including sporadic anovulation in healthy premenopausal women.
Prospective cohort study.
University. PATIENT(S): Participants included 259 healthy regularly menstruating women aged 18-44 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of E2, free E2, P, LH, FSH, and SHBG and sporadic anovulation in healthy premenopausal women. RESULT(S): Isoflavone intake was not associated with E2, free E2, P, LH, and FSH concentrations. Consumption in the highest quartile (Q4: 1.6-78.8 mg/d) was significantly associated with greater SHBG concentrations (β = 0.09; 95% confidence interval [CI] 0.02-0.16), compared with the first quartile (Q1: 0.0-0.3 mg/d). CONCLUSION(S): Isoflavone intake was not associated with sporadic anovulation (Q4 vs. Q1: odds ratio 0.87, 95% CI 0.32-1.66). Dietary isoflavone intake among young premenopausal women was not related to sex hormone concentrations or anovulation, but was associated with minimally increased SHBG concentrations. These results suggest potential endocrine effects with no subsequent effects on ovulation, easing concerns regarding their impacts on fertility.
Subclinical ovulatory disturbances (anovulation or short luteal phases within normal-length menstrual cycles) indicate lower progesterone-to-estrogen levels. Given that progesterone plays a bone formation role, subclinical ovulatory disturbances may be associated with bone loss or less than expected bone gain. Our purpose was to perform a meta-analysis of prospective studies in healthy premenopausal women to determine the overall relationship of subclinical ovulatory disturbances to change in bone mineral density. Two reviewers independently identified from serial literature searches 6 studies meeting inclusion criteria: a 2-year study in 114 young adult women, 2006-2009, Vancouver, Canada; a 2-year study in 189 premenopausal women, 2000-2005, Toronto, Canada; a single-cycle study in 14 young women, 1996-1997, Melbourne, Australia; an 18-month study in 53 women, 1990-1995, Santa Clara, California; a 4-year study in 27 women, 1988-1995, Vancouver, Canada; and a 1-year study in 66 women, 1985-1988, Vancouver, Canada. This meta-analysis included a combined sample size of 473 observations in 436 premenopausal women studied over 1-4 years and aged 14-47 years. The percentage of women with ovulatory disturbances varied significantly from 13% to 82%. Women with more frequent ovulatory disturbances had more negative percentage changes in spine bone mineral density (weighted mean difference = -0.86; P = 0.040) for random-effects analysis. There was significant heterogeneity among these 6 studies (I(2) = 80%). In summary, these data show that regularly menstruating women with more frequent ovulatory disturbances experience more negative changes in bone (approximately -0.9% per year). These cycles with silent estrogen/progesterone imbalance may be clinically important.
What are the characteristics of, and how variable are, individual normal menstrual cycle profiles of excretion rates for the urinary metabolites oestrone glucuronide (E1G) and pregnanediol glucuronide (PdG)? There is a continuum of menstrual cycle profiles that differ from standard textbook profiles but which can be understood simply in terms of growth, atresia and ovulation of ovarian follicles. Point-of-care assays with the Ovarian Monitor pre-coated assay tubes, using urine samples diluted to a constant volume per unit time, give laboratory accurate clinical data for individual menstrual cycles. Lay operators can perform the point-of-care assay system at home to achieve reliable and reproducible results, which can be used for natural family planning. STUDY DESIGN, SIZE, This prospective study involved 62 women, with normal menstrual cycles, recruited from three centres: Palmerston North, New Zealand, Sydney, Australia and Santiago, Chile. The study lasted 3 years. PARTICIPANTS/MATERIALS, SETTING, Women collected daily urine samples and determined their E1G and PdG rates with a pre-coated enzyme assay system known as the Ovarian Monitor. For two cycles, the assays were repeated in a study centre and the results were averaged to give 113 individual menstrual cycles for analysis. The cycles were displayed individually in a proprietary database program. MAIN The individual normal hormonal profiles were more complex than the classic composite curves for 40% of the cycles. Of 113 ostensibly normal cycles, only 91 were potentially fertile and 22 had some luteal phase defect. The oestrone glucuronide and PdG excretion rates were reliable and informative in the non-invasive elucidation of ovulation and ovarian function for both simple and complex profiles. Daily monitoring revealed the variability of normal menstrual cycle profiles. The LH peaks were variable and ambiguous markers for ovulation. LIMITATIONS, The study consisted of cycles only from women with regular cycles of 20-40 days duration. All the women were intending to avoid a pregnancy during the study thus the limits of the fertile window were not tested. The principles established in this study should apply to cycles of any length. All peaks in oestrone glucuronide excretion should be tested by concurrent measurements of PdG, which gives a positive indication of the fate of the follicle it represents. The Ovarian Monitor provides a useful addition for practitioners of natural family planning. STUDY FUNDING/COMPETING INTEREST(S): Financial support for this study was obtained from the UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction (HRP). D.G.C. is currently employed by and holds stock in Manawatu Diagnostics Ltd, a company in the development phase of a potentially competing product. The remaining authors have nothing to declare.
Numerous epidemiologic studies have demonstrated that premenstrual disorders (PMDs) begin during the teenage years. At least 20 % of adolescents experience moderate-to-severe premenstrual symptoms associated with functional impairment. Premenstrual syndrome (PMS) consists of physical and/or psychological premenstrual symptoms that interfere with functioning. Symptoms are triggered by ovulation and resolve within the first few days of menses. The prevalence of premenstrual dysphoric disorder (PMDD), a severe form of PMS accompanied by affective symptoms, is likely equal to or higher than in adults. The diagnosis of a PMD requires a medical and psychological history and physical examination but it is the daily prospective charting of bothersome symptoms for two menstrual cycles that will clearly determine if the symptoms are related to a PMD or to another underlying medical or psychiatric diagnosis. The number and type of symptoms are less important than the timing. Randomized controlled trials of pharmacologic treatments in teens with moderate-to-severe PMS and PMDD have yet to be performed. However, clinical experience suggests that treatments that are effective for adults can be used in adolescents. PMS can be ameliorated by education about the nature of the disorder, improving calcium intake, performing exercise and reducing stress, but to treat severe PMS or PMDD pharmacologic therapy is usually required. Eliminating ovulation with certain hormonal contraceptive formulations or gonadotropin-releasing hormone agonists will be discussed. Serotonergic agonists are a first-line therapy for adults, and some serotonin reuptake inhibitors such as fluoxetine and escitalopram can be administered safely to teens.
Progesterone with its anti-seizure effect plays a role in the pathophysiology of catamenial epilepsy which affects 31-60% of epileptic women. In this study, an attempt to treat women suffering from catamenial epilepsy with progesterone, as an adjuvant drug, was made. The treatment was given to 36 women aged 20-40 years (mean age: 30.75±6.05) with seizures in the entire second half of the menstrual cycle, who were found to have low serum levels of progesterone on days 22, 27, 28 of the cycle in comparison with a control group of healthy women. The patients were administered progesterone in a daily dose of 50 mg on days 16-25 of each cycle. The serum levels of antiepileptic drugs were assayed. The period of progesterone therapy ranged from 3 to 45 months (17.7 on average). Three patients were free of secondary generalized seizures, and one--of simple partial seizures. A decline in the frequency of primary and secondary generalized seizures by 20-96% (55.9% on average) was accomplished in 18 patients (primary generalized by 20-96%--54.7% on average, and secondarily generalized by 38-85%--59% on average). A decline in the frequency of complex partial seizures by 38-87% (63.1% on average) was achieved in 15 women. In 1 patient, the frequency of myoclonic seizures decreased by 46%. There was no improvement in 5 women (3 patients with generalized, 1 with complex partial and 1 with simple partial seizures). An exacerbation of seizure frequency occurred in 5 patients. Adverse effects were not found in any of the subjects. The average concentrations of antiepileptic drugs during hormonal therapy were in the therapeutic range. Progesterone combined with antiepileptic therapy was well tolerated and resulted in a significant reduction of seizure frequency in majority of patients with catamenial epilepsy.
Although a significant impact of cycle phase on olfactory thresholds has been shown in females, limited data exist regarding discrimination and identification. Therefore, we investigated a broader range of olfactory performance and analyzed the impact of cycle phase and oral contraception. We measured 80 healthy Caucasians, including 20 females taking oral contraceptives and 40 females without oral contraception who were further divided into follicular and luteal phase. Olfactory performance of all participants was assessed twice using the "Sniffin' Sticks" battery and intensity and pleasantness ratings of n-butanol were collected. Data analysis revealed that females outperformed males in odor discrimination and odor identification. In the luteal phase, higher thresholds and higher intensity ratings for n-butanol emerged. Duration of oral contraception correlated positively with olfactory performance pointing to better performance with longer intake. Hence, our data show that odor performance is affected by menstrual cycle phase and duration of oral contraception intake and thus can be modulated by hormonal changes.
Thyroid hormones and progesterone both influence core temperature, metabolism and are crucial during pregnancy. Our objective was to discover whether progesterone therapy caused changes in thyroid physiology compared with placebo.
Post hoc analysis from a randomized (1:1) placebo-controlled 12-week trial of oral micronized progesterone (Progesterone, 300 mg/d at bedtime) for hot flushes (vasomotor symptoms, VMS) conducted in an academic medical centre. Postmenopausal euthyroid, healthy (without cardiovascular diseases or risks) women, 1-11 years since last flow on no thyroid or ovarian hormone therapy with VMS participated. Primary outcomes were final and 12-week changes in TSH, FreeT3 and FreeT4 on progesterone vs placebo. Women with thyroid data (69 of 133 in original trial) were randomized to progesterone (n = 39) or placebo (n = 30)-baseline thyroid values were normal. There were no VMS-thyroid interactions-VMS Score (number × intensity) did not correlate with TSH, FreeT3 or FreeT4 (Spearman's rank correlations: -0.03 to -0.19, respectively; all P > 0.15). At 12 weeks on progesterone, TSH levels tended to be lower (1.7 mU) than on placebo (2.2), P = 0.06; FreeT4 levels were higher (16.4 pmol/l) than on placebo (15.3), P = 0.02. FreeT3 was unchanged throughout. Analysis of covariance showed a significant increase in FreeT4 on progesterone (+2.5 pmol/l; 1.9-3.0) vs on placebo (+1.7; 1.1-2.4) with 95% CI of difference = 0.8 pmol/l [0.0, 1.6], P = 0.04. Progesterone caused a significant FreeT4 increase that was discovered during this randomized controlled VMS trial. The clinical importance of this increased FreeT4 level remains to be documented. Registered at ClinialTrials.gov#NCT00152438.
To present a series of cases demonstrating successful reversal of mifepristone effects in women who chose to reverse the medical abortion process. Four of 6 women who took mifepristone were able to carry their pregnancies to term after receiving intramuscular progesterone 200 mg. Mifepristone has been available in the US since 2000. By 2008, approximately 25% of abortions prior to 9 weeks were accomplished with mifepristone. Some women who take mifepristone wish to reverse the medical abortion process. Progesterone competes with mifepristone for the progesterone receptor and may reverse the effects of mifepristone. A PubMed literature search from 1996 to May 2012 did not reveal any trials or case studies evaluating the efficacy of progesterone use to reverse the effects of mifepristone. Health care professionals should be aware of the possible use of progesterone to reverse mifepristone in women who have begun the medical abortion process by taking mifepristone and then change their minds.
Obesity and high body mass index (BMI) are known to be risks for anovulation and infertility. Little is known about how BMI levels affect parameters of the menstrual cycle. The purpose of this study was to determine the influence of BMI on parameters of the menstrual cycle and the likelihood for ovulation. The participants in this study were 244 women between the ages of twenty and fifty-four (mean thirty years) who charted from one to thirty-six menstrual cycles (mean seven cycles) for a total of 2,035 cycles. Urinary luteinizing hormone (LH) threshold tests were used to estimate the day of ovulation and the lengths of the follicular and luteal phases. The 244 participants were classified as normal weight with a BMI of 18.5-24.9 kg/m2 (N = 141), overweight with a BMI of 25-29.9 kg/m2 (N = 67), and obese with a BMI of 30 kg/m2 or greater (N = 36). One-way ANOVA indicated that there was a significant difference between groups in length of the luteal phase (F = 4.62, p < 0.01) and length of menses (F = 3.03, p < 0.05). Odds ratio indicated that the combined obese and overweight group was 34 percent less likely to have a positive detected urinary LH surge. We concluded that obesity might contribute to infertility by shortening the luteal phase and decreasing the probability of ovulatory menstrual cycles.
Collaborative Group on Hormonal Factors in Breast Cancer, 2012·Lancet Oncol·
Open Access
Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. Findings: Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons). Interpretation: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. Cancer Research UK.
Menstruation has many of the features of an inflammatory process. The complexity and sequence of inflammatory-type events leading to the final tissue breakdown and bleeding are slowly being unravelled. Progesterone has anti-inflammatory properties, and its rapidly declining levels (along with those of estrogen) in the late secretory phase of each non-conception cycle, initiates a sequence of interdependent events of an inflammatory nature involving local inter-cellular interactions within the endometrium. Intracellular responses to loss of progesterone (in decidualized stromal, vascular and epithelial cells) lead to decreased prostaglandin metabolism and loss of protection from reactive oxygen species (ROS). Increased ROS results in release of NFκB from suppression with activation of target gene transcription and increased synthesis of pro-inflammatory prostaglandins, cytokines, chemokines and matrix metalloproteinases (MMP). The resultant leukocyte recruitment, with changing phenotypes and activation, provide further degradative enzymes and MMP activators, which together with a hypoxic environment induced by prostaglandin actions, lead to the tissue breakdown and bleeding characteristic of menstruation. In parallel, at sites where shedding is complete, microenvironmentally-induced changes in phenotypes of neutrophils and macrophages from proto anti-inflammatory, in addition to induction of growth factors, contribute to the very rapid re-epithelialization and restoration of tissue integrity.
A controlled trial recently showed that oral micronized progesterone (Progesterone, 300 mg at h.s. daily) was effective for vasomotor symptoms (VMS) in 133 healthy early postmenopausal women. Here, we present subgroup data in women with severe VMS (50 VMS of moderate-severe intensity/wk) and also 1-mo withdrawal study outcomes. Women with severe VMS (n = 46) resembled the full cohort but experienced 10 VMS/d of 3 of 4 intensity. On therapy, the progesterone VMS number (#) decreased significantly more than placebo # to 5.5/day (d) versus 8/d (ANCOVA -2.0 95% CI: -3.5 to -0.4). Just after trial mid-point, a withdrawal substudy (D/C) was added--56 women were invited and 34 (61%) took part (progesterone 17; placebo 17). Those in the D/C cohort resembled the whole cohort. On stopping, VMS gradually increased--at D/C week 4, on progesterone, VMS daily # reached 78% and significantly less than baseline (-3.0 to -0.8) but placebo VMS # did not differ from run-in. In summary, progesterone is effective for severe VMS and does not cause a rebound increase in VMS when stopped. That progesterone may be used alone for severe VMS and unlike estrogen does not appear to cause a withdrawal rebound increases VMS treatment options.
The aim of this study was to compare oral micronized progesterone (progesterone) with placebo as therapy for postmenopausal hot flushes and night sweats (vasomotor symptoms [VMS]). Healthy volunteer community women 1 to 10 years since final menstruation were recruited for a randomized double-blind placebo-controlled trial of progesterone (300 mg daily at bedtime) between 2003 and 2009 and were screened for clinical, physical, or laboratory evidence of cardiovascular risks (nonsmoking, moderate body mass index [<35 kg/m], normal lipids, electrocardiogram, nondiabetic). Women recorded daily frequency and severity (1-4) of VMS in the Daily Menopause Diary during run-in (4 wk) and intervention (12 wk). Average daily VMS score (day frequency × day severity + night frequency × night severity) during final 28 therapy days was the primary outcome, analyzed by therapy, with run-in score as covariate. Randomized participants were 133 healthy community women with VMS, ages 44 to 62 years, with a mean (SD) VMS score of 17.0 (10.4) at run-in (VMS frequency 6.8 [3.2] episodes/d). Women were randomized to progesterone (n = 75) or placebo (n = 58); analysis included all with VMS data at run-in and on therapy (n = 68 and 46, respectively). The VMS scores of women taking progesterone were better than placebo (mean adjusted difference, -4.3 (95% CI, -6.6 to -1.9), with mean reductions of 10.0 (95% CI, -12.0 to -8.1) and 4.4 (95% CI, -6.6 to -2.2) in the progesterone and placebo arms, respectively. Discontinuation with adverse events was 9% (progesterone, 8; placebo, 4), with no serious cases. Oral micronized progesterone is effective for treatment of hot flushes and night sweats in healthy women early in postmenopause.
Menstrual bleeding patterns are considered relevant indicators of reproductive health, though few studies have evaluated patterns among regularly menstruating premenopausal women. The authors evaluated self-reported bleeding patterns, incidence of spotting, and associations with reproductive hormones among 201 women in the BioCycle Study (2005-2007) with 2 consecutive cycles. Bleeding patterns were assessed by using daily questionnaires and pictograms. Marginal structural models were used to evaluate associations between endogenous hormone concentrations and subsequent total reported blood loss and bleeding length by weighted linear mixed-effects models and weighted parametric survival analysis models. Women bled for a median of 5 days (standard deviation: 1.5) during menstruation, with heavier bleeding during the first 3 days. Only 4.8% of women experienced midcycle bleeding. Increased levels of follicle-stimulating hormone (β = 0.20, 95% confidence interval: 0.13, 0.27) and progesterone (β = 0.06, 95% confidence interval: 0.03, 0.09) throughout the cycle were associated with heavier menstrual bleeding, and higher follicle-stimulating hormone levels were associated with longer menses. Bleeding duration and volume were reduced after anovulatory compared with ovulatory cycles (geometric mean blood loss: 29.6 vs. 47.2 mL; P = 0.07). Study findings suggest that detailed characterizations of bleeding patterns may provide more insight than previously thought as noninvasive markers for endocrine status in a given cycle.
Battaglia C et al., 2012·The Journal of Sexual Medicine
Oral contraceptives (OCs) induce mood and libido changes. The aim of this study was to evaluate in young, eumenorrheic, healthy women the sexual behavior and the genital vascular effects of an OC containing 30 µg ethinylestradiol (EE) and 3 mg drospirenone (DRSP). The main outcome measures are McCoy Female Sexuality Questionnaire (MFSQ), the labia minora thickness and vaginal introitus area, the pulsatility index (PI) of clitoral and labia minora arteries, and hormonal and biochemical assays. Twenty-two adult, eumenorrheic, healthy women were administered the two-factor Italian MFSQ. The labia minora thickness was studied by two-dimensional ultrasonographic, and the clitoral and labia minora arteries were evaluated by color Doppler; three-dimensional static volumes of the vulvar area were calculated. Hormonal (estradiol, androstenedione, and testosterone) and biohumoral (sex hormone binding globulin) parameters were assayed. Subjects were studied in baseline conditions and after 3 months of therapy with an OC (Yasmin®, Bayer-Schering Italia, Milan, Italy; −30 µg EE + 3 mg DRSP). After 3-month treatment, the labia minora thickness and the vaginal introitus area significantly decreased in comparison with the baseline values, whereas the PI of the dorsal clitoral artery and the posterior labial artery significantly increased. The OC use induced a significant decrease of the two-factor Italian MFSQ score, a reduction of the number of intercourse/week, and a reduction of the frequency of orgasm during intercourse. The item 18 (pain during intercourse) worsened after OC. The treatment with Yasmin® (Bayer-Schering Italia) is associated with increased pain during intercourse, with decreased libido and spontaneous arousability, and with diminished frequency of sexual intercourse and orgasm.
Verrotti A et al., 2012·International journal of women's health
Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition. Thus, changes in serum estradiol/progesterone ratio throughout a normal reproductive cycle bring about an increased or decreased risk of seizure occurrence. To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed. The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Oner G et al., 2011·Eur J Obstet Gynecol Reprod Biol·
To evaluate the clinical, endocrine and metabolic effects of metformin and N-acetyl-cysteine (NAC) in patients with polycystic ovary syndrome (PCOS). In this prospective trial, 100 women with PCOS were randomly divided to receive metformin (500 mg p.o. three times daily) or NAC (600 mg p.o. three times daily) for 24 weeks. Hyperandrogenism, lipid profiles, hirsutism scores, menstrual irregularity, insulin sensitivity and tumour necrosis factor-α (TNF-α) levels were measured at baseline and after the treatment period. Both treatments resulted in a significant decrease in body mass index, hirsutism score, fasting insulin, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-α levels increased following treatment for both groups, the difference from baseline was not significant. Metformin and NAC appear to have comparable effects on hyperandrogenism, hyperinsulinaemia and menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-α.
Murcia-Lora JM et al., 2011·pers.bioét.·
Open Access
El objetivo de este artículo es revisar los principales conceptos en la literatura acerca de la ventana de la fertilidad en pacientes con ciclos menstruales normales. El énfasis principal del artículo se ha dirigido al análisis de la teoría de Brown de la ovulación, revisar conceptos básicos de la ovulación, secreción y metabolismo de la hormona folículo estimulante, y al estudio clínico, ecográfico y bioquímicos del desarrollo folicular de la ventana de la fertilidad. Este artículo también repasa los biomarcadores clínicos y los diferentes metabolitos endocrinos que delimitan en la fase fértil del ciclo. Se revisan diferentes estudios en los cuales las valoraciones en suero y orina de los esteroides sexuales, han corroborado tener una correlación directa para enmarcar el período fértil. Actualmente tienen relevancia estos conocimientos en diferentes grupos de interés, sobre todo en mujeres con un alto nivel de motivación interesadas en el reconocimiento de su fertilidad, las cuales pueden beneficiarse mediante la aplicación de conocimientos técnicos actuales que detectan la ventana fértil. También estos conocimientos suelen cobrar importancia en aquellas personas que pertenecen a programas de regulación de la fertilidad (PRF), con intención de distanciar un embarazo, o de reconocer el periodo fértil del ciclo para conseguir un embarazo espontáneamente, o mediante programas de NaProTecnología. Otros grupos de interés, son aquellos en los cuales no se tiene experiencia en cursos de PRF, pero desean mejorar sus conocimientos en el reconocimiento de la fertilidad por medio de una breve entrevista, o por medio de cursos de orientación familiar.
The paper presents the main concepts of NaProTECHNOLOGY. Such problems as family planning effectiveness, targeted hormonal assessment of the menstrual cycle, ovarian hormone and target organ dysfunction, disorders of human ovulation, cooperative progesterone replacement therapy, premenstrual syndrome, postpartum depression, unusual bleeding, infertility and antiadhesion therapy are discussed.
Griksiene R et al., 2011·Psychoneuroendocrinology·
Cognitive abilities, such as verbal fluency and mental rotation, are most sensitive to changes in sex steroids but poorly studied in the context of hormonal contraceptive usage. Therefore, we investigated the performance of mental rotation and verbal fluency in young (21.5±1.8 years) healthy oral contraceptive (OC) users (23 women) and non-users (20 women) during the follicular, ovulatory and luteal phases of the menstrual cycle. Salivary 17β-estradiol, progesterone and testosterone levels were assayed to evaluate hormonal differences between groups and the phases of the menstrual cycle. To assess the effects of progestins having androgenic/anti-androgenic properties, OC users were subdivided into the third and new generation OC users. In addition, positive and negative affects as factors possibly affecting cognitive performance were evaluated. Salivary 17β-estradiol and progesterone levels were significantly lower in hormonal contraception users. Level of salivary testosterone was slightly lower in the OC users group with significant difference only during ovulatory phase. Naturally cycling women performed better on verbal fluency task as compared to OC users. Subjects who used the third generation (androgenic) OCs generated significantly fewer words as compared to new generation (anti-androgenic) OC users and non-users. The third generation OC users demonstrated significantly longer RT in MRT task as compared to non-users. The MRT, verbal fluency and mood parameters did not depend on the phase of menstrual cycle. The parameters of the PANAS (Positive and Negative Affect Schedule) scales did not differ between OC users and non-users. Our findings show that hormonal contraception has an impact on verbal and spatial abilities. Different performances between users of oral contraceptives with androgenic and anti-androgenic properties suggest an essential role for the progestins contained in OCs on cognitive performance.
Nassaralla CL et al., 2011·J Womens Health (Larchmt)·
Menstrual cycle function may continue to be altered after discontinuation of oral contraceptives (OC). Few studies have been published on the effects of recent OC use on menstrual cycle parameters; none have examined characteristics of the menstrual flow or the quality of cervical mucus. The purpose of this retrospective matched cohort study is to assess biomarkers of the menstrual cycle after discontinuation of OCs. Among a sample of women who daily recorded observations of menstrual cycle biomarkers, 70 women who had recently discontinued OCs were randomly matched by age and parity with 70 women who had not used OCs for at least 1 year. Outcomes investigated included overall cycle length, length of the luteal phase, estimated day of ovulation, duration of menstrual flow, menstrual intensity, and mucus score. Differences between recent OC users and controls were assessed using random effects modeling. Recent OC users had statistically significantly lower scores for mucus quality for cycles 1 and 2. Additionally, OC users had a later estimated day of ovulation that was statistically significant in cycle 2 and a decreased intensity of menstrual flow that was significant in the first four cycles (difference = -0.48 days). In random effects modeling, all these parameters were significantly different for the first six cycles combined. Menstrual cycle biomarkers are altered for at least two cycles after discontinuation of OCs, and this may help explain the temporary decrease in fecundity associated with recent OC use.
Perimenopause, women's normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, -coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically - some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other's tissue effects, oral micronized P4 (OMP4 300 mg at -bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A
Perimenopause, rather than a time of declining estrogen, is characterized by three major hormonal changes that may begin in regularly menstruating women in their mid-thirties: erratically higher estradiol levels, decreased progesterone levels (in normally ovulatory, short luteal phase or anovulatory cycles), and disturbed ovarian-pituitary-hypothalamic feedback relationships. Recent data show that approximately a third of all perimenopausal cycles have a major surge in estradiol occurring de novo during the luteal phase. This phenomenon, named "luteal out of phase (LOOP)" event, may explain a large proportion of symptoms and signs for symptomatic perimenopausal women. Large urinary hormone data-sets from women studied yearly over a number of years in the Study of Women Across the Nation (SWAN) and in the Tremin data will eventually provide a more clear prospective understanding of within-woman hormonal changes. Predicting menopause proximity with FSH or Inhibin B levels is documented to be ineffective. Anti-Mullerian hormone levels may prove predictive. Finally, there is an urgent need to change perimenopause understandings, language and therapies used for midlife women's symptoms to reflect these hormonal changes.
The paper presents the main concepts of NaProTECHNOLOGY. Such problems as family planning effectiveness, targeted hormonal assessment of the menstrual cycle, ovarian hormone and target organ dysfucntion, disorders of human ovulation, cooperative progesterone replacement therapy, premustrual syndrome, postpartum depression, unusual bleeding, infertility and antiadhesion therapy are discussed.
Dr. Thomas W. Hilgers draws on decades of medical experience to provide educational and revolutionary insights into the world of women's health. The NaPro Technology Revolution provides real solutions to real problems such as infertility, repetitive miscarriage, menstrual cramps, postpartum depression, PMS, prematurity prevention, ovarian cysts, hormonal abnormalities, irregular/abnormal bleeding, chronic discharges, polycystic ovarian disease, and family planning. Hilgers sheds light on abnormal ovarian function, an issue that millions of women unknowingly suffer from. His methods have proven to assist infertile couples nearly three times more successfully than those who use In Vitro Fertilization, without the dangers of early abortions, frozen embryos, or high rates of multiple pregnancy. The NaProTechnology Prematurity Prevention Program cuts the rate from the national 12.7% to 7%. The NaPro Technology Revolution discusses what every woman has a right to know about her body, her health, and her future!
Kalyan S et al., 2010·Crit Rev Eukaryot Gene Expr·
Women's menstrual cycles and bone remodeling are linked in part by their co-dependency on the stressand resource-associated variables that govern both of their cyclical natures. Therefore, it is not surprising that evolution has resulted in the same signaling molecules and pathways that regulate normal ovarian function to be involved in bone remodeling and turnover. This review will first provide an overview of the normal menstrual cycle, its modification by age and ovulatory disturbances, and how it parallels bone remodeling. Epidemiological and clinical evidence will be presented that link bone remodeling, strength, and fractures with women's history of reproductive and menstrual cycle characteristics. This combined evidence will then be presented alongside a synthesis of current concepts derived from basic science investigations focused on understanding the molecular mechanisms underlying the influence of ovarian factors on bone physiology. Osteoporosis is a significant source of morbidity for older women. The data presented in this review suggest that a woman's reproductive cycle and ovulatory characteristics foreshadow the future health of her bones. More importantly, identifying the key mechanisms underlying reproductive and bone health would not only provide essential preventative strategies, but may also uncover attractive targets for the treatment of osteoporosis.
Yeung EH et al., 2010·The Journal of clinical endocrinology and metabolism·
Open Access
Conflicting findings have been reported regarding the effect of menstrual cycle phase and sex hormones on insulin sensitivity. The aim was to determine the pattern of insulin resistance over the menstrual cycle and whether variations in sex hormones explain these patterns. The BioCycle study is a longitudinal study that measured hormones at different phases of the menstrual cycle. Participants had up to eight visits per cycle; each visit was timed using fertility monitors to capture sensitive windows of hormonal changes. The study was conducted in the general community of the University at Buffalo (Buffalo, NY). A total of 257 healthy, premenopausal women (age, 27±8 yr; body mass index, 24±4 kg/m2) participated in the study. We measured fasting insulin, glucose, and insulin resistance by the homeostasis model of insulin resistance (HOMA-IR). Significant changes in HOMA-IR were observed over the menstrual cycle; from a midfollicular phase level of 1.35, levels rose to 1.59 during the early luteal phase and decreased to 1.55 in the late-luteal phase. HOMA-IR levels primarily reflected changes in insulin and not glucose. After adjustment for age, race, cycle, and other sex hormones, HOMA-IR was positively associated with estradiol (β=0.082; P<0.001) and progesterone (β=0.025; P<0.001), and inversely associated with FSH (adjusted β=-0.040; P<0.001) and SHBG (β=-0.085; P<0.001). LH was not associated with HOMA-IR. Further adjustment for BMI weakened the association with SHBG (β=-0.057; P=0.06) but did not affect other associations. Insulin exhibited minor menstrual cycle variability. Estradiol and progesterone were positively associated with insulin resistance and should be considered in studies of insulin resistance among premenopausal women.
Depot medroxyprogesterone acetate (DMPA) is commonly prescribed to women immediately postpartum due to its efficacy, convenience and lack of estrogen. It is unclear whether administering a progestin injection can affect the course of postpartum depression (PPD), which some suspect to be influenced by hormonal changes. In this retrospective study, the objective was to determine whether DMPA administered immediately postpartum influences the development of PPD. A retrospective review of a total of 404 charts was conducted of clinic patients who were scheduled for 6-week postpartum visits at a major medical center, where all patients are routinely asked to complete the Edinburgh Postnatal Depression Scale (EPDS). The average scores on the EPDS at these visits were compared between patients who had received DMPA prior to postpartum discharge from the hospital and patients who had not received any hormonal contraception by using an unpaired t test. In addition, the proportions of women diagnosed with PPD via the scale were compared via contingency tables. Fifty-five women who had received immediate DMPA were compared with 192 women with no hormonal contraception after delivery. The groups were similar in parity, race, mode of delivery and weight, but women receiving DMPA were significantly younger (24.2 vs. 26.2 years, p=.03). Mean EPDS scores at 6 weeks postpartum were not statistically significant between the groups (5.02 vs. 6.17, p=.16). Six patients (10.9%) who received immediate DMPA were diagnosed with PPD based on EPDS scores greater than or equal to 13, while 27 (14.1%) in the comparison group had PPD (p=.88). Administration of DMPA in the immediate postpartum period does not appear to predispose women to PPD.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
Cross-sectional studies have found associations among elevated cognitive dietary restraint (CDR), increased ovulatory disturbances, and lower bone mass, possibly mediated by cortisol. To determine whether healthy young women with higher CDR have more menstrual cycles with subclinical ovulatory disturbances (SOD), elevated 24-h urinary free cortisol (UFC), and less positive 2-yr areal bone mineral density change (Delta-aBMD). DESIGN, SETTING, We conducted a 2-yr longitudinal study of 123 healthy, community-dwelling, nonobese, regularly menstruating women aged 19-35 yr. Key variables were Three Factor Eating Questionnaire Restraint score, percent of cycles with anvoluation and/or luteal phase length <10 d (%SOD), UFC, and Delta-aBMD at the lumbar spine (L1-L4), total hip, and whole body. Anthropometrics, general stress, physical activity, and energy intake were measured. Adjusting for potential confounders, differences were examined by general linear modeling using median split of CDR score and %SOD. Women with higher CDR had higher %SOD (56 vs. 34%, P < 0.001) and higher UFC (28.0 vs. 24.0 microg/d, P = 0.021). Delta-aBMD did not differ by CDR. Women with higher %SOD had less positive Delta-aBMD at L1-L4 (0.7 vs. 1.9%, P = 0.034) and hip (-0.6 vs. 0.9%, P = 0.001), and higher CDR score (8.7 vs. 7.1, P = 0.04). Physical activity, general stress, body mass index, and energy intake did not explain differences by CDR or %SOD. UFC was not associated with %SOD or Delta-aBMD. Women with more frequent SOD reported higher CDR and experienced less positive Delta-aBMD. Although women with higher CDR had higher UFC, the mechanism linking CDR, SOD, and aBMD is not clear.
To compare the cardiovascular and metabolic effects of medroxyprogesterone acetate (MPA) with those of conjugated equine estrogen (CEE) as single-hormone therapies in women who underwent hysterectomy with bilateral ovariectomy.
Secondary analysis of a 12-month, double-blind, randomized, parallel-therapy trial.
Four teaching hospitals and one community hospital in Vancouver, Canada. Thirty-three healthy women who underwent premenopausal hysterectomy with bilateral ovariectomy. Subjects received either MPA 10 mg/day (18 women) or CEE 0.6 mg/day (15 women) for 12 months, started immediately after hysterectomy with bilateral ovariectomy. MAIN Lipid profiles (high-density lipoprotein cholesterol [HDL], total cholesterol, apolipoprotein B, and triglyceride levels), homeostatic measures (hemoglobin A(1c) and fasting blood glucose level), hormone levels (free and bioavailable testosterone, cortisol, sex hormone-binding globulin [SHBG], and dehydroepiandrosterone sulfate), inflammatory markers (C-reactive protein [CRP] and serum albumin levels), and anthropometric measures (body mass index [BMI], truncal fat, and total body fat) were assessed over the 12-month period. After 12 months, the women assigned to MPA had lesser increases in BMI (p=0.04), triglyceride (p=0.003), HDL (p<0.0005), SHBG (p<0.0005), total testosterone (p=0.003), and CRP values (p=0.01) and higher serum albumin levels (p<0.0005) compared with the women receiving CEE. Therapy with CEE, but not MPA, after surgical menopause appears to predispose healthy women to low-grade inflammation, as evidenced by its independent associations with elevated CRP and reduced albumin levels. In women treated with MPA, the favorable levels of inflammatory markers, BMI, and triglyceride levels need to be confirmed in larger controlled trials, as progesterone therapy may provide a safe and effective alternative to estrogen for vasomotor symptoms in women with surgical menopause.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
Cognitive dietary restraint (CDR) is the
perception
of limiting food intake to achieve/maintain a perceived ideal body weight. The objective of this 2‐yr prospective study was to determine if women with higher CDR have more subclinical ovulation disturbances (SOD; anovulation or luteal phase <10 d), elevated cortisol excretion and less positive changes in areal bone mineral density over two years (ΔaBMD). Participants were 123 healthy, non‐obese, regularly menstruating women aged 19–35. Annually participants completed questionnaires (Three Factor Eating Questionnaire, physical activity, general stress, dietary intake), anthropometrics and 24‐hr urine collections for measurement of 24‐hr urinary free cortisol (UFC). At baseline and final follow‐up, dual energy x‐ray absorptiometry scans measured ΔaBMD at the lumbar spine (L1‐4), hip and total body. Quantitative waking temperature was used to determine SOD frequency. SOD correlated positively with CDR and inversely with hip ΔaBMD but not with UFC. CDR and UFC were not associated with each other or ΔaBMD. Women with higher CDR had more SOD. Women with more SOD had less positive ΔaBMD and higher CDR. Physical activity, general stress, body mass and energy intake did not explain differences by CDR or SOD. In conclusion, CDR was the only study variable associated with SOD which was associated with less positive ΔaBMD. Canadian Institutes of Health Research 79563.
Grant Funding Source
: Canadian Institute of Health Research
Goldstein A et al., 2010·The journal of sexual medicine
To describe the clinical course of a young woman who developed vestibulodynia with introital dyspareunia while on oral contraceptive (OCs) and to provide a possible explanation for the etiology of her symptoms as well as her recovery after treatment. A single case is presented including subjective reporting, laboratory evaluation, and quantitative sensory testing. After topical hormonal therapy, the patient reported resolution of her dyspareunia and and her laboratory values normalized.
Physicians and menstruating women often ask pharmacists for recommendations about menstrual cycle–related problems. Progesterone and medroxyprogesterone may provide physiology-based treatment, but official indications in menstruating women in Canada are minimal. To describe pharmacists' responses to vignette-based questions about the treatment of common clinical problems in menstruating women and review evidence-based therapies. A pharmacist interviewer administered an 11-item questionnaire to a random sample of community pharmacists. Questions were based on clinical vignettes in adolescent, preand perimenopausal women and related to heavy flow, polycystic ovary syndrome, premenopausal osteoporosis, perimenopausal night sweats and side effects/contraindications for estrogens and progesterone/progestins. The participation rate was 58%, including equal numbers of male and female pharmacists. Seventy-two percent indicated that they would treat menorrhagia in an anemic 13-year-old with oral contraceptives — 21% would recommend ibuprofen and 86% iron. Half recommended that a 35-year-old smoker with heavy flow and acne stop oral contraceptives, but the other 50% recommended a switch to an oral contraceptive with cyproterone. For premenopausal osteoporosis, the majority recommended calcium and vitamin D, but 53% endorsed oral contraceptives — only 7% suggested cyclic medroxyprogesterone. For night sweats, the majority recommended progesterone/progestin in a regularly menstruating 42-year-old woman. Estrogens are contraindicated with past thrombosis and/or breast cancer family history, and they could cause nausea; 50% of pharmacists also attributed these adverse effects to progesterone/progestins. Community pharmacists vary widely in their treatment choices for common preand perimenopausal women's menstrual cycle–related problems. The evidence in support of most recommendations is minimal or lacking.
Livshits A et al., 2009·Women's health (London, England)
Diabetes mellitus Type 1 and Type 2 should be considered in the differential diagnosis of menstrual abnormalities and infertility. The reproductive period of diabetic women may be reduced due to delayed menarche and premature menopause. During the reproductive years, diabetes has been associated with menstrual abnormalities, such as oligomenorrhea and secondary amenorrhea. It was found that better glycemic control and prevention of diabetic complications improves these irregularities and increases fertility rates close to those that are seen in the general population. Women with persistent menstrual abnormalities despite adequate treatment need to be approached by broader evaluation, which will include the examination of the hypothalamic-pituitary-ovarian axis and the hormonal status, presence of autoimmune thyroid disease and antiovarian autoantibodies, and hyperandrogenism.
Harvey AT et al., 2009·J Psychosom Obstet Gynaecol·
We examined the cyclicity of negative mood relative to ovulation and ovulation disturbances in Menstrual Cycle Diary(c) data collected daily during a 1-year study of ovulation, exercise, and bone change. A validated quantitative basal temperature-based methodology was used to determine the onset of the luteal phase. 'Feeling depressed', 'feeling anxious', and 'feeling angry/frustrated' were scored on a scale of 0 (absent) to 4 (very intense). Mood scores were examined over two 15-day intervals centered on either ovulation/midpoint, or on the onset of flow. Data were available from 765 cycles of 62 healthy and initially ovulatory women with a mean age of 33.9 +/- 5.4 years. Of 739 cycles that could be classified, 532 (72%) were normally ovulatory, 185 (25%) were ovulatory with a short (<10 day) luteal phase, and 22 (3%) were anovulatory. Minor cyclic mood changes were present in both ovulatory and anovulatory menstrual cycles. In anovulatory cycles, mood tended to be more variable but less negative, with a time course that differed from that in ovulatory cycles. Mood scores did not differ based on luteal phase length or with hormone levels. Patterns and mechanisms of mood change in very symptomatic women appear to be essentially amplifications of normal experiences.
Gleicher N et al., 2009·Reprod Biol Endocrinol·
Open Access
Dehydroepinadrosterone (DHEA) supplementation improves pregnancy chances in women with diminished ovarian reserve (DOR), by possibly reducing aneuploidy. Since a large majority of spontaneous miscarriages are associated with aneuploidy, one can speculate that DHEA supplementation may also reduce miscarriage rates. We retroactively compared, utilizing two independent statistical models, miscarriage rates in 73 DHEA supplemented pregnancies at two independent North American infertility centers, age-stratified, to miscarriages reported in a national U.S. in vitro fertilization (IVF) data base. After DHEA supplementation the miscarriage rate at both centers was 15.1% (15.0% and 15.2%, respectively). For DHEA supplementation Mantel-Hänszel common odds ratio (and 95% confidence interval), stratified by age, was significantly lower, relative to odds of miscarriage in the general IVF control population [0.49 (0.25-0.94; p = 0.04)]. Miscarriage rates after DHEA were significantly lower at all ages but most pronounced above age 35 years. Since DOR patients in the literature are reported to experience significantly higher miscarriage rates than average IVF patients, the here observed reduction in miscarriages after DHEA supplementation exceeds, however, all expectations. Miscarriage rates after DHEA not only were lower than in an average national IVF population but were comparable to rates reported in normally fertile populations. Low miscarriage rates, comparable to those of normal fertile women, are statistically impossible to achieve in DOR patients without assumption of a DHEA effect on embryo ploidy. Beyond further investigations in infertile populations, these data, therefore, also suggest the investigations of pre-conception DHEA supplementation in normal fertile populations above age 35 years.
Comparative Studies · Contraception Versus Fertility Awareness
The study was conducted to investigate whether hormonal contraceptives administered via the oral and vaginal route exert a similar effect on insulin sensitivity (SI). This is a prospective, randomized study performed in the University Hospital. Subjects were healthy lean young women, needing a hormonal contraceptive, randomly allocated to receive for 6 months (a) an oral contraceptive (OC) containing 30 mcg ethinylestradiol (EE)/150 mcg desogestrel (DSG) (high-estrogen group; n=12), (b) an OC containing 20 mcg EE/150 mcg DSG (low-estrogen group; n=12) and (c) a vaginal ring contraceptive releasing, per day, 15 mcg EE/120 mcg etonorgestrel, the active DSG metabolite (n=12). SI and glucose utilization independent of insulin (Sg) were evaluated by the minimal model method. Modifications of total, high-density lipoprotein (HDL) and low-density lipoprotein cholesterol and triglycerides were also evaluated. Sg did not vary with any treatment. SI decreased during OCs (5.74+/-0.49 vs. 3.86+/-0.44; p=.0005), independently of the high/low-estrogen dose. SI did not decrease during vaginal ring use (4.64+/-1.03 vs. 5.25+/-1.36; p=.57; p=.019 vs. oral). Total cholesterol and HDL cholesterol increased (p=.02) during OCs, independently of the dose. Triglycerides increased during both oral (p=.01) and vaginal (p=.032) contraceptive use. The present data indicate that in contrast to OC use, vaginal contraception with the ring does not deteriorate SI. The vaginal ring may represent an appropriate choice for long-term contraception in women at risk for developing diabetes mellitus or metabolic syndrome.
Jonas W et al., 2009·Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine
Oxytocin and prolactin stimulate milk ejection and milk production during breastfeeding. The aim of the present study was to make a detailed analysis of maternal release of oxytocin and prolactin in response to breastfeeding during the second day postpartum in mothers who had received oxytocin either intravenously for stimulation of labor or intramuscularly for prevention of postpartum hemorrhage and/or epidural analgesia or those who had received no such treatment in connection with birth. In a descriptive comparative study plasma oxytocin and prolactin concentrations were measured in response to suckling during the second day postpartum in women who had received intravenous intrapartum oxytocin (n = 8), intramuscular postpartum oxytocin (n = 13), or epidural analgesia, either with (n = 14) or without (n = 6) intrapartum oxytocin infusion, and women who received none of these interventions (n = 20). Hormone levels were analyzed by enzyme immunoassay. All mothers showed a pulsatile oxytocin pattern during the first 10 minutes of breastfeeding. Women who had received epidural analgesia with oxytocin infusion had the lowest endogenous median oxytocin levels. The more oxytocin infusion the mothers had received during labor, the lower their endogenous oxytocin levels were during a breastfeeding during the second day postpartum. A significant rise of prolactin was observed after 20 minutes in all women, but after 10 minutes in mothers having received oxytocin infusion during labor. In all women, oxytocin variability and the rise of prolactin levels between 0 and 20 minutes correlated significantly with median oxytocin and prolactin levels. Oxytocin, released in a pulsatile way, and prolactin were released by breastfeeding during the second day postpartum. Oxytocin infusion decreased endogenous oxytocin levels dose-dependently. Furthermore, oxytocin infusion facilitated the release of prolactin. Epidural analgesia in combination with oxytocin infusion influenced endogenous oxytocin levels negatively.
Ecochard R et al., 2008·Reprod Biol Endocrinol·
Open Access
To assess the amount of variability in ovarian follicular growth rate and maximum follicular diameter related to different centers, women and cycles of the same women in a multicenter observational study of follicular growth. Secondary analysis of a prospective cohort study from eight centers in Europe. There were 533 ultrasound examinations in 282 cycles of 107 women with normal fertility. A random effects model with center, woman and cycle as hierarchical units of variation was used to analyze mean follicular diameter on days preceding ovulation. Follicular growth did not differ by center. There was homogenous growth across women and cycles, and the maximum follicular diameter before ovulation varied substantially across cycles but not across women. Many (about 40%) women had small maximum follicular diameter on the day before ovulation (<19 mm). Pre-ovulatory cycle length was not related to maximum follicular diameter. In normal fecundity, there is a substantial variation in maximum follicular diameter from cycle to cycle based on variation in the duration of follicular development, but the variation could not be explained by different characteristics of different women. Explanation of variation in follicular growth has to be found on the cycle level.
Roberts SC et al., 2008·Proceedings. Biological sciences
Previous studies in animals and humans show that genes in the major histocompatibility complex (MHC) influence individual odours and that females often prefer odour of MHC-dissimilar males, perhaps to increase offspring heterozygosity or reduce inbreeding. Women using oral hormonal contraceptives have been reported to have the opposite preference, raising the possibility that oral contraceptives alter female preference towards MHC similarity, with possible fertility costs. Here we test directly whether contraceptive pill use alters odour preferences using a longitudinal design in which women were tested before and after initiating pill use; a control group of non-users were tested with a comparable interval between test sessions. In contrast to some previous studies, there was no significant difference in ratings between odours of MHC-dissimilar and MHC-similar men among women during the follicular cycle phase. However, single women preferred odours of MHC-similar men, while women in relationships preferred odours of MHC-dissimilar men, a result consistent with studies in other species, suggesting that paired females may seek to improve offspring quality through extra-pair partnerships. Across tests, we found a significant preference shift towards MHC similarity associated with pill use, which was not evident in the control group. If odour plays a role in human mate choice, our results suggest that contraceptive pill use could disrupt disassortative mate preferences.
Popat VB et al., 2008·Ann N Y Acad Sci·
Open Access
Menstruation is the cyclic, orderly sloughing of the uterine lining on account of the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. There is a tendency among parents and clinicians to view oligo-amenorrhea as a normal variant in the teen years. In fact, the 95th percentile for the time interval between cycles is 90 days. Thus, it is abnormal for an adolescent to be amenorrheic for greater than 3 months, even in the early gynecologic years. Identification of abnormal menstrual patterns throughout adolescence may permit early identification of potential health concerns for adulthood. Few problems in gynecologic endocrinology are as complex or challenging to the clinician as amenorrhea. However, thorough evaluation of menstrual cycle disorders in adolescence provides a window of opportunity for early diagnosis and treatment of conditions affecting the hypothalamic-pituitary-ovarian (HPO) axis. Here we discuss a systematic approach to the evaluation and treatment of amenorrhea in adolescents who do not have androgen excess. There is strong evidence that estrogen deficiency is a risk factor for later development of osteoporosis and hip fracture. Delay in the evaluation and treatment of disordered menses in some cases may contribute to reduced bone density. Both patients and clinicians need to view the ovary as an important endocrine organ that helps maintain health, especially bone health.
Outcomes and Effectiveness · Outcomes by Diagnosis
To determine the effect of luteinized unruptured follicle (LUF) cycles on frozen thawed embryo transfer (FET).
A retrospective analysis comparing the clinical outcomes after FET among 144 cases of luteinized unruptured follicle (LUF) cycles and 866 cases of ovulation cycles.
Reproductive medical center, Beijing China. Chinese infertile women who underwent FET. None. Clinical pregnancy rate (PR), implantation rate. The implantation rate, clinical pregnancy rate, on-going pregnancy rate and live birth rate in LUF group were 12.76% (49/384), 27.78% (40/144), 24.31% (35/144) and 19.44% (28/144), respectively, and in ovulation group, 14.74% (332/2251), 31.29% (271/866), 28.29% (245/866) and 22.23% (193/866), respectively (p > 0.05). LUF does not affect the clinical outcomes of FET. Patients of LUF should be included in FET treatment.
Male Endocrine and Genetic Factors · Male Hormonal Axis
The acrosome is a secretory vesicle located in the sperm head. The acrosome reaction consists in the fusion of the sperm plasma membrane with the external acrosomal membrane. It has been observed that this reaction does not take place in spermatozoa incubated in cervical mucus, hydrogel that contains high concentrations of oestradiol in the peri-ovulatory period. The objective of the present study was to analyse the influence of oestradiol on the acrosome reaction in human spermatozoa to evaluate the possible inhibitory effect of this hormone. Spermatozoa were incubated in progesterone (10.1 nmol l(-1)); oestradiol plus progesterone (oestradiol at 840 pmol l(-1) and progesterone at 10.1 nmol l(-1)), oestradiol (840 pmol l(-1)) and control (without steroidal hormones) for 30 min, 60 min, 240 min and 24 h. The acrosome reaction was evaluated by stain with Hoechst 33258 and fluorescein isothiocyanate-conjugated Pisum sativum agglutinin lectin. Progesterone-incubated spermatozoa showed the highest percentage of acrosome reaction (P < 0.05). Spermatozoa incubated with oestradiol and oestradiol plus progesterone showed the lowest percentage of acrosome reaction. The present study demonstrates the inhibitory role of oestradiol on the acrosome reaction, stimulated by progesterone in human spermatozoa under physiological conditions.
The purpose of this study was to determine the variability in length of the fertile phase of the menstrual cycle with 140 participants who produced 1,060 cycles with an electronic hormonal fertility monitor. The length of the fertile phase, as defined by the first day with a threshold level of urinary E3G and ending with a second day above a threshold of LH, varied from <1 to >7 days, with the most frequent length being 3 days.
Obaydi H et al., 2008·The Journal of international medical research
A systematic, prospective observer-rated study was carried out to determine the prevalence of late luteal phase dysphoric disorder (premenstrual syndrome) in women with autism. A group of women with autism and learning disability (n = 26) was compared with a group of women with a non-autism learning disability (n = 36) matched for age, in-patient status, intelligence, marital status, parity, behavioural problems and ethnicity. Observers rated DSM-IV symptoms of late luteal phase dysphoric disorder every day from each subject over three consecutive menstrual cycles. Using a premenstrual increase in DSM-IV symptoms of >or= 30% as evidence of fulfilment of diagnostic criteria, the prevalence of late luteal phase dysphoric disorder was 92% in the autism group compared with 11% in the control group. This difference was highly statistically significant. The principal conclusion from this study is that there is a marked increase in premenstrual syndrome in women with autism compared with matched controls.
Women with ovulatory menstrual cycles have a circadian rhythm superimposed on the menstrual-associated rhythm; in turn, menstrual events affect the circadian rhythm. In this paper, we review circadian rhythms in temperature, selected hormone profiles, and sleep-wake behavior in healthy women at different phases of the menstrual cycle. The effects on menstrual cycle rhythmicity of disrupted circadian rhythms, for example, with shiftwork and altered circadian rhythms in women with menstrual-related mood disturbances, are discussed. Compared to the follicular phase, in the post-ovulation luteal phase, body temperature is elevated, but the amplitude of the temperature rhythm is reduced. Evidence indicates that the amplitude of other rhythms, such as melatonin and cortisol, may also be blunted in the luteal phase. Subjective sleep quality is lowest around menses, but the timing and composition of sleep remains relatively stable across the menstrual cycle in healthy women, apart from an increase in spindle frequency activity and a minor decrease in rapid eye movement (REM) sleep during the luteal phase. Disruption of circadian rhythms is associated with disturbances in menstrual function. Female shiftworkers compared to non-shiftworkers are more likely to report menstrual irregularity and longer menstrual cycles. There also is accumulating evidence that circadian disruption increases the risk of breast cancer in women, possibly due to altered light exposure and reduced melatonin secretion. Further investigations into the biological consequences of circadian disruption in women will offer insight into some menstrual-associated disorders, including mood changes, as well as reproductive function and possible links with breast cancer.
Poyastro Pinheiro A et al., 2007·The International journal of eating disorders
To describe menstrual disturbance in eating disorders (ED). We describe menstrual history in 1,705 women and compare eating, weight, and psychopathological traits across menstrual groups. Menstrual dysfunction occurred across all eating disorder subtypes. Individuals with normal menstrual history and primary amenorrhea reported the highest and lowest lifetime body mass index (BMI), respectively. Normal menstruation and oligomenorrhea groups reported greater binge eating, vomiting, and appetite suppressant use. Amenorrhea was associated with lower caloric intake and higher exercise. Harm avoidance, novelty seeking, perfectionism, and obsessionality discriminated among menstrual status groups. No differences in comorbid Axis I and II disorders were observed. Menstrual dysfunction is not limited to any eating disorder subtype. BMI, caloric intake, and exercise were strongly associated with menstrual function. Menstrual status is not associated with comorbidity. Menstrual irregularity is an associated feature of all ED rather than being restricted to AN only.
Oestrogen therapy is the gold standard treatment for hot flushes/night sweats, but it and oestrogen/progestin are not suitable for all women. MPA (medroxyprogesterone acetate) reduces hot flushes, but its effectiveness compared with oestrogen is unknown. In the present study, oral oestrogen [CEE (conjugated equine oestrogen)] and MPA were compared for their effects on hot flushes in a planned analysis of a secondary outcome for a 1-year randomized double-blind parallel group controlled trial in an urban academic medical centre. Participants were healthy menstruating women prior to hysterectomy/ovariectomy for benign disease. A total of 41 women {age, 45 (5) years [value is mean (S.D.)]} were enrolled; 38 women were included in this analysis of daily identical capsules containing CEE (0.6 mg/day) or MPA (10 mg/day). Demographic variables did not differ at baseline. Daily data provided the number of night and day flushes compared by group. The vasomotor symptom day-to-day intensity change was assessed by therapy assignment. Hot flushes/night sweats were well controlled in both groups, one occurred on average every third day and every fourth night. Mean/day daytime occurrences were 0.363 and 0.187 with CEE and MPA respectively, but were not significantly different (P=0.156). Night sweats also did not differ significantly (P=0.766). Therapies were statistically equivalent (within one event/24 h) in the control of vasomotor symptoms. Day-to-day hot flush intensity decreased with MPA and tended to remain stable with CEE (P<0.001). In conclusion, this analysis demonstrates that MPA and CEE are equivalent and effective in the control of the number of hot flushes/night sweats immediately following premenopausal ovariectomy.
Systemic lupus erythematosus (SLE) occurs predominantly in women, and hormones may play a role in its etiology. This study was carried out to examine associations between female reproductive and menopausal factors and the development of SLE. A cohort of 238,308 women was prospectively examined. Subjects were older women (ages 30-55 years at start) and younger women (ages 25-42 years at start) from the Nurses' Health Study (NHS) and NHSII cohorts. Incident SLE diagnosed between 1976 and 2003 was confirmed by medical record review. The relative risk (RR) of SLE was estimated separately in each cohort using Cox proportional hazards models, and then pooled using meta-analysis random effects models. Two hundred sixty-two incident cases of SLE were confirmed among the women. In multivariable models adjusted for reproductive and other risk factors, age<or=10 years at menarche (pooled RR 2.1, 95% confidence interval [95% CI] 1.4-3.2), oral contraceptive use (pooled RR 1.5, 95% CI 1.1-2.1), and use of postmenopausal hormones (RR 1.9, 95% CI 1.2-3.1) significantly increased the risk of SLE. An elevation of SLE risk was observed among postmenopausal women primarily after surgical menopause (RR 2.3, 95% CI 1.2-4.5), and also among women with earlier age at natural menopause (P for trend<0.05). Menstrual irregularity was associated with an increased risk of SLE among women in the younger (NHSII) cohort. Age at first birth, parity, and total duration of breastfeeding were not associated with SLE. Early age at menarche, oral contraceptive use, early age at menopause, surgical menopause, and postmenopausal use of hormones were each associated with an increased risk of SLE. These associations may point to the mechanisms underlying the pathogenesis of SLE.
For many years, osteoporosis in women was equated with estrogen deficiency. The recent articles by Zaidi and colleagues offer a new challenge to the estrogen-deficiency-osteoporosis hypothesis by showing that follicle-stimulating hormone (FSH) stimulates osteoclastic bone resorption perhaps through tumor necrosis factor-alpha (TNF-alpha). These authors, however, neglected to mention bone abnormalities and high testosterone levels that were previously shown in FSH-receptor knockout and other modified mice. It is also possible that they have overemphasized potential relationships of these new data with human bone loss. Despite these fascinating data, the paradigm of FSH causing hypogonadal bone loss is not yet ready to displace the estrogen-deficiency-osteoporosis paradigm, although that model already faces considerable challenge.
Prior et al., 2006·Journal of Reproductive and Infant Psychology·
Ordinary women and official statements confuse and conflate perimenopause—the long, complex, life phase of higher and chaotic estrogen levels—with the low and stable estrogen levels of menopause. This paints both perimenopause and menopause with an inaccurate ‘estrogen deficiency’ brush. Menopause is the hormonal, and (except for hot flushes) the experiential opposite of perimenopause. This feminist analysis is from my perspective as physician‐scientist who experienced a perimenopause that was scientifically enlightening, but personally agonizing. Denial of perimenopausal and menopausal differences causes perimenopause to be ‘lost’ in several ways: (1) we may assume that perimenopause is chronic rather than ending in a largely asymptomatic menopause; (2) societal taboos isolate us, depriving us of solidarity with perimenopause ‘survivors’; (3) we are told we have dropping estrogen levels when our experiences, like pregnancy dreams, tell us the opposite; (4) gynaecology treats heavy flow with estrogen despite higher perimenopausal estrogen levels; (5) feminists ignore hormonal changes and attribute perimenopausal symptoms to (real) stresses of inferior social status and ageing; and (6) many of us thus become menopausal without the unique, self‐actualization experience that perimenopause has the potential to provide. Thus perimenopause—a valuable transition into knowing and standing up for ourselves—becomes lost.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Hadziomerovic D et al., 2006·Fertility and Sterility
Evaluation of the effects of naltrexone on hyperinsulinemia and hyperandrogenemia in hyperandrogenemic, hyperinsulinemic women. Controlled clinical study. Department of Gynecologic Endocrinology and Reproductive Medicine, Center of Obstetrics and Gynecology, Medical University of Innsbruck, Austria. PATIENT(S): Thirty-nine hyperandrogenemic, hyperinsulinemic women were studied. INTERVENTION(S): Women were treated with naltrexone (50 mg/d) for >or=3 weeks. MAIN OUTCOME MEASURE(S): Body mass index (BMI), gonadotropin (LH, FSH) and androgen (T, free T, DHEAS) levels, and plasma levels of glucose, insulin, and C-peptide, during a standard 75-g oral glucose tolerance test (OGTT), were determined before and during chronic opiate receptor blockade. RESULT(S): The BMI did not change during therapy. When OGTT was repeated after treatment with naltrexone, glucose levels were not different from those before treatment. Insulin response, however, had dramatically declined. We also observed a significant decrease in the levels of serum androgens. CONCLUSION(S): Hyperinsulinemia associated with hyperandrogenemia can be improved or completely abolished by chronic opiate receptor blockade. This observation suggests that endogenous opiates play a critical role in the process leading to hyperinsulinemia in hyperandrogenemia.
Metabolic and Endocrine Agents · Thyroid Replacement
Thyroid disease in general, and hypothyroidism in particular, are very common in women. In the USA, the most common cause of primary thyroid deficiency is on an autoimmune basis due to lymphocytic (Hashimoto) thyroiditis. Because there are thyroid hormone receptors in virtually every tissue of the body, the manifestations of hypothyroidism are varied, but problems with abnormal menses, conception, fertility, and pregnancy can be especially troubling in young women. The single most important diagnostic test is measurement of serum thyrotropin (TSH). The overwhelming majority of patients with hypothyroidism are treated with a single daily dose of synthetic levothyroxine with the goal of therapy being restoration of a normal metabolic state with return of the TSH level down to the range of 0.5 to 1.5 mlU/L. "Subclinical" hypothyroidism refers to those patients with early or mild thyroid hypofunction manifested as slight elevations of thyrotropin (approximately 4-10 mlU/L) although serum thyroxine (T4) and triiodothyronine (T3) levels are within their reference ranges. The entity is somewhat controversial in regard to its consequences if left untreated, and whether or not we should be screening patients, at least susceptible populations, for the condition. Reports indicate an association between subclinical hypothyroidism and poor outcomes of pregnancy, as well as dyslipidemias, atherogenesis, and increased mortality in the long term. We believe these consequences are sufficiently compelling to warrant screening and treatment with levothyroxine when found to halt progression to overt hypothyroidism, and improve symptoms, pregnancy outcomes, lipid abnormalities, and cardiovascular function. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader should be able to recall that hypothyroidism is a common disease in women, has many protean manifestations, and can be successfully diagnosed and treated; explain that the condition of subclinical hypothyroidism can be diagnosed and if treated can prevent many untoward complications; and state that there should be heightened awareness of the disease so that proper screening tests can be performed.
Hormones and Aging Tissues · Skin and Connective Tissue
To the Editor: In the discussion of biologic differences between male and female fertility (April 6 issue),1 Federman states that women are fertile for only 12 hours each month. Although the egg is viable for 12 hours or less, the window of fertility in women is approximately five to six days in each menstrual cycle,24 depending on the presence of estrogenic cervical mucus that maximizes the storage, survival, and transport of sperm until ovulation.4,5 Dr. Federman replies: Stanford rightly calls attention to the elegant estrogen-dominated events that precede ovulation and that favor passage of sperm through the cervix . . .
Fehring RJ et al., 2006·J Obstet Gynecol Neonatal Nurs·
Open Access
To determine variability in the phases of the menstrual cycle among healthy, regularly cycling women.
A prospective descriptive study of a new data set with biological markers to estimate parameters of the menstrual cycles. One hundred forty one healthy women (mean age 29 years) who monitored 3 to 13 menstrual cycles with an electronic fertility monitor and produced 1,060 usable cycles of data. Outcomes: Variability in the length of the menstrual cycle and of the follicular, fertile, and luteal phases, and menses. The estimated day of ovulation and end of the fertile phase was the peak fertility reading on the monitor (i.e., the urinary luteinizing hormone surge). Mean total length was 28.9 days (SD = 3.4) with 95% of the cycles between 22 and 36 days. Intracycle variability of greater than 7 days was observed in 42.5% of the women. Ninety-five percent of the cycles had all 6 days of fertile phase between days 4 and 23, but only 25% of participants had all days of the fertile phase between days 10 and 17. Among regularly cycling women, there is considerable normal variability in the phases of the menstrual cycle. The follicular phase contributes most to this variability.
Exogenous estrogens affect the onset and clinical course of experimental allergic encephalomyelitis. Oral contraceptives, a frequent source of exogenous estrogens in humans, could have a role in the development of multiple sclerosis (MS). To examine whether recent oral contraceptive use and pregnancy history are associated with the risk of MS. DESIGN AND A case-control study nested in the General Practice Research Database. This database contains prospective health information (drug prescriptions and clinical diagnoses) on more than 3 million Britons who are enrolled with selected general practitioners. One hundred six female incident cases of MS, younger than 50 years, with at least 3 years of continuous recording in the General Practice Research Database before the date of first symptoms (index date), identified between January 1, 1993, and December 31, 2000, and 1001 controls matched on age, practice, and date of joining the practice. Main Outcome Measure Incidence of first symptoms of MS, confirmed through medical records. The incidence of MS was 40% lower (odds ratio, 0.6; 95% confidence interval, 0.4-1.0) in oral contraceptive users compared with nonusers during the previous 3 years. The risk of MS increased in the 6 months after pregnancy (odds ratio, 2.9, 95% confidence interval, 1.2-6.6), but it was not otherwise related to parity. The hormonal changes that occur during oral contraceptive use and pregnancy may be associated with a short-term reduction in the risk of MS, and the postpartum period may be associated with a short-term increase in the risk of MS.
Farquhar CM et al., 2005·BJOG : an international journal of obstetrics and gynaecology
To determine whether or not hysterectomy leads to an earlier onset of the menopause. A prospective cohort study. Gynaecology service of large urban hospital. Premenopausal women with and without hysterectomy. Multivariate survival analysis techniques were used to adjust for differences in initial follicle stimulating hormone (FSH) levels, body mass index, smoking and unilateral oophorectomy between the groups. FSH levels were measured for five years following hysterectomy and compared with the comparison group. Menopause was defined as a single FSH measurement of at least 40 IU/L. Two hundred and fifty-seven women undergoing hysterectomy were compared with 259 women who had not undergone a hysterectomy. Fifty-three women (20.6%) in the hysterectomy group and 19 women (7.3%) in the comparison group reached menopause over the five years of the study. Women in the hysterectomy group with a pre-operative FSH <10 IU/L reached menopause 3.7 years (95% CI 1.5-6.0 years) earlier than women in the comparison group independent of BMI, smoking and unilateral oophorectomy. Twenty-eight women in the hysterectomy group had unilateral oophorectomy and 10 (35.7%) of these women reached menopause over the five years of follow up. Women in the hysterectomy group with unilateral oophorectomy reached menopause 4.4 years (95% CI 0.6, 7.9 years) earlier than women with both ovaries in the hysterectomy group independent of baseline FSH, BMI and smoking. Hysterectomy is associated with an earlier onset of menopause. Hysterectomy with unilateral oophorectomy is associated with an even earlier onset of the menopause in this study.
To determine whether lung transfer factor for carbon monoxide (T(L(CO))) alters during menstrual phase and if steroid hormone levels relate to these changes, T(L(CO)) and T(L(CO)) adjusted for both alveolar volume (T(L)/V(A)) and haemoglobin concentration, were measured at five predefined and hormonally confirmed menstrual phases in 13 women. No difference between phases was observed in T(L(CO)) or adjusted values. Moreover, there was no association between the maximal change in oestradiol, progesterone, or oestradiol:progesterone ratio and the change in T(L(CO)) measured at the same time. When the first five chronological measurements, regardless of the menstrual phase at which they were measured, were analysed, T(L(CO)) changed significantly (p<0.05) with a maximal change between the first and fourth test (-2.69+/-2.53, 95% confidence interval). Although these results indicate that the first in a series of T(L(CO)) measurements may be higher, we found neither menstrual cycle phase nor ovarian hormone-related changes in T(L(CO)), and conclude that its adjustment for menstrual phase may not be necessary.
Chen C et al., 2005·Environ Health Perspect·
Open Access
Our recent study showed a dose-response relationship between environmental tobacco smoke (ETS) and the risk of early pregnancy loss. Smoking is known to affect female reproductive hormones. We explored whether ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. We prospectively studied 371 healthy newly married nonsmoking women in China who intended to conceive and had stopped contraception. Daily records of vaginal bleeding, active and passive cigarette smoking, and daily first-morning urine specimens were collected for up to 1 year or until a clinical pregnancy was achieved. We determined the day of ovulation for each menstrual cycle. The effects of ETS exposure on daily urinary PdG and E1C levels in a +/-10 day window around the day of ovulation were analyzed for conception and nonconception cycles, respectively. Our analysis included 344 nonconception cycles and 329 conception cycles. In nonconception cycles, cycles with ETS exposure had significantly lower urinary E1C levels (beta = -0.43, SE = 0.08, p < 0.001 in log scale) compared with the cycles without ETS exposure. There was no significant difference in urinary PdG levels in cycles having ETS exposure (beta = -0.07, SE = 0.15, p = 0.637 in log scale) compared with no ETS exposure. Among conception cycles, there were no significant differences in E1C and PdG levels between ETS exposure and nonexposure. In conclusion, ETS exposure was associated with significantly lower urinary E1C levels among nonconception cycles, suggesting that the adverse reproductive effect of ETS may act partly through its antiestrogen effects.
To analyze IVF outcomes in patients with a history of one or more elevations in basal FSH who have a normal basal FSH at the start of their IVF cycle, compared with the general IVF population.
Retrospective clinical study.
University hospital. PATIENT(S): General IVF patient population. INTERVENTION(S): Patients received standard IVF gonadotropin protocols, oocyte retrieval, and embryo transfer. MAIN OUTCOME MEASURE(S): Oocyte yield, fertilization, implantation, clinical pregnancy, and cancellation rate. RESULT(S): Oocyte yields were lower in patients with a history of elevated basal FSH, for all age groups, and showed an age-dependent decline in all patients. Over the age of 40 years, both implantation and clinical pregnancy rates were lower in these patients, with no significant difference observed in patients under the age of 40 years. No pregnancies were observed in patients with a history of three or more elevated FSH levels, regardless of age. CONCLUSION(S): A history of elevated basal FSH levels in patients under the age of 40 years predicts a lower oocyte yield in IVF cycles with normal basal FSH levels but does not translate to either lower pregnancy or implantation rates. Patients aged >40 years with prior elevations in basal FSH levels have both compromised ovarian response and compromised embryo quality relative to those with normal FSH levels, as illustrated by lower oocyte yield, higher cancellation rates, and lower implantation and pregnancy rates.
The goal of an integrative science of women's health is bringing together childbearing with women's health during the lifespan. Enhancing a woman's ability to conceive and maintain a pregnancy is influenced by decisions made well before the beginning of a pregnancy. Identifying ovulatory disorders makes it possible to intervene early in a young woman's childbearing years. Gynecologic charting typically used in natural family planning provides information to the woman and to the healthcare provider that is useful for diagnosis. If young women have a better understanding of fertility and menstrual cycle function, they are in a stronger position to make informed decisions about how they wish to manage their reproductive and sexual health. It may be possible to educate the young woman in health habits that will lead to a healthy pregnancy when she chooses and/or to treat the cause of the ovulatory disorder. This article focuses on polycystic ovary syndrome and hypothalamic dysfunction which can cause menstrual cycle abnormalities in which gynecologic charting is useful in young women.
Baerwald et al. (1) proposed a new model for ovarian follicular development in the human menstrual cycle. They showed additional waves of follicular development in the follicular and luteal phase of normal ovulatory cycles. Although no additional ovulation was observed, the authors speculated that the anovulatory follicles from the additional waves of follicular development may be able to ovulate in the presence of an additional LH surge.
Imprecise measures of ovulation obscure the relationship between women's sexuality and the menstrual cycle, as does studying women with different contraceptive goals in different social contexts. Here we present a novel noninvasive method to precisely pinpoint the preovulatory surge of Luteinizing Hormone (LH), demarcating hormonally distinct cycle phases with greater than 95% reliability. Women were more sexually active on days prior to and including the preovulatory (LH) surge. This pattern was evident only when women initiated sexual activity and not when their partners did, indicating an increase in women's sexual motivation rather than attractiveness. A second study replicated the 6-day increase in sexual activity beginning 3 days before the LH surge, accompanied by stronger sexual desire and more sexual fantasies. We propose the term 'sexual phase' of the cycle, since follicular phase is over inclusive and ovulatory phase is not sufficient. These findings are striking because the women were avoiding pregnancy and were kept blind to the hypotheses, preventing expectation bias. The sexual phase was more robust in women with regular sexual partners, although the increase in sexual desire was just as great in nonpartnered women, who also reported feeling less lonely at this time. We use these results to evaluate potential neuroendocrine mechanisms underlying women's sexual motivation and activity.
Since the 1990 National Institutes of Health-sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
The CREIGHTON MODEL FertilityCare System (CrMS) rests on a decades-long body of research demonstrating that cervical mucus functions as a physiologically regulated biological valve, opening predictably at the periovulatory estrogen rise and closing in the post-Peak phase. Chapter 15 of Hilgers (2004) synthesizes hormonal, ultrasound, cytologic, and biophysical evidence to establish that a woman's external observation of her Peak Day reliably identifies the fertile window, and documents the system's effectiveness data for both achieving and avoiding pregnancy across a five-study meta-analysis of nearly 1,900 couples.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
PCOS (polycystic ovary syndrome), increasingly designated PMOS (polycystic metabolic ovary syndrome) to reflect its metabolic complexity, is far more prevalent than its classic presentation suggests, affecting roughly six percent of reproductive-age women and carrying systemic consequences well beyond fertility disruption. This chapter from the foundational NaProTECHNOLOGY textbook maps the hormonal architecture of the condition, its ovulatory defect patterns, its frequent co-occurrence with endometriosis, and the restorative surgical and cycle-tracking approaches developed at the Pope Paul VI Institute.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Luteal phase and early pregnancy progesterone supplementation protocols are detailed, including indications derived from Creighton Model hormone profiles and dosing regimens for intramuscular and vaginal routes. Targeted progesterone support addresses a correctable physiological deficit identified through CrMS-guided monitoring, reducing early pregnancy loss in women with documented luteal insufficiency.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
NaProTECHNOLOGY utilizes a defined panel of cycle-phase-specific biomarkers — including targeted progesterone, estradiol, LH, FSH, and prolactin drawn at CrMS-standardized cycle days — to characterize the hormonal profile underlying each patient's reproductive dysfunction. This biomarker summary consolidates reference ranges, collection timing rules, and clinical interpretation frameworks that govern diagnosis and treatment decisions across infertility, endometriosis, recurrent pregnancy loss, and cycle irregularity.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Medical protocols in NaProTECHNOLOGY are cycle-phase-targeted regimens — covering ovulation induction, luteal phase hormonal support, hyperprolactinemia management, thyroid optimization, and pre-conceptual supplementation — derived from the biomarker-defined diagnosis rather than empirical stimulation. Consolidating these protocols in a single reference enables practitioners to apply evidence-based, individualized treatment sequences that address root hormonal pathology while supporting natural conception.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Preconceptional optimization using CrMS cycle data establishes hormonal baselines, identifies correctable pathologies, and guides targeted supplementation before conception is attempted. Systematic preconceptional evaluation reduces early pregnancy loss and improves obstetric outcomes by ensuring the endocrine environment supports implantation and early embryonic development.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Unusual uterine bleeding -- including premenstrual spotting, tail-end brown bleeding, mid-cycle intermenstrual bleeding, and heavy menses -- is evaluated in NaProTECHNOLOGY through prospective CrMS charting combined with cycle-phase-targeted estradiol and serial post-Peak progesterone profiles, which typically reveal luteal phase deficiency, follicular estradiol insufficiency, or anovulation as the primary etiology. Treatment is etiology-directed and cycle-synchronized: cooperative progesterone replacement for luteal defects, follicular support or ovulation induction for follicular phase insufficiency, and fertility-sparing surgical correction for structural pathology such as endometriosis, polyps, or fibroids, without routine recourse to contraceptive suppression.
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Compounding pharmacists prepare individualized hormone formulations — including HCG, progesterone, and thyroid preparations — that are central to NaProTECHNOLOGY treatment protocols, where standardized commercial doses are often inadequate for patient-specific needs. Collaborative prescribing between NaPro practitioners and licensed compounding pharmacists ensures consistent bioidentical formulation quality, dosing precision, and regulatory compliance within fertility and reproductive endocrine management.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Chronic anovulation and progesterone or estradiol deficiency identified through CrMS charting represent periods of suboptimal bone accrual in women of reproductive age, because both estradiol and progesterone contribute to skeletal maintenance -- estradiol through suppression of osteoclast activity and progesterone through osteoblast stimulation. NaProTECHNOLOGY uses longitudinal CrMS records of ovulatory status and hormone profiles as a bone-health risk screen, guiding cycle-synchronized bioidentical hormone replacement to restore normal estrogen-progesterone balance and potentially mitigate progression toward osteoporosis in women with chronic cycle-based endocrine deficiencies.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Postpartum depression in susceptible women is linked to abrupt postpartum progesterone withdrawal following the high-progesterone state of pregnancy, particularly in those with prior PMS, luteal phase defects, or recurrent miscarriage, and NaProTECHNOLOGY evaluates this through serum progesterone, thyroid function, and prolactin assessment in the postpartum period. Treatment uses bioidentical progesterone -- preferably intramuscular for reliable absorption -- with serum levels monitored every two weeks for dose titration, and once cycles resume, dosing is resynchronized to the CrMS Peak day; Hilgers reports no increase in congenital anomalies in over 2,000 progesterone-supported pregnancies in the Pope Paul VI Institute series.
Measurement and Statistics · Research Tooling and Reproducibility
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Serum estradiol and progesterone assays vary substantially across laboratories because of differences in antibody specificity, calibration standards, detection platforms, and quality-control practices, meaning that a value within one laboratory's generic reference range may represent a clinically significant deficiency when interpreted against NaPro Peak-day-specific norms. NaProTECHNOLOGY requires consistent use of a single reference laboratory and interpretation relative to cycle-phase-specific NaPro standards rather than broad lab-generated reference intervals, to avoid missing subtle follicular or luteal phase defects that standard reporting would classify as normal.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Physiological and psychological stress disrupts hypothalamic GnRH pulsatility via CRH-cortisol pathways, producing downstream impairments in LH and FSH secretion that manifest as anovulation, delayed ovulation, follicular phase prolongation, or luteal phase deficiency -- all of which are documented cycle-by-cycle on the CrMS chart. NaProTECHNOLOGY addresses stress-induced HPO axis dysfunction by identifying the specific cycle-level disorder through charting and targeted hormone profiling, then applying cycle-appropriate ovulation induction and cooperative hormone support alongside correction of the underlying physical or psychological stressor.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Ovarian wedge resection reduces androgen-producing stromal tissue in women with polycystic ovary syndrome who have failed medical ovulation induction, restoring spontaneous or treatment-responsive ovulatory cycles. Within NaProTECHNOLOGY, the procedure is performed with precise tissue economy and anti-adhesion technique to preserve ovarian reserve while correcting the underlying hormonal dysfunction identified through CrMS biomarker monitoring.
Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.
Endometriosis is an estrogen-dependent condition that affects 5 million American women; however, its etiology is not fully understood. The development of the baboon model of endometriosis provides an extremely powerful tool to investigate the development and progression of endometriosis from the early invasive phase to the advanced established disease. The inflammatory reaction that occurs in the peritoneal cavity at the site of endometriotic lesions does not clear the refluxed endometrial fragments. Moreover, this reaction appears to promote the survival of the tissue and the development of the disease. Exploration of the interactions between peritoneal macrophages and cytotoxic T cells and endometrial cells will determine whether their ability to scavenge and induce apoptosis is altered. Determining the mechanism(s) that induces the expression of estrogen and its receptor (ERbeta) is crucial to our understanding of the progression of the disease. The effects of ERbeta activation in endometriotic lesions should be investigated. It is important to determine the effects of estrogen on the function of the immune cells, either directly or indirectly. Finally, determining the effect of events at sites of ectopic endometrium on the eutopic endometrium may elucidate the mechanism(s) of infertility associated with endometriosis.
Lebrun CM et al., 2003·Br J Sports Med·
Open Access
Oral contraceptives are commonly used by women athletes. However, their effect on athletic performance is unclear. To examine the effects of a moderate dose, triphasic oral contraceptive on measures of athletic performance in highly trained women athletes. This is a double blind, placebo controlled trial in 14 women with ovulatory menstrual cycles and maximal aerobic capacity (VO(2)MAX) >/==" BORDER="0">50 ml/kg/min. Four measures of athletic performance were tested: VO(2)MAX, anaerobic capacity (anaerobic speed test), aerobic endurance (time to fatigue at 90% of VO(2)MAX), and isokinetic strength (Cybex II dynamometer). Height, weight, and six skinfold measurements were also recorded. All these observational tests were completed during both the follicular and mid-luteal phases of an ovulatory menstrual cycle. Cycle phases were confirmed by assaying plasma oestradiol and progesterone. Participants were subsequently randomly assigned to either a tricyclic oral contraceptive or placebo and retested in identical fashion (oral contraceptive phase). Absolute and relative changes in VO(2)MAX from follicular to oral contraceptive phase decreased in the oral contraceptive group by 4.7%, whereas the placebo group showed a slight increase (+1.5%) over the same time period. Two of the women taking oral contraceptive had decreases of 4 and 9 ml/kg/min. In contrast, most women in the placebo group improved or maintained VO(2)MAX. There was also a significant increase in the sum of skinfolds in women taking oral contraceptive compared with those taking placebo (p<0.01). There were no significant changes in other physiological variables (maximum ventilation, heart rate, respiratory exchange ratio, packed cell volume) or measures of performance (anaerobic speed test, aerobic endurance, isokinetic strength) as a function of oral contraceptive treatment. The decrease in VO(2)MAX that occurs when oral contraceptive is taken may influence elite sporting performance in some women. Further studies are required to determine the mechanisms of this change.
The purpose was to explore cyclicity of breast tenderness and vasomotor symptoms in menstruating mid-life women using the Daily Perimenopause Diary. Untreated mid-life women from a convenience sample completed the Daily Perimenopause Diary for clinical (n = 14) or research (n = 10) assessments. Breast tenderness, sleep disturbance and day and night vasomotor intensity were rated on a 0-4 scale with vasomotor number as a count. Daily oral temperature data were analyzed using the Quantitative Basal Temperature algorithm to assess ovulation and estimate luteal phase length. Analysis of variance tested cyclicity using the mean of three 3-day windows (during flow, at mid-cycle and premenstrually). Ninety-eight complete flow-to-flow diaries (from 24 women, mean age 47 years, cycle length 27 +/- 6.4 (standard deviation) days) were available, with quantitative temperature data for 60 cycles in 16 women. Of assessed cycles, 90% were ovulatory; 25% had luteal phases < 10 days. Breast tenderness was maximal in the premenstrual window overall (p < 0.0001) and in the ovulatory subset. Night sweats were maximal premenstrually (p = 0.0035) except in anovulatory cycles. Daytime flushes were not cyclic (p = 0.1333) except in ovulatory cycles (p = 0.031). Daily Perimenopause Diaries from mid-life women show premenstrual increases in breast tenderness and night sweats.
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
To determine whether self-selected women with polycystic ovary syndrome (PCOS) are abnormal compared with a control population. Case-control. Support group meeting organized and initiated by patients. PATIENT(S): Forty-five self-selected women with PCOS and 80 control women. INTERVENTION(S): Self-selected women with PCOS at a peer support conference completed a questionnaire, had a brief physical, and gave a fasting blood sample. MAIN OUTCOME MEASURE(S): Historical, biometric, and assay results. RESULT(S): Sixty percent of the women attending the conference participated in the study. Most had been diagnosed with PCOS on the basis of ovarian morphology (35%). They were more likely to be nulliparous and have a history of oligomenorrhea (96%). They were hyperandrogenemic (significantly elevated testosterone and DHEAS levels) compared with control women. Self-selected women with PCOS displayed multiple metabolic abnormalities compared with control women, including elevations in blood pressure, waist-hip ratio, fasting insulin, fasting total cholesterol, and fasting low-density lipoprotein cholesterol levels, as well as a significant decrease in fasting glucose-insulin ratio and high-density lipoprotein cholesterol levels. CONCLUSION(S): Self-selected women with PCOS have reproductive and metabolic abnormalities. The majority of these women received inadequate treatment despite having risk factors for endometrial cancer, diabetes, and/or heart disease. Our study also suggests that women attending or participating in a PCOS support group are willing and likely to participate in clinical studies.
This study examined pain sensitivity and pain modularity mechanisms (e.g., beta-endorphin levels, blood pressure) in women with premenstrual dysphoric disorder (PMDD; n = 27) and healthy controls (n = 27) during the follicular and luteal phases of the menstrual cycle. Physiological measures were taken during rest and ischemic pain testing. In both cycle phases, PMDD women (a) displayed lower resting cortisol and beta-endorphin levels and (b) exhibited shorter pain threshold and tolerance times and greater pain unpleasantness ratings during pain. PMDD women also reported greater pain unpleasantness and intensity and had lower beta-endorphin levels in their luteal phase and tended to display higher blood pressure levels at rest and during pain testing. Results suggest that endogenous opioids may be pathophysiologically relevant to PMDD and that the hypothalamic-pituitary-gonadal axis may modulate pain sensitivity in PMDD.
To compare the effects of cyproterone acetate and desogestrel, as part of combined oral contraceptives, on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome (PCOS). Prospective randomized clinical trial. Outpatient gynecology clinic (referral center) of a university. PATIENT(S): Twenty-eight adolescent girls with clinical and biological hyperandrogenism and six or less menses during the past 12 months. INTERVENTION(S): Group A (n = 14) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily. Group B (n = 14) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily. Treatment was given for 21 days followed by a 7-day rest for a period of 12 months. MAIN OUTCOME MEASURE(S): Hirsutism and lipid profile were evaluated before initiation and at 3, 6, 9, and 12 months of treatment. Androgen profile was evaluated before and at 12 months of treatment. RESULT(S): A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups. During therapy, the levels of testosterone, free testosterone, Delta(4)-androstenedione, and 17OH-progesterone decreased significantly, whereas sex hormone-binding globulin (SHBG) increased significantly in both groups. The level of total cholesterol and low density lipoprotein (LDL) cholesterol increased significantly, whereas high density lipoprotein (HDL) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged. The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month. CONCLUSION(S): Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and androgen levels. Both combined oral contraceptives are associated with an increase of total cholesterol, LDL cholesterol, and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides.
Women suffer more often from depression than males, indicating that hormones might be involved in the etiology of this disease. Low as well as high testosterone (T) levels are related to depression and well-being in women, T plasma levels correlate to depression in a parabolic curve: at about 0.4-0.6 ng/ml plasma free T a minimum of depression is detected. Lower levels are related to depression, osteoporosis, declining libido, dyspareunia and an increase in total body fat mass. Androgen levels in women decrease continuously to about 50% before menopause compared to a 20-year-old women. Androgen levels even decline 70% within 24 h when women undergo surgical removal of the ovaries. Conventional oral contraception or HRT cause a decline in androgens because of higher levels of SHBG. Hyperandrogenic states exist, like hirsutism, acne and polycystic ovary syndrome. Social research suggests high androgen levels cause aggressive behavior in men and women and as a consequence may cause depression. Higher androgen values are more pronounced at young ages and before and after delivery of a baby and might be responsible for the "baby blues". It was found that depression in pubertal girls correlated best with an increase in T levels in contrast to the common belief that "environmental factors" during the time of growing up might be responsible for emotional "up and downs". T replacement therapy might be useful in perimenopausal women suffering from hip obesity, also named gynoid obesity. Abdominal obesity in men and women is linked to type 2 diabetes and coronary heart diseases. Testosterone replacement therapy in hypoandrogenic postmenopausal women might not only protect against obesity but also reduce the risk of developing these diseases. Antiandrogenic progestins might be useful for women suffering from hyperandrogenic state in peri- and postmenopause. Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary. Substantial interindividual variability in T plasma values exists, making it difficult to utilize them for diagnostic purposes. Therefore a "four-level-hormone classification scheme" was developed identifying when estradiol (E) and T levels are out of balance. (1) Low E-low T levels are correlated with osteoporosis, depression, and obesity; (2) high E-low T with obesity, decreased libido; (3) high T-low E levels with aggression, depression, increased libido, and substance abuse; (4) high E-high T with type II diabetes risk, breast cancer and cardiovascular risk. Testosterone delivery systems are needed where beneficial and negative effects can be balanced. Any woman diagnosed for osteoporosis should be questioned for symptoms of depression.
To the Editor: In their recent article, "Characterization of Perimenopausal Bone Loss," Recker and colleagues present unique longitudinal bone mineral density (BMD) and hormonal data.1 We acknowledge the work involved in recruiting, motivating, and continuing to follow 75 women each for an average of 8 years. The data from this study are an important contribution to our knowledge of bone changes through the natural perimenopausal transition. Unfortunately, these authors have chosen to reduce the complex endocrinological and physiological changes of perimenopause2 to one idea—"estrogen deprivation." Our first concern is that "estrogen deprivation" or "depletion" is not an adequate concept with which to explain the rapid bone loss during perimenopause. The author's own data show that 50% of spinal BMD loss has occurred by 6 months before the final menstrual period at which time estradiol levels are not lower than in the so called "estrogen replete" group. In this study, perimenopausal bone loss appears to begin approximately 3 years before the final menstrual flow, which is about the time when menstrual cycles become irregular.3 Several other studies also show accelerated rates of perimenopausal bone loss.2, 4, 5 During these later phases of perimenopause, estradiol levels can be very high and certainly are not consistently low.2, 6, 7 If estradiol levels are not low in perimenopause, how can we explain the rapid bone loss? First, estradiol levels vary widely.2 Perhaps, acute drops in estradiol levels (often from abnormally high values) cause increased bone resorption much like that which has been shown to occur within seven days of premenopausal ovariectomy.8 A second possibility is that perimenopause causes psychosocial stress.9 Social stress coupled with high estradiol levels in men have been experimentally shown to cause increased cortisol levels10 that are known to be negative for bone. Finally, ovulatory changes that increase as women progress through perimenopause,11 are associated with accelerated cancellous bone loss, despite normal estradiol levels and regular cycles in premenopausal women.12 Replacement of luteal phases with cyclic progestin in a double-blind randomized study in premenopausal women with abnormal cycles caused an important positive change in spinal BMD.13 As a mechanism to allow use of all of their data, the authors labeled "estrogen replete" those women who continued to menstruate as well as those who started hormone therapy before menopause. It seems odd to us to combine data from three women who have undergone ovariectomy and seven women on exogenous hormone therapy with 10 preor perimenopausal women. The estrogen deprivation hypothesis has led the authors to overlook important physiological differences within this group. We request that the data for the 10 untreated preor perimenopausal women be provided and that we be told whether or not they continued to menstruate regularly. In women's life cycle, low levels of estrogen are as natural for menopausal women as for toddlers. To label menopause as a hormone deficiency condition is to ignore the normal hormonal pattern of women's lives. Recker and colleagues suggest that "hormone replacement therapy" should "begin as early as 2 years before the last menstrual period." Although we acknowledge that vasomotor symptoms commonly begin in perimenopause and have a very negative impact on quality of life, we suggest that progesterone would be a more appropriate therapy. Progesterone is truly low at this phase of perimenopause11 and is effective for night sweats/hot flushes. We fear that prescription of estrogen to women in late perimenopause may have negative consequences in both the short and the long-term. In the short term, it may exacerbate symptoms such as breast tenderness, headaches, and fluid retention. In the long term, having experienced side effects from estrogen treatment these women may refuse it when they are menopausal, a time when it has the potential to be valuable therapy. In summary, this important study is flawed because it relies on a clearly inadequate "estrogen deprivation" concept as the sole explanation for differences found in the prospective data from midlife women.
This review presents data to suggest that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants. During pregnancy, maternal plasma levels of estradiol and progesterone increase up to 100-fold compared to the nonpregnant status. The fetus is also exposed to these increasing hormone levels. After delivery, estradiol and progesterone levels drop by a factor of 100 within 1 day. Whereas this is a physiological condition for an infant born at term, preterm delivery means withdrawal from the placental supply of these hormones at an earlier developmental stage. Seventy years ago, the idea was raised that preterm infants may benefit from the replacement of estrogens. Studies in which estrogen was injected subcutaneously showed only a slightly better bodyweight gain compared to placebo-treated controls and therefore routine use was not established. The effective treatment of postmenopausal osteoporosis with hormone replacement therapy led to a pilot study of estradiol and progesterone therapy to prevent osteopenia of prematurity. The highest median bone mineral accretion rate was found in the replacement group when the supplementation with calcium and phosphorus was also sufficient. None of the previous studies dealing with estrogen replacement controlled for achieved plasma levels of estradiol in the infants. In our controlled randomised pilot study with 30 preterm infants (15 in each group), we aimed to maintain intra-uterine plasma levels of estradiol and progesterone. Preterm infants with replacement of estradiol and progesterone for 6 weeks postnatally showed trends to higher bone mineral accumulation. In addition, a trend towards a lower incidence of chronic lung disease was found. Neurodevelopmental follow-up showed normal psychomotor development in infants given estradiol and progesterone, whereas the untreated infants (controls) showed a trend towards delayed development. Recent research emphasises that estradiol and progesterone may be important for brain development. Thus, while there is data indicating that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants, experience with this new therapy is limited and extensive research is needed to address the potential benefits and to rule out adverse effects.
To evaluate the efficacy of progesterone and progestogens in the management of premenstrual syndrome. Systematic review of published randomised, placebo controlled trials. 10 trials of progesterone therapy (531 women) and four trials of progestogen therapy (378 women). Proportion of women whose symptoms showed improvement with progesterone preparations (suppositories and oral micronised). Proportion of women whose symptoms showed improvement with progestogens. Secondary analysis of efficacy of progesterone and progestogens in managing physical and behavioural symptoms. Overall standardised mean difference for all trials that assessed efficacy of progesterone (by both routes of administration) was -0.028 (95% confidence interval -0.017 to -0.040). The odds ratio was 1.05 (1.03 to 1.08) in favour of progesterone, indicating no clinically important difference between progesterone and placebo. For progestogens the overall standardised mean was -0.036 (-0.014 to -0.060), which corresponds to an odds ratio of 1.07 (1.03 to 1.11) showing a statistically, but not clinically, significant improvement for women taking progestogens. The evidence from these meta-analyses does not support the use of progesterone or progestogens in the management of premenstrual syndrome.
To improve prediction of ovulation in normal cycles. Collection of women's characteristics and their menstrual cycles. Monitoring and analysis of time relationships between several indicators of ovulation: transvaginal ultrasonography, cervical mucus, basal body temperature, urinary luteinising hormone, and ratio of urinary oestrogen to progesterone metabolites. Each of eight natural family planning clinics was to study 12 women for at least three cycles. One hundred and seven normally fertile and cycling women aged 18 to 45. Daily measurements of urinary luteinising hormone, follicle stimulating hormone, oestrone-3-glucuronide and pregnanediol-3alpha-glucuronide. Basal body temperature recording and cervical mucus checking. Transvaginal ultrasound examination of the ovaries. Delays between the expected day of ovulation according to the luteinising hormone peak or to ultrasound evidence and the expected days according to the other indices of ovulation. Ultrasonography was able to show evidence of ovulation in 283 out of 326 cycles. The average time lag between luteinising hormone peak and ultrasound evidence was less than one day (+0.46) but premature and late luteinising hormone-expected date of ovulation were observed in nearly 10% and 23% of cycles, respectively. Basal body temperature rise was observed in 98% of cycles. Cervical mucus peak symptom, rapid drop in the ratio of urinary metabolites, and luteinising hormone initial rise were all close to ultrasonographic evidence in more than 72% of cycles. For accuracy and practical reasons, the cervical mucus peak symptom, the ratio of urinary metabolites and luteinising hormone initial rise might be better indices of ovulation than the luteinising hormone peak.
To compare the effectiveness of i.m. P and 17alpha-hydroxyprogesterone caproate (17-HPC) for luteal phase support, in patients undergoing IVF-ET cycles. Prospective, randomized study. Patients undergoing IVF-ET in our Centers. PATIENT(S): The inclusion criteria were the use of GnRH down-regulation and aged <40 years. INTERVENTION(S): A total of 300 cycles were randomly treated with either 17-HPC (341 mg every 3 days) or P (50 mg daily). MAIN OUTCOME MEASURE(S): The outcomes of IVF in both study groups were evaluated for biochemical pregnancy, miscarriage, clinical pregnancy, and ongoing pregnancy. RESULT(S): No difference was found in the main outcome parameters considered. CONCLUSION(S): Although the results of the study encourage the use of 17-HPC for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that it can replace i.m. P-in-oil.
To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. Clinical research center in an academic medical institution. PATIENT(S): Seventy-seven women > or =18 years old with time since menarche > or =5 and < or =25 years were recruited by advertisement. INTERVENTION(S): Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. MAIN OUTCOME MEASURE(S): Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. RESULT(S): Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. CONCLUSION(S): The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.
The postpartum period is a time when women are vulnerable to depressive disorders, which can be severe and have long-lasting adverse sequelae. In spite of multiple contacts with health care providers, women with postpartum depression often remain unrecognized and untreated. To evaluate the association between estradiol and postpartum depression, we measured serum estradiol concentration and performed an open-label study of physiologic 17beta-estradiol. Twenty-three women fulfilling ICD-10 criteria for major depression with postpartum onset were consecutively recruited from a psychiatric emergency unit. Serum estradiol concentrations were measured at baseline and weekly during sublingual 17beta-estradiol treatment for 8 weeks. The treatment effect was assessed using a clinician-rated depression symptom scale, the Montgomery-Asberg Depression Rating Scale (MADRS). At baseline, all patients were severely depressed (mean MADRS total score = 40.7; range, 35-45) and had a low serum estradiol concentration (mean = 79.8 pmol/L; range, 23-140 pmol/L); in 16/23 patients, the concentration was even lower than the threshold value for gonadal failure. During the first week of estradiol treatment, depressive symptoms diminished significantly, resulting in a mean MADRS score of 11.0 (Z = -4.20, p < .001), and serum estradiol concentrations approached those of the follicular phase (mean +/- SD = 342 +/- 141 pmol/L). At the end of the second week of treatment, the MADRS scores were compatible with clinical recovery in 19/23 patients. This preliminary study shows that depression symptoms may be rapidly reduced in patients with postpartum depression who have documented estradiol deficiency by treatment with 17beta-estradiol and suggests that estradiol can have significance in the pathophysiology of this condition and may be an option in the treatment of women vulnerable to postpartum depression.
This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. New treatment approaches resulting from a refined understanding of the pathophysiology are evolving. The literature shows that PCOS is an endocrinopathy resulting from insulin resistance and the compensatory hyperinsulinemia. This results in adverse effects on multiple organ systems and may result in alteration in serum lipids, anovulation, abnormal uterine bleeding, and infertility. In addition, PCOS may place the patient at long-term risk for the development of type 2 diabetes, hypertension, endometrial cancer, and cardiovascular disease. Oral contraceptives, progestins, antiandrogens, and ovulation induction agents remain standard therapies. However, insulin-sensitizing agents are now being shown to be useful alone or combined with standard therapies. Early identification of patients at risk and prompt initiation of therapies, followed by long-term surveillance and management, may promote the patient's long-term health.
Over the past 20 years, it has been clearly documented that the polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and that insulin resistance plays an important role in the pathogenesis of the reproductive disturbances of the disorder. Family studies have indicated a genetic susceptibility to PCOS. Polycystic ovaries and hyperandrogenemia are present in approximately 50% of sisters of affected women. Increased androgen secretion and insulin resistance persist in cultured theca cells and skin fibroblasts, respectively, from women with PCOS; this finding suggests that these are intrinsic, presumably genetic, defects. Insulin resistance and elevated low-density lipoprotein (LDL) levels also cluster in the sisters of women with PCOS, consistent with genetic traits. Moreover, the brothers of women with PCOS have insulin resistance and elevated dehydroepiandrosterone sulfate (DHEAS) levels, which supports a genetic basis for these findings. Family-based studies of linkage and association have implicated several genes in the pathogenesis of PCOS. The strongest evidence to date points to a gene in the region of the insulin receptor. Insulin-sensitizing therapy mitigates the reproductive disturbances of PCOS.
To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome. Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles. General medicine community clinics. 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days. Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles. Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms). Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment. Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.
To relate serum allopregnanolone and progesterone levels postpartum to maternity "blues." Forty primiparous, healthy, married women (24-39 years of age; at least 13 years of education) who delivered healthy neonates in the Department of Obstetrics at the University of Pavia entered the present study. Blood samples were drawn at 8:30 AM on postpartum day 3 for measurements of serum allopregnanolone, progesterone, cortisol, prolactin, and estradiol. On the same day, every woman was interviewed using the Hamilton Rating Scale for Depression for psychometric testing and completed a self-administered version of the Stein Questionnaire for symptoms of the "blues." Eighteen of 40 women (45%) experienced maternity "blues" (12 who delivered vaginally and six who delivered by cesarean). Serum allopregnanolone levels were significantly lower in those women experiencing postpartum "blues" with respect to euthymic women (1.1 +/- 0.4 versus 2.3 +/- 1.0 nmol/L; P <.001), whereas progesterone levels did not differ significantly (11.6 +/- 5.6 versus 19.1 +/- 15.6 nmol/L; P >.058). Allopregnanolone and progesterone levels correlated significantly in euthymic women (r =.648; P =.001) but not in those with postpartum "blues" (r =.317; P =.199). There was a significant negative correlation between the Hamilton score and levels of serum allopregnanolone (r = -.62; P =.001) and progesterone (r = -.36; P =.024). Serum allopregnanolone levels were detectable postpartum and were significantly decreased in women with maternity "blues."
Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.
Cognitive dietary restraint, assessed by the Three-Factor Eating Questionnaire restraint subscale, is associated with subclinical menstrual cycle disturbances. This association may be mediated by stress-activated cortisol release. We assessed whether 24-h urinary cortisol excretion differs between women with high and low restraint scores.
Participants (aged 21.6+/-2.5 y; n = 62) with normal-length menstrual cycles and high (n = 33) or low (n = 29) restraint scores completed a questionnaire describing weight history, dietary practices, and exercise. Cortisol, calcium, and creatinine were measured in urine collected over 24 h on a day when all food and beverages were provided and measured. Previously, 3-d food records and anthropometric measurements were obtained. Age, height, weight, body mass index, and length of menstrual cycle were similar between groups. The reported amount of exercise was higher (3.4+/-1.7 compared with 2.2+/-1.8 h/wk; P<0.05) and energy intakes (assessed from 3-d and 24-h food records) were lower in the highthan in the low-restraint group. Ratios of urinary cortisol (nmol) to creatinine (mmol) were higher in the high-restraint than in the low-restraint group (42.9+/-12.9 compared with 36.3+/-8.9; P<0.05), whereas ratios of urinary calcium (mmol) to creatinine were lower (0.3+/-0.1 compared with 0.4+/-0.2; P<0.05) in the high-restraint group. Urinary cortisol was not associated with exercise, nutrient intakes, or anthropometric measurements. High dietary restraint scores are associated with urinary cortisol, a biological marker of stress, and high cortisol excretion may affect bone health. Our results suggest that further research is warranted to clarify these associations and to determine whether they persist over time.
Behre HM et al., 2000·Human reproduction (Oxford, England)
The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception. Daily serum LH measurements or transvaginal ultrasonography are not practical to determine ovulation in consecutive cycles for an individual. A prospective study was initiated to test the home use performance of the ClearPlan Fertility Monitor (CPFM) in ovulation prediction compared with transvaginal ultrasonography and serum hormone measurements. A total of 53 women aged 18-39 years with a normal uterus and at least one ovary, cycle length between 21-42 days and not using medication which interferes with ovarian function contributed 150 cycles for analysis. One cycle was anovulatory and no LH surge, indicating peak fertility, was detected by the monitor. Of the remaining 149 cycles, 135 (90.6%) had a monitor LH surge and ultrasonographically confirmed ovulation. Ovulation was detected in 91.1% of cycles during the 2 days of CPFM peak fertility. Ovulation was observed in 51.1% of cycles 1 day and in 43.2% of cycles 2 days after the surge in serum LH. Ovulation never occurred before CPFM peak fertility or the serum LH surge day. CPFM can help women who desire pregnancy to time intercourse. It may also have potential as a diagnostic aid and for monitoring the treatment of infertility.
To provide specific estimates of the likely occurrence of the six fertile days (the "fertile window") during the menstrual cycle.
Prospective cohort study. 221 healthy women who were planning a pregnancy. The timing of ovulation in 696 menstrual cycles, estimated using urinary metabolites of oestrogen and progesterone. The fertile window occurred during a broad range of days in the menstrual cycle. On every day between days 6 and 21, women had at minimum a 10% probability of being in their fertile window. Women cannot predict a sporadic late ovulation; 4-6% of women whose cycles had not yet resumed were potentially fertile in the fifth week of their cycle. In only about 30% of women is the fertile window entirely within the days of the menstrual cycle identified by clinical guidelines-that is, between days 10 and 17. Most women reach their fertile window earlier and others much later. Women should be advised that the timing of their fertile window can be highly unpredictable, even if their cycles are usually regular.
Recent diagnostic and pharmacologic developments have focused renewed attention on polycystic ovary syndrome. Clinical features of the syndrome include anovulation, hyperandrogenism and menstrual dysfunction, but several other abnormalities, including hyperinsulinemia, luteinizing hormone hypersecretion, elevated testosterone levels and acyclic estrogen production, have been documented. Accompanying obesity and lipid abnormalities compound the risk of developing diabetes mellitus or cardiovascular disease, and chronic anovulation increases the risk for endometrial cancer. A careful history and physical examination should guide diagnostic testing. Slowly progressive hyperandrogenic symptoms with anovulation of peripubertal onset often represent polycystic ovary syndrome. Treatment goals include symptom management and the identification and prevention of potential cardiovascular risks. Treatment should take into account the patient's desire for fertility. Advances in transvaginal ultrasonography and infertility treatments, including newer medications, have facilitated assisted reproduction in patients with polycystic ovary syndrome. Ongoing pharmacologic research focusing on the treatment of insulin resistance appears promising in reversing the longterm complications of the syndrome.
Bulletti C et al., 2000·Human reproduction (Oxford, England)
The non-pregnant uterus shows different patterns of contractility during the menstrual cycle. A renewed interest in uterine contractility has resulted from reports of non-invasive ultrasound (US) based studies. To clarify the changes in uterine contractility occurring throughout the menstrual cycle, we prospectively studied uterine contractions (UC) at six representative stages with US and intrauterine pressure (IUP) based approaches in 30 cycling volunteers. Results showed UC frequency could be measured by either US or IUP. UC amplitude and resting pressure tone could only be assessed by IUP. Conversely, direction of UC displacement could only be assessed by US. UC frequency increased at mid-cycle and decreased throughout the luteal phase suggesting oestradiol and progesterone exert positive and negative actions on uterine contractility, respectively. UC amplitude increased throughout the menstrual cycle to maximum values in the late luteal phase. Retrograde UC were most frequent at mid-cycle and convergent ('opposing') UC predominated during the luteal phase. While the former pattern ensures sperm transport, the latter may facilitate embryo implantation. In conclusion, UC changes throughout the menstrual cycle assessed by US and IUP emphasize the hormonal dependence of uterine contractility. Although UC patterns favouring sperm transport appear regulated by oestradiol, uterine quiescence and the dominance of convergent UC prevailing at the time of implantation are linked to progesterone. These data will serve to identify and treat possible dyskinetic changes in uterine contractility, particularly in women suffering from infertility, endometriosis, and dysmenorrhea.
Endocrine factors are purported to play a role in the etiology of postpartum depression, but direct evidence for this role is lacking. The authors investigated the possible role of changes in gonadal steroid levels in postpartum depression by simulating two hormonal conditions related to pregnancy and parturition in euthymic women with and without a history of postpartum depression. The supraphysiologic gonadal steroid levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by inducing hypogonadism in euthymic women-eight with and eight without a history of postpartum depression-with the gonadotropin-releasing hormone agonist leuprolide acetate, adding back supraphysiologic doses of estradiol and progesterone for 8 weeks, and then withdrawing both steroids under double-blind conditions. Outcome measures were daily symptom self-ratings and standardized subjective and objective cross-sectional mood rating scales. Five of the eight women with a history of postpartum depression (62.5%) and none of the eight women in the comparison group developed significant mood symptoms during the withdrawal period. Analysis of variance with repeated measures of daily and cross-sectional ratings of mood showed significant phase-by-group effects. These effects reflected significant increases in depressive symptoms in women with a history of postpartum depression but not in the comparison group after hormone withdrawal (and during the end of the hormone replacement phase), compared with baseline. The data provide direct evidence in support of the involvement of the reproductive hormones estrogen and progesterone in the development of postpartum depression in a subgroup of women. Further, they suggest that women with a history of postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal steroids.
Different routes of natural progesterone supplementation have been tried as luteal phase support in infertility treatments. Orally administered progesterone is rapidly metabolized in the gastrointestinal tract and its use has proved to be inferior to i.m. and vaginal routes. Progesterone i.m. achieves serum progesterone values that are within the range of luteal phase and results in sufficient secretory transformation of the endometrium and satisfactory pregnancy rates. The comparison between i.m. and vaginal progesterone has led to controversial results as regards the superiority of one or the other in inducing secretory endometrial transformation. However, there is increasing evidence in the literature to favour the use of vaginal progesterone. Vaginally administered progesterone achieves adequate endometrial secretory transformation but its pharmacokinetic properties are greatly dependent on the formulation used. After vaginal progesterone application, discrepancies have been detected between serum progesterone values and histological endometrial features. Vaginally administered progesterone results in adequate secretory endometrial transformation, despite serum progesterone values lower than those observed after i.m. administration, even if they are lower than those observed during the luteal phase of the natural cycle. This discrepancy is indicative of the first uterine pass effect and therefore of a better bioavailability of progesterone in the uterus, with minimal systematic undesirable effects.
to assess the therapeutic efficacy and safety of oral estriol for the treatment of climacteric symptoms in postmenopausal women. 68 postmenopausal women with climacteric symptoms received oral estriol, 2 mg/day, daily for 12 months. We evaluated the degree of climacteric complaints with estriol therapy; serum levels of gonadotropins, estradiol (E2) and lipids; biochemical markers of bone metabolism; blood pressure; and side effects both at baseline and during treatment. Climacteric symptoms were assessed according to the menopausal index (MI), a version of the Kupperman index that had been modified for Japanese women. oral estriol therapy significantly reduced total MI scores. The greatest relief was noted for hot flushes, night sweats, and insomnia. Estriol treatment significantly lowered serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations but did not affect any of the other parameters (lipids, bone, liver and blood pressure) during the study period. Slightly vaginal bleeding occurred in 14.3% of those who underwent natural menopausal women. Histologic evaluation of the endometrium and ultrasound assessment of the breasts following 12 months of estriol treatment found normal results in all women. Estriol is a safe and effective alternative for relieving climacteric symptoms in postmenopausal Japanese women.
To determine the prevalence of the polycystic ovary syndrome (PCOS) among women seeking electrology, clients presenting to nine electrology centers completed a questionnaire. Women with potential risk factors were referred to the University of Alabama at Birmingham. They underwent a detailed history and physical examination, including hirsutism scoring by a modified Ferriman-Gallwey (F-G) method. Serum was assayed for total testosterone, sex hormone binding globulin and dehydroepiandrosterone sulfate. Three hundred fifteen (40%) of 779 patients had potential risk factors for hyperandrogenism and were referred. Eighty-two (26%) completed their evaluation. Six were excluded secondary to prepubertal or menopausal status. Of the remaining 76 patients, 20% had F-G scores of 7 or 8, 13% had scores of 9 or 10, and 21% had scores > 10. Forty-nine (64%) patients reported irregular menstrual cycles. Sixty-four patients were not receiving hormonal therapy: 25 reported regular menstrual cycles, and 39 reported irregular cycles. Seventeen (68%) of the 25 had at least one abnormal androgen value, while 33 (85%) of the 39 women had at least one abnormal value (nonsignificant difference). Overall, PCOS was evident in 39 of the 76 women, or 12% of the 315 patients who were referred for further evaluation. Thirty-nine of the 315 referred patients (12%) fulfilled the diagnostic criteria for PCOS. However, they were not receiving medical care for this condition. In addition, this percentage is a conservative estimate in that 74% of the referred patients did not pursue a medical evaluation. Therefore, efforts to educate both electrologists and their clients of the possibility of underlying endocrine disorders and subsequent metabolic morbidity should be undertaken.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
Exercise is understood to exert positive effects on bone. However cancellous bone has not been shown to increase with exercise. Previous results of our 1-yr observational prospective study in ovulatory women related 20% of the change in cancellous spinal bone mineral density (BMD), measured by quantitative computed tomography (QCT), to luteal phase length (the time from ovulation to menstruation, LL). The 66 women who documented exercise daily included normally active women (N = 23) and those who ran consistently or were increasing running in preparation for a marathon (N = 43). Exercise did not affect BMD change in the women as a whole. We re-evaluated those data to determine whether exercise-related effects on spinal cancellous BMD change in regularly cycling premenopausal women were related to ovulatory characteristics. The potential relationship of exercise to BMD change was reanalyzed by stratifying women into tertiles according to average LL documented by quantitative basal temperature analysis. Repeated-measures ANOVA indicated independent positive effects of both luteal length (P = 0.001) and activity (P = 0.041). The 11 runners with LL > 10.9 d had a nonsignificant 0.5% increase in lumbar BMD while the 15 who averaged short LL (<9.9 d) experienced a significant 3.6% loss. In the runners as a group, however, kilometers run per week was negatively related to BMD change throughout (r = -0.347, P = 0.024). These data are the first to indicate that, in women with regular cycles, luteal length and exercise independently and positively affect change in spinal cancellous BMD.
To evaluate the efficacy of oral micronized progesterone compared with IM progesterone in oil for luteal support in patients undergoing IVF who are treated with a GnRH agonist. Randomized prospective clinical trial. University-based IVF center. PATIENT(S): Women <40 years of age who were undergoing IVF with luteal GnRH pituitary down-regulation. INTERVENTION(S): Patients were randomized to receive either oral micronized progesterone (200 mg three times daily) or IM progesterone (50 mg daily). MAIN OUTCOME MEASURE(S): Progesterone levels at standardized days 21 and 28, and pregnancy and embryo implantation rates. RESULT(S): Day 21 progesterone levels were 77.6+/-13.2 ng/mL in the IM group and 81.5+/-16.2 ng/mL in the oral group. Day 28 progesterone levels were 76.3+/-15.0 ng/mL in the IM group and 53.6+/-10.1 ng/mL in the oral group. The clinical pregnancy rates were 57.9% and 45.8% for the IM and oral groups, respectively. The implantation rate per embryo was significantly higher in the IM group (40.9%) than in the oral group (18.1%). CONCLUSION(S): When used according to our protocols, oral progesterone and IM progesterone result in comparable levels of circulating progesterone. However, oral progesterone results in a reduced implantation rate per embryo.
To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. Prospective follow-up study. Healthy couples recruited throughout Denmark. PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval 0.09-0.68). When the combined effect of cycle variation and cycle length was assessed, cycle variation was a persistent strong predictor of fecundity. CONCLUSION(S): The mechanisms of the present findings probably are female functional disturbances in ovulation, conception, implantation, or sustained pregnancy, linked with variable menstrual cycle length. Thus, identification of medical and environmental causes of abnormal menstrual cycle patterns may provide clues to the causes of infertility. Moreover, the menstrual cycle pattern also should be taken into consideration in the clinical decision-making process.
This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women.
To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on carotid and uterine vascular impedance. Sixty-three postmenopausal women were randomized to 1 year's treatment with oral or transdermal sequential combined HRT. Carotid and uterine artery pulsatility indices (PIs) were assessed by color Doppler at baseline, and after 2, 6, and 12 months of treatment. Fifty-eight women completed the trial, 27 in the oral and 31 in the transdermal group. In a subgroup of 30 women, we also performed Doppler measurements in the estrogen-progestin combined phase. The study had 90% power to detect a difference between treatment groups of 0.05 in the carotid artery and of 0.25 in uterine artery PI at the 5% significance level. The carotid PI decreased significantly (P < .001) and similarly during both regimens. This drop was already clearly detectable during the second month, from 0.97 (0.95, 1.01) (mean and 95% confidence intervals [CII) to 0.94 (0.91, 0.97) in the oral and from 0.98 (0.94, 1.00) to 0.92 (0.89, 0.95) in the transdermal group, but it continued up to 12 months (0.85 [0.82, 0.88], 13% of baseline values in the oral group and 0.84 [0.81, 0.871, 14% in the transdermal group). In the uterine arteries, the drop in PI was steeper and greater and reached its maximum at 6 months (39% and 40%, respectively). Drops in carotid and uterine PI correlated positively with baseline PI values, but were not affected by patient age, time from menopause, previous HRT and smoking. Addition of norethisterone acetate did not counteract drops in carotid and uterine PI in either group. Oral and transdermal sequential HRT are similarly effective at 1 year in reducing impedance to flow in carotid and uterine circulation. This long-term vascular effect might explain how HRT protects women from cardiovascular disease.
I. Introduction II. Defining the Perimenopause III. Classic Studies of the Perimenopause A. Historical studies B. Early reports of women’s experiences in the perimenopause C. Early prospective menstrual cycle interval and basal temperature documentation IV. Prospective Epidemiological Studies of the Perimenopause A. Manitoba Project on Women and Their Health in the Middle Years B. Massachusetts Women’s Health Study C. Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study V. Systematic Studies of the Endocrinology of the Perimenopause A. Cross-sectional (single-cycle) hormonal studies in the perimenopause B. Prospective ovarian hormonal levels in the perimenopause VI. Histological Studies of Ovarian Changes Across the Lifespan VII. Physiological Studies of Changing Ovarian Hormones in Women in Their Forties and Fifties A. Folliculogenesis and ovarian hyperstimulation for in vitro fertilization (IVF) B. Inhibin physiology in women over forty VIII. Hypotheses to Explain Perimenopausal Endocrinology A...
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.
To determine the serum concentrations of the sex steroid hormones with respect to the concentrations of the biologically active fractions of magnesium and calcium during the different phases of the menstrual cycle. Controlled clinical study. An academic research environment. PATIENT(S): Six parous and four nulliparous healthy cycling female volunteers. MAIN OUTCOME MEASURE(S): Concentrations of the sex steroid hormones estrogen, progesterone, and testosterone as well as the ionized Ca and Mg levels were measured in the serum of normal cycling women during five different stages: the menstrual, early follicular, late follicular, ovulatory (ovulatory/early luteal), and luteal phases. RESULT(S): In each woman, there was a comparatively high ionized Mg level coincident with the early follicular phase, a statistically significant decrease in ionized Mg around the time of ovulation, a significant decrease in ionized and total Mg when the serum progesterone concentration peaked, and a significant increase in the serum Ca2+/Mg2+ ratio at both the ovulatory and luteal phases. In addition, a decrease in ionized Mg was found with increased testosterone levels. CONCLUSION(S): Healthy women of reproductive age demonstrate recurring cycling of ionized Mg and cyclic alterations in the ionized Ca to Mg ratio in their serum. The changes in serum concentrations of these important physiologically active cations, in the range at which they occur, can affect such entities as the vasculature, synaptic transmission, and excitation-secretion coupling and thus can produce the well-known premenstrual syndromes during the luteal phase in women who are somewhat deficient in Mg or in those who have an unusually increased Ca2+/Mg2+ ratio.
To study the effects of estradiol and progesterone on the proliferation of normal human breast epithelial cells in vivo. Double-blind randomized study. Departments of gynecology and of cell biology at a university hospital. PATIENT(S): Forty postmenopausal women with untreated menopause and documented plasma FSH levels of >30 mIU/mL and estradiol levels of <20 pg/mL. INTERVENTION(S): Daily topical application to both breasts of a gel containing a placebo, estradiol, progesterone, or a combination of estradiol and progesterone during the 14 days preceding esthetic breast surgery or excision of a benign lesion. MAIN OUTCOME MEASURE(S): Plasma and breast tissue concentrations of estradiol and progesterone. Epithelial cell cycles were evaluated in normal breast tissue by counting mitoses and performing quantitative proliferating cell nuclear antigen immunolabeling analyses. RESULT(S): Increasing the estradiol concentration enhanced the number of cycling epithelial cells, whereas increasing the progesterone concentration significantly limited the number of cycling epithelial cells. CONCLUSION(S): Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal breast epithelial cells in vivo.
The months following childbirth are a time of heightened vulnerability to depressive mood changes. Because of the abrupt and dramatic changes occurring in hormone levels after delivery, many studies have examined the role of hormonal factors in postpartum depression. The authors review the literature on potential hormonal etiologies in postpartum depression, in particular for progesterone, estrogen, prolactin, cortisol, oxytocin, thyroid, and vasopressin. While evidence for an etiologic role is lacking for most hormones, changes in certain hormonal axes may contribute to depressive mood changes in some women following childbirth.
The purpose of this pilot study was to correlate the three biologic markers of the Ovulon fertility monitor (a long-term predictive peak about 6 days before ovulation, a short-term predictive peak about 1 day before ovulation, and a nadir at the time of ovulation) with the peak in cervical mucus and the luteinizing hormone (LH) surge in the urine. Ten volunteer subjects (mean age 30.2 years) monitored their cervical-vaginal mucus, the surge of LH in the urine with a home assay test, and their vaginal electrical readings (with Ovulon monitors) on a daily basis for one to four menstrual cycles. In 19 of the 21 cycles that indicated a LH surge, there was a strong positive correlation between the LH surge and the peak of cervical-vaginal mucus (r = 0.96, P < or = .01), and between the LH surge and both the Ovulon nadir and Ovulon short-term predictive peak (r = 0.84, P < or = .01), and a modest positive correlation between the long-term Ovulon predictive peak and the LH surge (r = 0.62, P < or = .01). The time of optimal fertility as determined by the peak in cervical mucus, the LH surge, and the Ovulon was similar. The Ovulon has potential as a reusable device to help women determine their fertile period.
It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.
To evaluate the anxiolytic 3alpha-5alpha-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls. Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data. Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 +/- 0.8 versus 7.5 +/- 1.3 ng/mL; P < .04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 +/- 0.3 versus 3.2 +/- 1.3 ng/mL; P < .05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels. Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.
Both hyperand hypothyroidism may result in menstrual disturbances. In hyperthyroidism, amenorrhea was described as early as 1840 by von Basedow. The most common manifestation is simple oligomenorrhea (decreased menstrual flow). Anovulatory cycles are very common. Increased bleeding may occur, but is rare in hyperthyroidism. Nowadays hyperthyroidism is diagnosed earlier than it once was, and so the clinical picture is generally milder. So, menstrual disorders are less common than in previous series. In a recent paper, 21.5% of 214 patients had disturbances in their cycle, compared to 50% in some older series. In hypothyroidism, on the contrary, polymenorrhea (increased menstrual bleeding) is more common. Defects in hemostasis may contribute to this. Anovulation may be represent. Fertility is reduced in both hyperand hypothyroidism, and the outcome of pregnancy is more often abnormal than in euthyroid women. It is of interest that in juvenile hypothyroidism precocious puberty has been described. This is probably due to a "spillover" effect of the glucoprotein hormones: TSH,
The objectives of this study were to assess (1) whether treatment with oral contraceptives, in comparison with medroxyprogesterone and placebo, improved bone mineral in women with hypothalamic amenorrhea and (2) whether treatment with medroxyprogesterone, in comparison with placebo, improved bone mineral in women with hypothalamic oligomenorrhea. The study was a randomized, controlled clinical trial. Twenty-four white women, aged 14 to 28 years, with hypothalamic amenorrhea or oligomenorrhea were prospectively enrolled for a 12-month intervention period. Amenorrheic subjects were randomized to receive oral contraceptives, medroxyprogesterone, or placebo. Oligomenorrheic subjects were randomized to receive medroxyprogesterone or placebo. Bone mineral was measured by dual-energy x-ray absorptiometry at baseline and at 6 and 12 months. In amenorrheic subjects spine and total body bone mineral measurements at 12 months were greater in the oral contraceptive group than in the medroxyprogesterone and placebo groups when baseline bone mineral measurements, body weight, and age were controlled for (p < or = 0.05). There were no differences in hip bone mineral calcium and bone mineral density measurements at 12 months among the three groups. In oligomenorrheic subjects there was no detectable improvement in bone mineral associated with medroxyprogesterone use. This study supports the hypothesis that oral contraceptive use in women with hypothalamic amenorrhea will improve lumbar spine and total body bone mineral.
Petit MA et al., 1997·Medicine & Science in Sports & Exercise·
Current concepts suggest that normal estrogen levels are necessary for exercise to have an osteogenic effect on bone. In a population of running and sedentary women Prior et al. (NEJM, 1990) have shown that consistent ovulation is necessary to prevent spinal cancellous bone loss. Change in spinal bone mineral density was measured by quantitative computed tomography (QCT) in running and sedentary women over one year, along with prospective documentation of dietary, menstrual cycle, hormonal, and exercise variables. Of the 66 women studied only 12 remained ovulatory throughout the year. Forty-two women were runners of which 6 were consistently ovulatory. We hypothesized that ovulation would interact with an exercise effect on cancellous bone. Analysis of the 42 runners showed an average loss in bone of 1.8%. Luteal phase index (r = 0.509) and average progesterone (r = 0.381) were correlated with change in QCT, but not estrogen, calcium, or any other hormonal, dietary, or morphometric variable. There was a negative association between change in QCT and number of km run/week (r = -0.319). In the 12 consistently ovulatory women, average cancellous bone increased in runners(≈2%) and decreased in nonrunners (N) by ≈1% (seefig.). These data are the first to show an increase in purely cancellous bone with moderate levels of aerobic activity. The results suggest that the presence of consistently ovulatory cycles, and thus progesterone in addition to estrogen, may be necessary for an osteogenic effect of low impact exercise (running) on cancellous bone.
To investigate the predictive value of polycystic ovaries for endocrine signs of polycystic ovary syndrome (PCOS). Controlled descriptive study. Academic tertiary care fertility clinic. PATIENT(S): Normogonadotropic (FSH levels between 1 and 10 mIU/mL conversion factor to SI unit, 1.0) oligomenorrheic or amenorrheic women visiting our fertility clinic and a control group of regularly cycling, healthy, normal weight volunteers recruited by advertisement. INTERVENTION(S): Single blood samples and transvaginal sonography were performed. MAIN OUTCOME MEASURE(S): Serum levels of FSH, LH, androstenedione (A), and T and ovarian volume, ovarian stroma density, and follicle number. RESULT(S): In control women, the 95th percentile was calculated for ovarian volume, follicle number, and stroma count as well as endocrine parameters. The use of these upper limits of normal in the study group resulted in 217 (66%) patients with polycystic ovaries on ultrasound (defined as increased mean ovarian volume and/or mean follicle number per ovary), whereas only 120 (36%) patients exhibited elevated serum androgens (increased A and/or T concentrations) and 155 (47%) showed elevated LH levels. Sensitivity and specificity of single or combined sonographic parameters for prediction of elevated serum LH or androgen concentrations were limited. CONCLUSION(S): In the study group of normogonadotropic oligomenorrhea or amenorrheic infertile women, we set strict cutoff levels for various criteria used in the literature for defining PCOS. Groups defined by sonographic or endocrine PCOS criteria did overlap, but sonographic parameters had limited predictive value for abnormal hormone serum levels.
To evaluate the luteal phase in women with rigorously defined unexplained infertility. Prospective study. National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria for unexplained infertility: [1] infertility of > or = 24 months duration, with no male factor, anatomic-functional disorders of the reproductive tract, or immunologic infertility; [2] normal body mass index (BMI); [3] ovulatory cycles ranging from 26 to 32 days; [4] normal luteal phase determined by endometrial biopsy; and [5] normal baseline hormonal profile. Controls (n = 12) were healthy, parous women with normal ovulatory cycles, normal hormonal screen, and were matched for age and BMI to patients. MAIN OUTCOME MEASURE(S): Pattern of follicular growth rate and luteal phase hormonal profile. RESULT(S): Women with unexplained infertility did not differ in menstrual cycle characteristics, follicular growth rate or mean preovulatory follicle diameter, or endometrial biopsy dating. The mean levels of P tended to be lower in the unexplained infertility group throughout the luteal phase, but only the midluteal interval reached statistical significance. Luteal phase mean integrated P or urinary PDG levels of unexplained infertility women did not differ from those of fertile controls. The ratio of integrated E2:P also was significantly greater in women with unexplained infertility than in fertile controls. CONCLUSION(S): Women with rigorously defined unexplained infertility have subtle hormonal anomalies during the luteal phase when compared with fertile controls.
Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.
Kupesic S et al., 1997·Eur J Obstet Gynecol Reprod Biol·
To evaluate intraovarian resistance index (RI) in 47 healthy fertile volunteers with ovulatory cycles, 28 patients with luteal phase defect (LPD) and four patients with luteinized unruptured follicle (LUF Sy). Transvaginal color Doppler assessment of the follicular and corpus luteum blood flow and plasma progesterone (P) levels were obtained in each patient. Significantly higher intraovarian artery RI (< 0.001) was obtained for LPD group than for controls during the luteal phase. In the control group both follicular and corpus luteum RI were significantly lower (P < 0.001) on the dominant side, while in LPD group no difference (P > 0.05) between the sides occurred. Mean P levels were significantly lower (P < 0.001) in the LPD group (6.9 +/- 2.3 ng/ml) than in controls (24.1 +/- 11.4 ng/ml). In all the LPD patients histopathology revealed delayed endometrial pattern, while normal endometrial dating was found in all the evaluated patients form the control group (n = 15). In the patients with LUF Sy (n = 4) similar RI values were obtained in the follicular and corpus luteum phase. There was no difference between the sides in terms of the intraovarian RI, while subnormal values of P were obtained in all the examined patients (14.1 +/- 6.2 ng/ml). Transvaginal color Doppler may predict the function capacity of the corpus luteum.
To study the effects of clomiphene citrate (CC) on the endometrium by ultrasound and to reveal the echogenic difference between the control cycle and the CC cycle. Retrospective study of patients before and during a CC treatment. Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. PATIENT(S): Seventy-nine infertile women who had a spontaneous ovulation and a normal luteal function. INTERVENTION(S): Patients received 50 mg/d CC between days 5 and 9 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Endometrial thickness, echogenic pattern of the endometrium, serum E2 content, and E2 and P receptor contents in the endometrium. RESULT(S): Endometrial thickness was significantly thinner during the CC cycle (7.6 +/- 1.4 mm, mean +/- SD, n = 79) than during the control cycle (8.5 +/- 1.7 mm, n = 79) on late proliferative days, but there was no significant difference on midsecretory days (10.8 +/- 2.2 mm during the CC cycle, n = 79; 11.2 +/- 2.2 mm during the control cycle, n = 79). The echogenic patterns, however, were different between the two cycles on midsecretory days. Moreover, the incidence in which patients showed a grade 3 endometrium on midsecretory days was significantly higher during the conceived CC cycle compared with the not-conceived CC cycle. Serum E2 levels were significantly higher, but E2 receptor contents in the endometrium were significantly lower during the CC cycle (67 +/- 46 fmol/mg, n = 13) compared with the control cycle (123 +/- 89 fmol/mg, n = 15) on late proliferative days. CONCLUSION(S): Clomiphene citrate affected the echogenic pattern of the endometrium, and most of the endometrium showed a grade 3 pattern on midsecretory days during the conceived CC cycle. Under the CC treatment, the comfortable endometrium for embryos might be different from the control cycle.
Postpartum mood disorders are common. The clustering of mood-disorder episodes after birth compels a search for factors particularly potent during childbearing. In this article, the complex relationships between the dynamic postbirth physiological environment and mood disorder are discussed. Available studies show a lack of evidence that serum levels of gonadal hormones account for mood disturbance in women. However, substantial amounts of data demonstrate their ability to modulate other neuroendocrine systems. Alterations in hypothalamic-pituitary-adrenal (HPA) axis function attributable to childbearing show remarkable similarity to those observed in depressed women. Postpartum women are also at increased risk for hypothalamic-pituitary-thyroidal (HPT) axis dysfunction that may increase affective-disorder vulnerability. A decreased rate
Breast cancer incidence rates are high in societies with a Western lifestyle characterized by low levels of physical activity, and by an energy-dense diet rich in total and saturated fat and refined carbohydrates. Epidemiologic studies, so far mostly on postmenopausal women, have shown that breast cancer risk is increased in hyperandrogenic women, with decreased levels of plasma sex-hormone binding globulin, and with increased levels of testosterone and of free estrogens. This paper describes the role of hyperinsulinemia as a physiologic link between nutritional lifestyle factors, obesity, and the development of a hyperandrogenic endocrine profile, and reviews evidence that may or may not support the theory that chronic hyperinsulinemia is an underlying cause of breast cancer. An hypothesis is presented, stipulating that breast cancer risk is increased not only in hyperandrogenic postmenopausal women, but also in premenopausal women with mild hyperandrogenism and normal (ovulatory) menstrual cycles. The author suggests further investigation as to whether there is a positive association between risk of breast cancer before menopause and subclinical forms of the polycystic ovary syndrome (PCOS), and to what extent diet and physical activity during childhood, by modulating the degree of insulin resistance during adolescence, may or may not be determinants of a PCO-like hyperandrogenic endocrine profile persisting into adulthood.
Two progesterone presentations, a vaginal application of 90 mg progesterone per day (Crinone) or 300 mg progesterone administered orally (Utrogestan), were compared for luteal phase support of patients undergoing an in-vitro fertilization (IVF) procedure. A total of 283 patients were randomly allocated to either treatment. The treatment started within 24 h after the embryo transfer procedure and continued until day 30 in cases of implantation. Efficacy was assessed using the pregnancy and delivery rates. Safety was assessed through specific symptoms and usual safety monitoring. The pregnancy rates per transfer were not significantly different in the Crinone and Utrogestan groups at days 12 (Crinone 35.3%, Utrogestan 29.9%, P = 0.55), 30 (Crinone 28.5%, Utrogestan 25.0%, P = 0.61) and 90 (Crinone 25.9%, Utrogestan 22.9%, P = 0.69). No differences in the spontaneous abortion rates were seen thereafter. The delivery rates (number of deliveries per patient; Crinone 23.0%, Utrogestan 22.2%, P = 1.00), as well as the ratio of newborn babies per embryo transferred (Crinone 11.7%, Utrogestan 11.1%, P = 0.91), were not significantly different. Safety parameters were similar in both groups, except for drowsiness, which was more significantly frequent in the oral progesterone group than in the Crinone group at all time points. No serious adverse events were recorded in this study. The fact that Crinone matches the efficacy of the larger doses of progesterone used orally reflects an advantage of the transvaginal route of administration which avoids the metabolic inactivation of progesterone during its first liver pass.
1. The effect of the different phases of the menstrual cycle on skeletal muscle strength, contractile properties and fatiguability was investigated in ten young, healthy females. Results were compared with a similar group on the combined (non-phasic) oral contraceptive pill (OC). Cycle phases were divided into the early and mid-follicular, mid-cycle (ovulatory) and mid- and late luteal. Cycle phases were estimated from the first day of the menstrual bleed. 2. Subjects were studied weekly through two complete cycles. Measurements included quadriceps and handgrip maximum voluntary isometric force and the relaxation times, force-frequency relationship and fatigue index of the quadriceps during percutaneous stimulation at a range of frequencies from 1 to 100 Hz. 3. In the women not taking the OC there was a significant increase of about 11% in quadriceps and handgrip strength at mid-cycle compared with both the follicular and luteal phases. Accompanying the increases in strength there was a significant slowing of relaxation and increase in fatiguability at mid-cycle. No changes in any parameter were found in the women taking the OC. 4. The changes in muscle function at mid-cycle may be due to the increase in oestrogen that occurs prior to ovulation.
Healthy premenopausal women with regular cycles are believed to be increasing or maintaining bone density. However, few studies have prospectively documented spinal cancellous bone, the bone that changes rapidly in response to reproductive hormones, in this population. Furthermore, our previous one-year study documented that 24% of the one-year bone change by quantitative computed tomography (QCT) was related to subclinical ovulatory disturbances (short luteal phase and non-ovulation) in the presence of regular menstrual cycles. The purpose of this study was to document the cancellous bone change over five years in this initially ovulatory, premenopausal cohort of 66 healthy women. Thirty-seven women, who continued to be premenopausal and have regular cycles, completed this five-year study. Those enrolled differed only by being older and weighing less than those who could not be contacted (n = 19) or who declined to participate (n = 10). Documentation of current ovulatory characteristics was obtained for at least three cycles in 27 women. At the five-year assessment, the volunteers were 40.6 (range 26-47) years old, weighed 58.5 (41-77) kg, and were 160.9 (149-174) cm in height. All were premenopausal, healthy, nonsmokers with regular menstrual cycles (mean 27.7, range 24-33 days). Six women with intervening events (such as pregnancy or use of oral contraceptives) had interval (12 to 60 months) QCT changes similar to the remaining 31 (-7.98 vs. -4.92 mg/cm, p = 0.1, respectively). Mean five-year QCT was 143.0 +/- 20.2 mg/cm, whereas the initial mean value was 151.9 +/- 20.1 mg/cm. Significant QCT loss over five years (-8.9 +/- 6.2 mg/cm) (95% Cl -6.9 to -11.0) correlated with QCT change in the first year (r = 0.629, p < 0.001). First-year change was not related to the subsequent four-year interval change (r = -0.056, p = 0.74), however. Five-year QCT change was not related to age, weight, osteoporosis family history, estimated calcium intake, or exercise, but did correlate with year one luteal index (luteal/cycle length) (r = 0.339, p = 0.043). Significant cancellous spinal bone loss occurs in healthy, ovulatory premenopausal women, and is influenced by subclinical disturbances of ovulation.
To compare the expression of endometrial P receptors (PR) levels with markers of endometrial receptivity during the window of implantation. Prospective, controlled study to examine endometrial PR and three cycle-specific integrins in endometrial biopsies obtained during the window of implantation. An academic teaching hospital. One hundred seventy-five endometrial biopsies from regularly cycling women with luteal phase defect (LPD; group 1; n = 80), medically treated LPD (group 2; n = 16), minimal and mild endometriosis with aberrant alpha v beta 3 expression (group 3; n = 21), fertile controls (group 4; n = 26), and infertile controls (group 5; n = 32). Immunohistochemical staining intensity of each antigen using the semi-quantitative grading system (HSCORE), compared using analysis of variance with Scheffe's correction. Among the five groups studied, nuclear PR expression was significantly elevated in glandular epithelial cells from tissue samples with histologic delay > or = 3 days consistent with luteal phase deficiency (LPD; group 1). Failure of PR down-regulation was associated with aberrant alpha v beta 3 integrin expression. Medical correction of LPD was associated with return of normal endometrial histology, normal integrin expression, and the loss of epithelial PR, similar to controls. The other two cycle-dependent integrin markers, alpha 1 beta 1 and alpha 4 beta 1, were not different between groups. In women with aberrant alpha v beta 3 and "in phase" endometrium, epithelial PR expression was not different from controls. The establishment of normal endometrial receptivity appears to be tightly associated with the down-regulation of epithelial PR. Histologic delay, consistent with LPD, is associated with a failure of PR down-regulation and the lack of normal markers of endometrial receptivity. Occult uterine receptivity defects (aberrant beta 3 expression in otherwise normal histology) are regulated differently, suggesting alternate mechanisms also exist which influence endometrial receptivity.
Seven women with histories of puerperal psychosis and four with histories of puerperal major depression were consecutively treated with high-dose oral estrogen immediately following delivery. None of the women had histories of nonpuerperal affective disorder, and all women were affectively well throughout the current pregnancy and at delivery. Despite the high risk for recurrent illness in this population, only one woman developed relapse of postpartum affective disorder. All others remained entirely well and required no treatment with psychotropic medications during the 1 year follow-up period. This low rate of relapse, 9% compared to an expected 35-60% without prophylaxis, suggests that oral estrogen may stem the rapid rate of change in estrogen following delivery, thereby preventing the potential impact on dopaminergic and serotonergic neuroreceptors. It is hypothesized that the rapid rate of change of estrogen after delivery creates an "estrogen withdrawal state." This may be a critical factor in driving acute puerperal affective psychosis and early-onset puerperal major depression.
To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.
Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.
Sahmay S et al., 1995·Int J Fertil Menopausal Stud·
Endometrial biopsy has been an important way of assessing infertile couples for several years. In this review of a wide-ranging series of endometrial biopsies of infertile couples in the Turkish population it was our aim to find the distribution of results according to the years 1956-1966, 1967-1980, 1981-1992. University hospital. 12,949 endometrial biopsies, referred to our gynecological pathology laboratory for infertility investigation between 1956 and 1992. Patient report files from pathology laboratory data, analyzed retrospectively. The assessment of the biopsies is made by the same pathologist. 78.8% of cases had primary infertility, 21.2% secondary. Most of them were in the age group 26-35 years (48.8%). 37.58% of cases were found to show normal secretory endometrium, 20.95% proliferative endometrial changes, and 28.22% signs of luteal phase defect (LPD). Other local endometrial factors were also encountered, but in 1.79% the sample was considered insufficient for diagnosis. Moreover, in nine cases, malignancy was diagnosed with the help of endometrial biopsy. During the study period, cases of normal secretory endometrium and tuberculous endometritis were observed to decrease and LPD to increase significantly. It is worthy to note that in only 28 (0.21%) cases had endometrial biopsies been performed during a pregnancy cycle. We conclude that endometrial biopsy not only shows the hormonal response of endometrium but gives additional information about the local factors of endometrium concerning atrophy, specific and non-specific infections, and malignancy.
This open trial assessed the effects of adjunctive progesterone therapy on seizure frequency in 25 women with catamenial exacerbation of complex partial (CPS) and secondary generalized motor (SGMS) seizures. Progesterone was well tolerated by 23 of the 25 women and had readily reversible dose-related side effects of asthenia and emotional depression in two. Eighteen women (72%) experienced a decline in seizure frequency during a 3-month treatment period compared with the 3 months prior to therapy (p < 0.01). Average daily CPS frequency declined by 54% (p < 0.01), SGMS by 58% (p < 0.02).
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.
To determine whether color flow pulsed Doppler analysis of corpus luteum blood flow in normal cycles differs from cycles with a luteal phase defect. A prospective study of natural ovarian cycles. The University of Vermont Reproductive Endocrinology and Infertility Service. Ten women with regular menstrual cycles and at risk for luteal phase defect (LPD) four with unexplained infertility, two with recurrent abortion, and four with age > 35 years. All women were examined by transvaginal color flow pulsed Doppler during the early follicular, late follicular, early luteal, midluteal, and late luteal phase of the menstrual cycle. Venous blood for P concentration was drawn on each day of Doppler exam. Urine testing for LH surge and endometrial biopsy during the late luteal phase were performed on each patient. Lowest resistance index associated with the highest amplitude signal from intraovarian vessels of each ovary, dated endometrial biopsies, serum P. Mean resistance indexes in LPD patients (n = 3) were significantly higher compared with normal women (n = 6) throughout the follicular and luteal phases. One patient remained anovulatory and was excluded from statistical analysis. Although systolic and diastolic velocities generally were observed to be lower in LPD patients compared with normal women, these differences were not statistically significant. High correlations were observed between P and resistance index within each luteal time point, achieving its highest value during the midluteal phase. This initial study provides evidence that color flow pulsed Doppler analysis of blood flow impedance to the corpus luteum may aid in assessing luteal phase adequacy.
To determine the effectiveness of oral micronized progesterone, alprazolam, and placebo in premenstrual syndrome (PMS) treatment and the effect of clinical contact on treatment responses. Randomized, double-blind, placebo-controlled 3-month parallel treatment arms with flexible dosage and with the length of clinical contact randomized within each treatment group. University hospital PMS medical treatment outpatient program in obstetrics/gynecology department. Among volunteers for PMS treatment, 444 were evaluated and 185 meeting defined PMS criteria were randomized to treatment; treatment data are available for 170. There were no medical withdrawals for adverse events. A double-blinded protocol in which 300 mg of oral micronized progesterone, 0.25 mg of alprazolam, or placebo was administered four times a day from day 18 of the menstrual cycle through day 2 of the next cycle, including taper. The mean daily dose at the third treatment was 1760 mg of progesterone or 1.5 mg of alprazolam. Subjects were randomized to brief (< 20 minutes) or extended (50 minutes) visits. Daily symptom report (DSR) scored for total DSR symptoms, four DSR factors. Alprazolam was significantly better than placebo or progesterone for total premenstrual symptoms and DSR factors of mental function, pain, and mood. Thirty-seven percent of the alprazolam group experienced a 50% reduction in total DSR scores. There were no clinically significant withdrawal symptoms when alprazolam administration was restricted to the luteal phase. Oral micronized progesterone therapy was no better than placebo. Brief vs extended visits had no effect on treatment outcome. Treatment response was associated with severity of premenstrual symptoms at baseline but with no other diagnostic variables. Alprazolam has a role in PMS treatment and offers a therapy limited to the luteal phase. Oral micronized progesterone is ineffective for PMS.
To assess whether temperature is increased by medroxyprogesterone (MPA) and thus whether basal temperature records could be used to determine ovulation during cyclic MPA therapy.
A 2-month double-blind placebo-controlled crossover trial in which oral basal temperature was measured daily.
Normal human volunteers in an academic medical environment. Eleven postmenopausal women not taking gonadal hormones. Medroxyprogesterone acetate (10 mg/d) or placebo, calendar days 16 to 25, with crossover. Comparison of mean temperature days 17 to 26 during MPA versus placebo; comparison of differences between temperatures days 7 to 16 and 17 to 26 in MPA versus placebo months; and analysis for a significant monthly thermal shift. The mean temperatures during MPA treatment averaged 0.27 degrees C higher than during the placebo phase and showed a significant change from pretreatment to "treatment" phases during MPA but not during placebo cycles. Eight of the MPA and one of the placebo cycles showed a shift from lower to higher temperatures days 16 to 25. Medroxyprogesterone acetate has a physiological progesterone-like thermal effect. Therefore basal temperature data cannot reliably indicate ovulation during cyclic MPA administration.
To study the effect of E2 and P on the epithelial cell cycle of normal human breast in vivo. Double-blind, randomized study. Topical application to the breast of a gel containing either a placebo, E2, P, or a combination of E2 and P, daily, during the 10 to 13 days preceding breast surgery. Forty premenopausal women undergoing breast surgery for the removal of a lump. MAIN OUTCOME MEASURES. Plasma and breast tissue concentrations of E2 and P. Epithelial cell cycle evaluated in normal breast tissue areas by counting mitoses and proliferating cell nuclear antigen immunostaining quantitative analyses. Increased E2 concentration increases the number of cycling epithelial cells. Increased P concentration significantly decreases the number of cycling epithelial cells. Exposure to P for 10 to 13 days reduces E2-induced proliferation of normal breast epithelial cells in vivo.
Women with hyperandrogenic disorders represent a unique group among those with infertility due to anovulation. Although antiestrogens are effective in restoring ovulation in most women, it remains unclear whether these treatments restore fecundability per ovulatory cycle and the ability to maintain pregnancy in these individuals. Moreover, antiestrogens are ineffective in restoring ovulation in some hyperandrogenic anovulatory women, whose condition poses unique and vexing challenges for the infertility therapist. Gonadotropin treatment in antiestrogen-resistant women often leads to ovarian hyperstimulation syndrome, which has been addressed by modification of dosing schedules (e.g., low-dose administration), pretreatment with gonadotropin-releasing hormone (GnRH) analogs, and elimination of luteinizing hormone from the administered gonadotropins. Surgical reduction in ovarian volume has met with some success, although there may be a risk of inducing surgical adhesions of the adnexa. The second major reproductive adversity facing these patients is their elevated risk of endometrial cancer. Unopposed estrogen exposure probably contributes to this risk, but hyperandrogenicity and hyperinsulinism may act independently or in concert with estrogen to amplify the risk in these women. While the risks and strategies for preventive care in these women need to be better defined, reproductive health specialists are urged to continue using presently accepted measures, including education, to maintain these women's reproductive health.
We compared energy and macronutrient intakes across the menstrual cycle in participants (n = 42) in a study that assessed the frequency of ovulatory disturbances in regularly cycling vegetarians and nonvegetarians. Women kept daily basal body temperature records for six consecutive menstrual cycles and provided 3-d diet records near the beginning, middle, and end of different cycles. On completion of the study, temperature records were quantitatively analyzed to determine whether cycles were ovulatory, and if so, the date the luteal phase began. Diet records kept near the beginning and end of cycles were matched with temperature analysis results, and women were grouped according to whether the end-of-cycle record was kept during the luteal phase of an ovulatory cycle (group 1, n = 29), or during an anovulatory cycle or before luteal phase onset of a short luteal phase cycle (group 2, n = 13). Group 1 had higher energy intakes during the luteal than during the follicular phase (9.27 +/- 2.69 vs 8.01 +/- 2.36 MJ/d, P < 0.0001), whereas intakes of group 2 did not differ across the cycle (7.91 +/- 2.18 vs 8.20 +/- 1.48 MJ/d, NS). Both groups' macronutrient intakes were similar in records kept near the beginning and end of cycles. Documentation of ovulation is necessary in studies assessing premenopausal women's energy intakes.
Ovulatory function was prospectively assessed over 6 mo in 23 vegetarians and 22 nonvegetarians with clinically normal menstrual cycles. Subjects were 20-40 y of age, of stable weight (body mass index, in kg/m2, of 18-25), on current diets for > or = 2 y, and not using oral contraceptives. Quantitative analysis of basal body temperature records classified cycles as normally ovulatory, short luteal phase (< 10 d), or anovulatory. Subjects completed the Three-Factor Eating Questionnaire (subjects completed the Three-Factor Eating Questionnaire (subscales for restraint, hunger, and disinhibition) and kept three 3-d food records. Vegetarians had lower BMIs (21.1 +/- 2.3 vs 22.7 +/- 1.9, P < 0.05), percentage body fat (24.0 +/- 5.5% vs 27.4 +/- 5.1%, P < 0.05), and restraint scores (6.4 +/- 4.4 vs 9.5 +/- 3.7, P < 0.05). Mean cycle lengths were similar, but vegetarians had longer luteal phase lengths (11.2 +/- 2.6 vs 9.1 +/- 3.8 d, P < 0.05). Cycle types also differed (chi 2 = 9.64, P < 0.01): vegetarians had fewer anovulatory cycles (4.6% vs 15.1% of cycles). Compared with those with restraint scores below the median, highly restrained women had fewer ovulatory cycles (3.6 +/- 2.3 vs 5.0 +/- 1.4, P < 0.05) and shorter mean luteal phase lengths (7.4 +/- 4.1 vs 10.7 +/- 3.1 d, P < 0.05). We conclude that ovulatory disturbances and restrained eating are less common among vegetarians, and that restraint influences ovulatory function.
To investigate the efficacy of hCG in the management of recurrent early pregnancy loss. A prospective, randomized, controlled trial. Miscarriage Clinic, Women's Hospital, Liverpool, United Kingdom. Eighty-one women attending the miscarriage clinic with idiopathic recurrent pregnancy loss were randomized to receive hCG supplementation or placebo in early pregnancy. The success rate or live birth rate. In women with regular menstrual cycles it was found that hCG had no beneficial effect, the pregnancy success rate being 86% in both groups. However, women with oligomenorrhea had a pregnancy success rate of 40% in the placebo group but a statistically significant improvement to 86% if hCG was given. Human chorionic gonadotropin can be recommended for idiopathic recurrent pregnancy loss in women with oligomenorrhea.
Two long and broad streams of medical literature, from the 1950's to date, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ("android") obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally: binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF-I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer.
To assess the sensitivity and specificity of common clinical tests used for the diagnosis of luteal phase defect (LPD). The sensitivity and specificity of these tests for predicting low integrated P levels over the luteal phase were calculated. Outpatient reproductive endocrinology and infertility clinic at a university medical center. Fifty-eight strictly defined normal women were used to determine normal integrated luteal phase P levels. The study population was a separate 34 women who either were normal (n = 15) or were being evaluated for infertility or recurrent abortion (n = 19). These 34 study subjects all had the following tests performed in the same menstrual cycle: daily reproductive hormone levels, daily assessment of preovulatory follicle size, late luteal endometrial biopsies, and BBT charts. Basal body temperature, maximum preovulatory follicle size, dated endometrial biopsies, and serum P levels (single and multiple) were used in an attempt to predict which patients had low integrated P levels. Unacceptably low sensitivity and/or specificity levels were found for the following tests: appearance of BBT charts, luteal phase length, and preovulatory follicle diameter. Timed endometrial biopsy was found to have marginally acceptable sensitivity and specificity levels whether dated by next menstrual period or midcycle events. The best test for the prediction of low integrated P was a single serum P level from the midluteal phase that was < 10 ng/mL (31.8 nmol/L) or a sum of three random serum P measurements that was < 30 ng/mL (95.4 nmol/L) (also obtained in the midluteal phase). Luteal phase defect is a relatively uncommon but important cause of infertility and/or habitual abortion. The recommended test for the determination of LPD is a midluteal phase single serum P level < 10 ng/mL or the sum of three serum P levels that is < 30 ng/mL. The endometrial biopsy is a second line test that is only recommended when LPD needs to be evaluated in a treated cycle (ovulation induction or supplemental P).
Bone loss occurs in young women who experience amenorrhea or ovulatory disturbances. The purpose of this study was to determine whether bone loss could be prevented by simulating a more normal hormonal pattern, using treatment with cyclic medroxyprogesterone, with or without calcium supplementation, in physically active women with disturbed menstruation.
This study was a 1-year randomized, double-blind, placebo-controlled trial. Women who were stratified by menstrual cycle disturbance were randomized into four groups. The outcome variable was the change in spinal bone density measured by dual energy techniques.
A large metropolitan area. Sixty-one healthy, normal-weight physically active premenopausal women aged 21 to 45 years who experienced amenorrhea, oligomenorrhea, anovulation, or short luteal phase cycles completed the study. Therapies were cyclic medroxyprogesterone (10 mg/day for 10 days per month) and calcium carbonate (1,000 mg/day of calcium) in four groups: (A) (n = 16) cyclic medroxyprogesterone plus calcium carbonate; (B) (n = 16) cyclic medroxyprogesterone with calcium placebo; (C) (n = 15) placebo medroxyprogesterone with active calcium; or (D) (n = 14) both medroxyprogesterone and calcium placebos. The initial bone density (mean = 1.12 g/cm2) did not differ by group (P = 0.85). The 1-year bone density change was strongly related to treatment with medroxyprogesterone (P = 0.0001) and weakly to calcium (P = 0.072) treatment. Bone density increased significantly (+1.7% +/- 0.5%, +/- SEM, P = 0.004) in the medroxyprogesterone-treated groups (A and B), did not change in the calcium-treated group (C) (-0.7% +/- 0.6%, P = 0.28), and decreased on both placebos (D) (-2.0% +/- 0.6%, P = 0.005). Cyclic medroxyprogesterone increased spinal bone density in physically active women experiencing amenorrhea or ovulatory disturbances. POTENTIAL Amenorrhea, oligomenorrhea, anovulation, and short luteal phase cycles are common in premenopausal women and associated with spinal bone loss occurring at a stage of life when bone density would normally be stable or increasing. This controlled trial shows a significant gain in bone in women in the cyclic medroxyprogesterone intervention group, whereas those subjects in the placebo group lost bone. Calcium supplementation appeared to be helpful but did not reach statistical significance. The implications of these findings for the prevention of osteoporosis warrant further investigation.
To define relation between mood and concentrations of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. Antenatal clinic in university hospital, obstetric inpatient unit, patients' homes. 120 of 156 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because caesarean section required. Concentrations of progesterone and cortisol in saliva samples; women's moods assessed by various scores for depression. Changes in salivary progesterone and cortisol concentrations were similar to those already characterised for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day five postpartum (P < 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P < 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P > or = 0.01), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score > or = 8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmol/l v 3210 pmol/l respectively, P = 0.03; ten days postpartum 88 pmol/l v 114 pmol/l, P = 0.048). Cortisol concentrations were not significantly associated with mood. Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.
To determine whether cyclic medroxyprogesterone treatment given without estrogen causes adverse symptoms in postmenopausal women. This was a placebo-controlled, double-blind, crossover trial of 10 days/month of medroxyprogesterone and placebo treatments given during 2 consecutive months in random order. Participants recorded their physiologic and emotional experiences on a 0-4 scale using a daily diary form. Eleven postmenopausal women aged 43-63 completed the study. The subjects were not taking hormones. Height, weight, and serum estradiol concentration were measured once. In each woman, the sum of scores for the 10 days of medroxyprogesterone was compared to the sum of scores for the 10 days of placebo using nonparametric tests. No significant differences in scores were found between the 10 days on medroxyprogesterone and the 10 days on placebo. The median and range for the composite scores for premenstrual-like symptoms were 26 (20-67) during medroxyprogesterone and 25 (19-40) during placebo (P = .39). Medroxyprogesterone given alone does not cause adverse symptoms in postmenopausal women. Therefore, medroxyprogesterone therapy, by itself, cannot explain the side effects reported by postmenopausal women taking combined hormones.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
We assessed the relationship between dietary restraint and menstrual cycle characteristics in 27 ovulatory women, previous participants in a longitudinal study of spinal cancellous bone mineral density (BMD). Subjects completed the restraint scale of the Three Factor Eating Questionnaire, recorded basal temperature and exercise for at least three menstrual cycles, and completed a 3-d food record. Cycle lengths of women in the upper and lower tertiles of scores for restraint were similar [27.8 +/- 1.0 (mean +/- SE) vs 27.6 +/- 0.8 d], but luteal phase length was shorter in the former group (8.6 +/- 0.9 vs 10.8 +/- 0.5 d, P < 0.05). Age, body mass index, percent body fat, waist-hip ratio, reported energy intake, and activity were similar between groups. Because the previous longitudinal study found associations between ovulatory disturbances and bone loss, we assessed spinal BMD using dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). BMD of women in upper and lower restraint tertiles, respectively, did not differ: DXA, 1.15 +/- 0.05 vs 1.20 +/- 0.06 g/cm2; and QCT, 140 +/- 7 vs 133 +/- 7 mg/cm3. Additional prospective studies, however, appear warranted. In conclusion, this study's results provide evidence that high dietary restraint is associated with a shortened luteal phase length.
Fulghesu AM et al., 1993·Obstetrics and gynecology
To evaluate the involvement of endogenous opiates in the pathophysiology of the hyperinsulinism in patients affected by polycystic ovary disease by administering naloxone and naltrexone. We also studied the hormonal status following long-term opioid antagonist administration. Twenty-one women affected by polycystic ovary disease participated in the study. An oral glucose tolerance test (GTT) was performed at baseline and repeated after short-term naloxone infusion and after 6 weeks of naltrexone administration. Plasma glucose and insulin levels were evaluated in all samples. Gonadotropins, sex hormone-binding globulin, and androgen levels were determined initially and after the naltrexone treatment. None of the patients showed any alteration of glucose tolerance. Based on the insulin response to the GTT, the patients were classified as normo- or hyperinsulinemic. Opioid antagonist administration significantly reduced the insulin response to the GTT in hyperinsulinemic patients, without affecting their glycemic levels. In normoinsulinemic patients, glucose plasma levels were increased whereas insulin levels were not modified by the treatments. Gonadotropin and androgen plasma concentrations were not modified after naltrexone administration. This work supports a role for the endogenous opiates in the regulation of exaggerated insulin secretion in patients with polycystic ovary disease. The reduction of insulin secretion failed to demonstrate any hormonal modification in such hyperandrogenized patients.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To evaluate the involvement of endogenous opiates in the pathophysiology of the hyperinsulinism in patients affected by polycystic ovary disease by administering naloxone and naltrexone. We also studied the hormonal status following long-term opioid antagonist administration. Twenty-one women affected by polycystic ovary disease participated in the study. An oral glucose tolerance test (GTT) was performed at baseline and repeated after short-term naloxone infusion and after 6 weeks of naltrexone administration. Plasma glucose and insulin levels were evaluated in all samples. Gonadotropins, sex hormone-binding globulin, and androgen levels were determined initially and after the naltrexone treatment. None of the patients showed any alteration of glucose tolerance. Based on the insulin response to the GTT, the patients were classified as normo- or hyperinsulinemic. Opioid antagonist administration significantly reduced the insulin response to the GTT in hyperinsulinemic patients, without affecting their glycemic levels. In normoinsulinemic patients, glucose plasma levels were increased whereas insulin levels were not modified by the treatments. Gonadotropin and androgen plasma concentrations were not modified after naltrexone administration. This work supports a role for the endogenous opiates in the regulation of exaggerated insulin secretion in patients with polycystic ovary disease. The reduction of insulin secretion failed to demonstrate any hormonal modification in such hyperandrogenized patients.
Women diagnosed as suffering from premenstrual syndrome and symptom free controls were compared on hormonal parameters, glucose tolerance, mineralocorticoids, cholesterols, triglycerides, apolipoprotein (a), magnesium and calcium in the follicular and luteal phases of the menstrual cycle. The effect of treatment with essential fatty acids on the biochemical variables was also evaluated in a randomized, double-blind crossover design. The results showed that the hormonal and biochemical profiles of women with PMS and symptom free controls were markedly similar, except for aldosterone which was lower in the follicular and luteal phases and cholesterol which was higher in the follicular phase in women with PMS. No effects of treatment with essential fatty acids were found for any of the biochemical variables studied.
To assess the endocrinologic and clinical outcome after laparoscopic ovarian electrocautery because of polycystic reaction to ovarian stimulation in anovulatory infertility patients. Between 1986 and 1989, 133 patients with polycystic ovarian disease underwent laparoscopic electrocoagulation of the ovarian surface in an outpatient clinic after conventional ovarian stimulation had led to polycystic reaction. All patients were referred to our outpatient clinic affiliated with the university hospital. The reduction of androgen levels and normalization of cycle length were highly significant. The overall pregnancy rate was 70% (73 of 104), ranging from 27% in smokers to 94% in nonsmoking couples. In 26 second-look operations de novo adhesions were found in 26.9% of the patients. Laparoscopic coagulation of the ovarian surface is an effective tool to reduce elevated androgen levels and to improve the intraovarian mechanism of selecting a dominant follicle. A postoperative complication may be adhesion formation.
Premenstrual syndrome (PMS) is a menstrual cycle-related disorder of mood and behavior with unknown etiology and lack of evidence of endocrine imbalances. The absence of menstrual cyclicity eliminates PMS symptoms, and cyclic gonadal changes appear necessary but not sufficient cause for behavioral symptoms in predisposed women. As there are many depressive symptoms in PMS, we focused on the neuroendocrine characteristics of depression, primarily hypothalamic-pituitary-adrenal hyperactivity, and investigated plasma adrenocorticotropin (ACTH) and cortisol levels in the menstrual cycle. Blood samples were drawn daily from ten patients with PMS and eight asymptomatic control subjects who also reported symptoms daily throughout one menstrual cycle. The ACTH levels were significantly lower in patients with PMS compared to control subjects in the luteal phase. Two PMS subgroups were identified by cluster analysis applied to symptom scores. Plasma ACTH levels of PMS Cluster 1 subjects were significantly lower compared to controls. The ACTH levels of PMS Cluster 2 subjects were nearly identical to controls. These preliminary results suggest distinct hormonal subgroups in the heterogeneous PMS population and support further study of ACTH as a biological correlate of PMS.
Gammon and Thompson (1) recently reported in the Journal the results of an analysis of data from the Center for Disease Control's Cancer and Steroid Hormones Study to examine the association between a history of physician-diagnosed polycystic ovaries and the risk of breast cancer. Despite the small number of exposed cases (n =23) and controls (nm 44), their data strongly support the conclusion that a history of polycystic ovaries protects against premenopausal and carly postmenopausal breast cancer. These results are in apparent conflict with those reported in a previous cohort study by Coulam et al. (2), who found a threefold increase in postmenopausal breast cancer in women with polycystic ovaries. Such discrepancy may reflect real, albeit unexplained differences between premenopausal and postmenopausal women in the influence of endogenous hormones on breast cancer.
A prospective and randomized study was performed to investigate the effect of supportive hormones on the development and outcome of early pregnancies following in vitro fertilization and embryo transfer. Immediately after pregnancies were confirmed endocrinologically on day 15 after oocyte collection, 17 alpha-hydroxyprogesterone caproate and oestradiol valerate (PC/EV) was administered to half of the patients in a randomly controlled trial. One group received supportive treatment until the twelfth week of gestation, whereas the other group received no treatment at all. Both groups were followed up by measurements of serum levels of human chorionic gonadotrophin (HCG), oestradiol and progesterone every three days until day 35, when a first ultrasound examination was carried out to confirm fetal vitality. Subsequently, pregnancies were monitored sonographically at regular intervals. In cases of miscarriage, dilatation and curettage was performed and histology analysed. A total of 120 pregnant patients entered the study: 55 of them received hormone treatment and 65 patients were controls. Within the treatment group 48 (89%) clinically ongoing pregnancies were observed, five (9%) miscarriages occurred after the seventh week of gestation and one preclinical pregnancy was noted. In the control group, 38 (59%) ongoing pregnancies were observed, nine (14%) miscarriages occurred and 17 (27%) preclinical pregnancies were recorded. Two ectopic pregnancies, one in each group, were excluded from evaluation. A significantly higher percentage of pregnancies were intact at 7 weeks of gestation after treatment with PC/EV (p less than or equal to 0.01).
Natural family planning (NFP) is based on the knowledge *largely nonexistent) of a women as to whether she is in her fertile period or not. In contrast to the calendar method, the Billings method consists of observing bodily functions, whereby women learn about the fertile and infertile period during the menstrual cycle. This method is very safe as long as the woman has been instructed thoroughly. The Pearl index (the number of pregnancies/100 woman years) can be 1. In a Swedish province, 7/1000 population used this method and had an abortion rate of .5/1000, a fact contradicting the allegation of mass abortion as a result of the method. Only well-trained NFP instructors can teach women, and at the University of Umea such training has been available for some years. The biological basis of the Billings method rests on the fact that every release of an egg is preceded by a ripening process of a follicle in the ovary. This follicle secretes increasing amounts of estrogen which stimulates the cervix to produce secretions for the sperm. Right before ovulation, the follicle reduces estrogen production and noradrenaline takes over, stimulating the peak-day secretion (P-secretion) for further selection of sperm. Ovulation usually occurs on the peak day, which is the day of maximum fertility and the last day of mucous symptoms. For 3 days after peak day until menstruation, the risk of becoming pregnant diminishes successively until it is as low as after sterilization. The instructor is trained to recognize and overcome certain factors that make it more difficult to identify the mucous symptoms, such as the previous use of oral contraceptives, certain illnesses, drugs, and life styles. NFP can also be used for attaining pregnancy by identifying the peak day; women with premenstrual syndrome can calculate when their symptoms start, and sportswomen can predict the time of their menstruation. NFP is fascinating when it is compared to other methods because of its human dimension, and there is still a great deal to be learned about it.
Serum levels of progesterone, total testosterone, free testosterone, androstenedione (A2), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone binding globulin (SHBG) were measured in the follicular phase, around ovulation, and in the luteal phase of 11 women with severe premenstrual irritability and dysphoria and in 11 age-matched controls with no premenstrual complaints. Serum levels of free testosterone were significantly higher in the subjects with premenstrual syndrome (PMS) than in the controls in the luteal phase (p < 0.01), the follicular phase (p < 0.05), and around ovulation (p < 0.01). DHEA levels were significantly higher in the PMS subjects, as compared to controls, around ovulation (p < 0.05), while 17-OHP levels were higher in the PMS women in the luteal phase (p < 0.05). With respect to the other steroids measured, as well as SHBG, no differences between PMS subjects and controls were found. These results indicate a possible involvement of androgens in the pathophysiology of premenstrual irritability and dysphoria.
To determine if the hormonal imbalance in women with polycystic ovary syndrome (PCOS) continues into and after menopause and to analyze factors constituting an increased risk for developing metabolic disorders. The study was a transectional retrospective cohort follow-up of patients with PCOS. The women with PCOS were recruited from hospital clinics, and referents were randomized from a population study of women. Thirty-three women ages 40 to 59 years with ovarian histopathology typical of PCOS at wedge resection 22 to 31 years previously; 132 age-matched referents were analyzed. Clinical data were collected via a questionnaire supplemented with an interview in connection to a clinical examination that also included fasting venous sampling. Infertility, hirsutism, and oligomenorrhea were more common among the subjects with PCOS, but there was a considerable spontaneous restitution of cyclic regularity with time. Women with PCOS were more often hysterectomized and entered menopause later compared with referents. The hormone data show a typical profile for PCOS. Compared with referents women with PCOS showed marked increase in prevalence of central obesity, higher basal serum insulin concentrations, and a higher prevalence of diabetes mellitus and hypertension. Perimenopausal women with PCOS have an increased morbidity in hypertension and diabetes mellitus that adds to the classic symptoms, such as anovulation, hirsutism, and infertility.
Some randomized studies have suggested a significant beneficial effect of 17-hydroxyprogesterone caproate in the prevention of preterm labor [1, 2], The therapy in both studies was initiated at approximately 12-16 weeks and continued until labor.
We considered the possibility that a deficient proges terone effect during the first trimester may lead to a higher rate of preterm deliveries. A retrospective study was thus performed comparing the incidence of preterm versus full-term pregnancies in women with luteal phase defects who were either treated or not treated with proges terone supplementation during the first trimester.
Data from a case-control study that was conducted between 1980 and 1982 were analyzed to investigate the possible association between polycystic ovaries and the risk of breast cancer. The multicenter, population-based study included in-home interviews with 4,730 women with breast cancer and 4,688 control women aged 20-54 years. The age-adjusted odds ratio for breast cancer among women with a self-reported history of physician-diagnosed polycystic ovaries was 0.52 (95% confidence interval 0.32-0.87). The inverse association was not an artifact of infertility, age at first birth, or surgical menopause. Because women with this syndrome have abnormal levels of certain endogenous hormones, the observation of a low risk of breast cancer in this group may provide new insights into hormonal influences on breast cancer.
The incidence of polycystic ovarian disease (PCOD) varies from 0.6 to 92%, depending on the parameters analysed, PCOD has been reported to appear in association with Cushing's Syndrome, adrenal hyperplasia, hypothyroidism, adrenal and ovarian tumours and some genetic abnormalities. The controversy regarding the pathophysiological mechanism underlying the disease still persists. Critical evaluation of old data, assessment of new findings concerning the possible role of insulin, growth factors and their binding proteins, and extrapolation of neuroendocrinological experiments enabled the construction of a concise hypothesis of the pathophysiology of PCOD. According to this hypothesis, PCOD is a multifactorial disease. The sequence of events finally leading to clinical manifestation of the disease (hyperandrogenism, abnormal luteinizing hormone pulsatility pattern and ovulation disturbances) may originate in different organs or be triggered by different mechanisms. It may stem from the adrenals, the hypothalamus or higher central nervous system centres, or from the ovary itself; it may originate from excess of fat tissue usually combined with hyperinsulinism; or may be the result of a net increase in active growth factors. Each of the above disturbances probably appears early in life, much before the clinical signs of the disease are evident. Predisposing factors such as gestational diabetes of the mother, childhood obesity, borderline adrenal hyperplasia and late menarche have to be looked for as early as possible in order to prevent the late consequences of the disease, such as increased risk of infertility, endometrial and breast cancer and cardiovascular disease.
Endovaginal sonography of the endometrium demonstrates characteristic findings throughout the menstrual cycle. To correlate these findings with histologic criteria for normal endometrial development, we compared endometrial biopsies with ultrasonographic findings. Nineteen cycles were monitored in 18 women with ovarian failure whose endometrial cycles were induced exogenously by sequential transdermal 17 beta-estradiol (E2) and intramuscular progesterone. These subjects underwent ultrasonography of the endometrium prior to the day of progesterone initiation (luteal day +1) and continuing throughout the mid-secretory phase. On luteal day +1, ultrasonography characteristically demonstrated a multilayered endometrium consisting of a hyperechoic perimeter (endometrial-myometrial interface), a hypoechoic inner layer, and a hyperechoic midline (luminal interface). By luteal day +7, a gradual increase in echogenicity of the inner layer was detected, while the inner myometrium remained hypoechoic. Eleven of 19 cycles demonstrated a completely hyperechoic endometrium on luteal day +7 and also demonstrated normal stromal development on endometrial biopsies. Three patients who had endometrial biopsies consistent with their chronological development failed to demonstrate a hyperechoic endometrium by luteal day +7. All five biopsies that were histologically out of phase were detected by ultrasonography. Thus, ultrasonography demonstrated a sensitivity of 100% and a specificity of 62% for the detection of histologically normal endometrial development. Endometrial thickness could not be used to discriminate between biopsies that were normal (13 +/- 1.0 mm) and those out of phase (13.8 +/- 1.8 mm). Endometrial histology demonstrated asynchrony of glands and stroma in nine cases in which ultrasonography correlated with stromal, but not with glandular dating, suggesting that the increased echogenicity may reflect stromal edema.(ABSTRACT TRUNCATED AT 250 WORDS)
Fertility and the mechanism of ovulation is complex. The processes of fertilization and ovulation are described in this report. Information includes a description of the natural indicators of fertility and infertility, the cervical mucus pattern, and the Guidelines for the Billings Ovulation Method. The ovarian monitor which provides for the measurement of ovarian hormones (estrone glucuronide (EIG) and pregnanediol glucuronide (PdG) in a timed specimen of urine is also described. The cervical mucus pattern method measures ovarian hormones and fertility. No more than 2% of women who have been taught the Ovulation Method and performed the charting would need to use the Ovarian Monitor. It is commonly used to assure that the women's observations and interpretations are correct when there is a strong desire to either achieve or postpone pregnancy. For research, the monitor is useful in accurately measuring the timing of ovulation within the phase of potential fertility during the cycle and the changing probabilities of conception on days within the fertile period. The limits of the fertilizing life span of sperm can be measured as well as the factors which influence this life span. The day of maximum fertility, the correlation of the mucus pattern with fertility and time of ovulation, and assessment of conception cycles are measurable. Diagnostic information can be gleaned which will help to explain bleeding patterns, particularly around menopause, where fluctuating ovarian hormonal levels influence unexplained bleeding patterns. The Monitor can be useful as a test for pregnancy in measurement of high PdG and E1G levels. Four phases are identified for interpreting the ovulatory cycle: 1) the E1G and PdG levels are declining during the beginning of menstruation to reach a constant level (20-60 nmol/24 hours and .9 - 3.3 mcmol/24 hours); 2) rising E1G values and low PdG values and changing mucus pattern of the preovulatory cycle; 3) the ovulatory phase of peak E1G values (150-450 nmol/24 hours) followed by a distinct fall and the beginning of a rise in PdG values and the Peak of the mucus pattern; and 4) the luteal phase of rising PdG (9-36 mcmol/24 hours), and rising E1G values (100-400 nmol/24 hours) to maximum, and then falling before menstruation.
For those women who have not been contraceptively sterilized, midlife is a period of waning fertility. However, the occurrence of anovulatory menstrual cycles is unpredictable. Contraceptive methods also become increasingly contraindicated, both medically and physiologically. This article reviews the physiology of waning fertility and midlife contraceptive options, and discusses implications for helping women meet their contraceptive needs throughout the perimenopausal period.
Parry BL et al., 1990·Archives of general psychiatry
The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.
Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary. We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon, 22 ran regularly but less intensively, and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases, diet, exercise levels, and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases. The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles, however. Bone loss was strongly associated with these disturbances (r = 0.54, 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups. Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Progesterone is the most widely used treatment for premenstrual syndrome. To answer definitely the question of whether progesterone suppositories are effective for the treatment of premenstrual syndrome, a randomized, placebo-controlled, double-blind crossover study of 168 women, receiving progesterone in doses of 400 and 800 mg or placebo, was carried out. Premenstrual symptoms were not significantly improved by progesterone compared with placebo in any measure used in the study, including daily symptom reports maintained throughout treatment, clinician evaluation of improvement, and patient global reports of symptoms severity, relief, and disruption of daily activity. No symptom cluster or individual symptom differed significantly between progesterone and placebo treatment. These treatment results were not significantly affected by fluctuations in response during the placebo washout period, pretreatment levels of depression or anxiety at either postmenstrual or premenstrual times, or any of 19 other background, medical history, or symptom variables examined individually as covariates with treatment.
A prospective, controlled study of ovarian function using ovarian ultrasound and daily plasma hormone estimations (estradiol, progesterone [P], follicle-stimulating hormone [FSH], luteinizing hormone [LH]) was carried out on 175 spontaneously cycling patients with unexplained infertility. Forty-one (23.4%) demonstrated luteal phase cyst formation. In 21 cycles the dominant follicle reduced in size after the LH peak (cystic corpus luteum cycles), and in 20 no shrinkage was seen (luteinized unruptured follicles). Progesterone concentrations in the early luteal phase were significantly reduced in the luteinized unruptured follicle cycles. Elevation in plasma FSH was seen in the early follicular and luteal phases of both cyst forming groups and may be due to disturbances in ovarian metabolism. Follicular rupture is important for efficient P release by the corpus luteum.
Fehring RJ, 1990·J Obstet Gynecol Neonatal Nurs·
Open Access
Time of ovulation as detected by a self-test of luteinizing hormone (LH) in the urine was compared with time of ovulation as detected by self-observation of cervical mucus. Twenty regularly cycling women monitored their cervical mucus and urine LH for two complete menstrual cycles. Of the cycles that had an LH surge, 100% were on the peak day of cervical mucus or within three days before the peak day. Self-observation of cervical mucus, therefore, can be an accurate method of determining optimal fertility.
Experimental, epidemiological, and clinical data indicate that progesterone is active in bone metabolism. Progesterone appears to act directly on bone by engaging an osteoblast receptor or indirectly through competition for a glucocorticoid osteoblast receptor. Progesterone seems to promote bone formation and/or increase bone turnover. It is possible, through estrogen-stimulated increased progesterone binding to the osteoblast receptor, that progesterone plays a role in the coupling of bone resorption with bone formation. A model of the interdependent actions of progesterone and estrogen on appropriately-"ready" cells in each bone multicellular unit can be tied into the integrated secretions of these hormones within the ovulatory cycle. Figure 5 is an illustration of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a stylized ovulatory cycle. Increasing estrogen production before ovulation may reverse the resorption occurring in a "sensitive" bone multicellular unit while gonadal steroid levels are low at the time of menstrual flow. The bone remodeling unit would then be ready to begin a phase of formation as progesterone levels peaked in the midluteal phase. From this perspective, the normal ovulatory cycle looks like a natural bone-activating, coherence cycle. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling. Much further data are needed about the interrelationships between gonadal steroids and the "life cycle" of bone. Feldman et al., however, may have been prophetic when he commented; "If this anti-glucocorticoid effect of progesterone also holds true in bone, then postmenopausal osteoporosis may be, in part, a progesterone deficiency disease."
Audebert A, 1990·J Gynecol Obstet Biol Reprod (Paris)·
Luteinization of a follicle without its rupture and without the oocyte being expelled which is also called the LUF-syndrome by English speaking authors is one of a number of functional abnormalities that can occur to the follicle in the ovary and is diagnosed by ultrasound methods. It is one that has been known for quite a long time. Many publications have appeared since 1978 to describe this syndrome, which all the same is still very controversial. One has learnt how to diagnose it fairly well. One knows more about its physiopathogenesis and how often it occurs. This seems to be more often when there is pelvic endometriosis or so-called unexplained infertility. What is more difficult however is to find out how important it is as a cause of lowered fertility, and it is also difficult to decide whether: it just happens occasionally or is a true syndrome? It is still not possible today to give a definite answer to this question because of reasons of methodology. Finally, as far as treatment goes, even if the facts about its pathogeneiity have been found out and should be able to help decide on a logical treatment there have been no controlled studies to find out whether the treatment works.
Eighty-seven patients who underwent a late secretory phase endometrial biopsy while taking clomiphene citrate (CC) for ovulation induction were studied. Of the endometrial biopsies, 21 (24%) showed an endometrium greater than 2 days out of phase (OOP) with respect to the subsequent menstrual cycle. All 87 patients were categorized by age, weight, CC dosage, and underlying disease entity. The patients then were evaluated by these categories in relation to the incidence of an OOP biopsy while taking CC. Patients with a diagnosis of hypothalamic amenorrhea were statistically more likely to have an OOP endometrium. No other subgroup showed an increased or decreased incidence of OOP biopsies. Conception and spontaneous abortion rates were similar among patients with in-phase biopsies and those with out-of-phase biopsies, which subsequently were corrected with further medical therapy. An aggressive approach to the diagnosis and treatment of luteal phase insufficiency in patients who receive CC for ovulation induction is recommended.
Five regularly menstruating women of proven fertility, with normal prolactin and thyroid function studies, underwent a total of 39 endometrial biopsies (EMBs). The slides were dated in blinded fashion, and the cycle date determined by considering the date of the next menstrual period as day 28 and counting backward. Using a 2-day or greater lag in endometrial maturity to define a luteal phase defect (LPD), the incidence of single and sequential out-of-phase EMBs was 51.4% and 26.7%, respectively. Using a 3-day or greater lag to define a LPD, the incidence of single and sequential out-of-phase EMBs was 31.4% and 6.6%, respectively. These incidences in normal, fertile women are as high as the rates quoted for infertile populations, and call into question the standard criteria for defining this condition and evaluating therapies to correct it.
Dating of maturity of the endometrium by histologic examination was correlated with four methods of ovulation detection in 13 cycling parous women. Histologic dating was assessed independently by two pathologists and correlated with the postovulatory duration as determined by daily transvaginal ultrasound scanning, serum LH measurements, basal body temperature (BBT), and subtraction of 14 days from the onset of menses. In addition, progesterone and estradiol (E2) were measured in daily serum samples. Dating of the endometrial biopsy was highly correlated (P less than .002) with the day of ovulation as determined by ultrasound, and was found to be within 2 days of the correct postovulatory day on evaluation of 25 of 26 (96.1%) of the interpretations. The accuracy of dating using the LH surge was 84.6% (22 of 26 interpretations), and with the BBT thermogenic shift was 76.9% (20 of 26 interpretations). However, dating of the endometrium was within 2 days of the correct day in only 17 of the 26 interpretations as determined by subtracting 14 days from the onset of the subsequent menses. The accuracy of dating was significantly better correlated (P less than .025) with days from ovulation as determined by ultrasound than as calculated from the onset of menses. There was a significant correlation between endometrial dating and the amount of progesterone (P less than .01) and E2 (P less than .01) secreted from the day of ovulation, as determined by transvaginal ultrasound, to the day of biopsy. These data confirm a strong correlation between endometrial dating and ovarian hormone secretion during the postovulatory phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.
Lumbar bone mineral density (BMD) was evaluated by dual photon absorptiometry (DPA) in 38 women with laparoscopically diagnosed and staged endometriosis. DPA was performed before and at the completion of 26 weeks of treatment with either gonadotropin releasing hormone agonist (GnRHa) or danazol. Twenty-five women received GnRHa either nasally or subcutaneously and 13 women received danazol 200 mg four times daily by mouth. During treatment amenorrhea and suppressed estradiol levels were observed in all patients. Each patient took a supplement of oral calcium 1 gm daily. DPA (reproducibility +/- 1.5%) was read by a single observer unaware of the treatment assignment of the patient. The mean (+/- standard error) of the entire group prior to treatment was 98.8% +/- 0.03% of a control population of women from the same geographic area matched for race, age, and weight. At the completion of treatment, BMD was slightly decreased in the GnRHa group and marginally increased in the danazol group but neither change was significant. Women with endometriosis have lumbar BMD in the normal range and ovarian suppression with either GnRHa or danazol produces no significant change in BMD.
Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.
Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.
A central, reversible decrease in male sexual function appears related to some aspect of obstructive sleep apnoea (OSA). Lower serum testosterone (T) levels were documented in 15 men with OSA versus nine snorers (no OSA), (9.18 +/- 0.92 vs 11.55 +/- 0.90 nmol/l, mean +/- SEM), P less than 0.05 in a consecutive case series of 24 men referred for diagnostic overnight sleep studies. Gonadotrophins did not differ between the two groups. Although the men with OSA did not differ in body mass index (BMI) or weight from the snorers, they were older (51 +/- 3.9 vs 44 +/- 3.1 years), P less than 0.02. Serum T did not correlate with age, but was correlated with minimum nocturnal arterial oxygen saturation (Min SaO2) (r = 0.589), P less than 0.02. A prospective controlled trial of uvulopalatopharyngoplasty therapy (UPP) for OSA in 12 subsequent subjects showed reproductive improvement which was parallel with improved apnoea at 3 months postsurgery. T increased (13.31 +/- 1.07 to 16.59 +/- 0.72 nmol/l), P less than 0.02, without significant changes in BMI, serum PRL, LH or FSH. All seven of the men who reported decreased sexual interest prior to surgery felt their libido and sexual functioning had returned to normal 3 months following UPP. Some aspect of OSA in men appears to produce a reversible hypothalamic-pituitary reproductive dysfunction.
The authors studied the effects of clonidine on a subgroup of women who had symptoms associated with premenstrual syndrome; the subgroup comprised 24 women aged 19 to 41 years who had "moderate" to "severe" cyclic decreases in beta-endorphin levels. All of the women received clonidine and placebo in a double-blind cross-over design that spanned four menstrual cycles. Clonidine was significantly (p less than .05) more effective than placebo in reducing symptoms.
Progesterone, the naturally-occurring 21-carbon steroid produced by the corpus luteum of the ovary and by the placenta, plays an important role in re-production. It is not surprising, then, that it has been used extensively as a supplement in the treatment of disorders of fertility and pregnancy. For example, progesterone is necessary for maintenance of pregnancy in mammals, including humans, and has been given for threatened or habitual miscarriage. The relaxant effect of progesterone on smooth muscle, including that of the uterus, has led to administration of this agent for preterm labor. The effect of progesterone in preparing the endometrium for implantation of the blastocyst has given rise to use of this hormone after natural or induced ovulation to supplement the function of the corpus luteum. How well such treatments work has been argued for many years; however, the fact remains that large numbers of women of reproductive age have received this hormone. It is pertinent, then, to consider whether progesterone or similar agents exert adverse effects on embryo development.
Cervical mucus observation may be difficult for women who experience continuous mucus throughout their menstrual cycles. This study aims to prove the value of cervical mucus methods for these women. Rather than examining a woman's onset of cervical mucus, this study evaluates the "Point of Change" in the mucus and its correlation to the woman's hormone levels.
A variety of hypotheses have been proposed to explain the premenstrual syndromes. These hypotheses serve as rationales for an equally diverse range of proposed treatments. To investigate these hypotheses, we obtained multiple blood samples across the menstrual cycle in women with well-characterized menstrually related mood disorder and in control subjects. No diagnosis-related differences were observed in the levels or patterns of secretion of progesterone, estradiol, follicle-stimulating hormone, luteinizing hormone, testosterone-estradiol-binding globulin, dehydroepiandrosterone sulfate, dihydrotestosterone, prolactin, or cortisol. Our data suggest that premenstrual syndrome does not represent a simple hormonal deficiency and that the cited rationales for several of the proposed treatments are of questionable merit.
It is now well accepted that a woman can conceive from an act of intercourse for a maximum of only about 7 days of her menstrual cycle. The reliability of natural family planning depends on identifying this window of fertility without ambiguity. Several symptomatic markers, cervical mucus and basal body temperature, have been used extensively and with considerable success in most women but failures occur. Ovarian and pituitary hormone production show characteristic patterns during the cycle. Urinary estrogen and pregnanediol measurements yield reliable information concerning the beginning, peak, and end of the fertile period, provided that the assays are accurate and performed on timed specimens of urine. We have developed such enzyme immunoassays for urinary estrogen and pregnanediol glucuronides that can be performed at home. In the early versions of the assays, enzyme reaction rates were measured by eye, but more recently, a simple photoelectronic rate meter has been used. The final problem to be solved is not technologic but whether women are sufficiently motivated to expend the same time and effort each day for 10 days a month, with less cost, on fertility awareness as they spend on making a cup of tea.
Endometrial biopsies from 90 women with regular menstrual cycles and a hormonal profile compatible with normal luteal function were morphometrically assessed using 11 different indices and the results were plotted in 48-hour periods around the day of the luteinizing hormone (LH) surge (LH +/- 0). The endometrial dating reached its highest significance from days LH -3/-2 to days LH +7/+8, when the changes occurred with a high degree of regularity regardless of the length of the preovulatory and postovulatory phases. It is proposed therefore that the dating of the endometrium should be related to the LH surge rather than to the "ideal" 28-day cycle. The results also seem to suggest the existence of a regulatory mechanism for the synchronization of follicular maturation and midcycle endometrial development. Further study of the factors involved in this mechanism may result in a better understanding of certain forms of unexplained infertility.
Eight castrate, estrogen-replaced women were given 200 mg spironolactone daily for 4 weeks. The response of plasma dehydroepiandrosterone sulfate (DHEAS), testosterone (T), and androstenedione (delta 4A), all indicators of adrenal C19-steroid production, varied greatly among individuals. Sixteen women with idiopathic hirsutism were given night-time dexamethasone (DEX) and then superimposed spironolactone for 4 weeks, followed by DEX without spironolactone for an additional 4 weeks. As expected, DHEAS, T, and delta 4A declined on DEX treatment. On addition of spironolactone, there was little further change in DHEAS, while plasma T declined in 7 of 16 women, including all those whose T level had remained elevated despite DEX treatment; most values rebounded when spironolactone was discontinued. The authors conclude from intact DEX-suppressed women that ovarian T, especially when increased, is frequently lowered by spironolactone. Thus, both adrenal and ovarian androgen production (as measured by prevailing plasma levels) may be diminished by this agent. These highly variable effects on androgen production are unlikely to account for the consistent antiandrogenic effects reported clinically.
Exercise is commonly listed as a remedy for the premenstrual syndrome (PMS), although no study has proven that it is an effective therapy. Numerous reports have suggested that exercise is associated with improved mood and symptoms. In those reports, however, the diagnosis of PMS was not clearly documented, nor was the exercise carefully controlled. Preliminary evidence suggests that exercise training in ovulatory, sedentary women and intensified training in women athletes decrease mild premenstrual symptoms. Although conditioning exercise is associated with short luteal phase and anovulatory cycles, decreases in mild premenstrual symptoms occur prior to menstrual cycle changes. Controlled studies of PMS and exercise training may not only document an effective, nonpharmacologic therapy for PMS but also clarify the hormonal etiology of this complex biobehavioral phenomenon.
A study was designed to see if the use of prophylactic progesterone vaginal suppositories (PVS) reduced the risk of spontaneous abortions in women with a history of at least one spontaneous abortion. PVS was employed during the luteal phase to the end of the first trimester. The dosage was initially 50 mg/day, but was increased according to the endometrial biopsy and doubled as soon as pregnancy was established. Only 10 women (10%) aborted, and 8 of these 10 were successful in their next PVS-treated pregnancies. Overall there were 12 losses in 132 pregnancies (9%) in these PVS-treated patients. Forty-two percent of untreated controls aborted (10/24). The results suggest that PVS is effective in reducing the risk of spontaneous abortions in high-risk patients.
Plasma beta-endorphin (beta-EP), beta-lipotropin (beta-LPH), and cortisol concentrations were measured by perimenstrual period in 11 patients affected by premenstrual syndrome (PMS) and in 8 asymptomatic healthy volunteers. Blood samples were collected every 2 to 3 days, for 1 month, starting from midcycle. The Menstrual Distress Questionnaire (MDQ) was administered during the testing period. Plasma beta-LPH and cortisol levels remain stable during the perimenstrual period, in both controls and PMS patients. On the contrary, PMS patients showed a decrease of plasma beta-EP in the week preceding menses and during the first days of menstrual flow. Beta-EP values of PMS patients regain normal levels during the next follicular phase. No changes of beta-EP levels were recorded in asymptomatic women. MDQ scores revealed that PMS patients complained of water retention, pain discomfort, and mood swings. The transient and reversible decrease of plasma beta-EP in PMS patients near to and at menses remains to be clarified.
Controversy still exists as to the proper therapy of luteal phase defects. Some advocate using drugs to improve follicular dynamics, e.g., clomiphene citrate, while others treat luteal phase defects with progesterone. The possibility exists that in some cases the luteal phase defect is secondary to failure to produce a mature follicle, the better drug then being an ovulation-inducing drug, e.g., clomiphene. However, if the follicle is mature, then progesterone may be the best treatment. We defined mature follicle as one between 18 and 24 mm while the serum estradiol (E2) level is over 200 pg/mL. The efficacy of exclusive P therapy was evaluated in 50 women, all with a minimum of 1 1/2 years infertility and with no obvious fertility problems other than luteal phase defect. Seventy percent of the women conceived within 6 months. The abortion rate was 14.7%. The average period of infertility was 2.8 years in the 35 patients who conceived within 6 months. These data suggest that determining the degree of follicular maturation by serum E2 and pelvic sonography plus excluding the luteinized unruptured follicle syndrome by pelvic sonography helps determine the proper therapy for luteal phase defect.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
We previously reported that circulating beta-endorphin levels are increased in obese hirsute women and that plasma immunoreactive insulin (IRI) levels are increased in proportion to the degree of hyperandrogenism in women with the polycystic ovary (PCO) syndrome. We, therefore, tested the hypothesis that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in this syndrome. In the first study, acute naloxone administration significantly reduced the plasma IRI response and IRI/glucose ratio in three euglycemic obese women with PCO and acanthosis nigricans (AN) and marked insulin resistance, but did not alter the glucose response. Naloxone had no effect on these parameters in the normal weight control subjects. In the second study, nalmefene, a new, orally active opiate antagonist, reduced IRI and the IRI/glucose ratio in four women with PCO-AN and marked hyperinsulinemia in a randomized, double blind, crossover protocol. We conclude that endogenous opiates are at least partially responsible for the hyperinsulinemia and insulin resistance in PCO-AN.
Gerhard I et al., 1987·Biol Res Pregnancy Perinatol·
Between 1983 and 1984 a double-blind randomized study with progesterone substitution in threatened abortion was carried out. Fifty-six patients with vaginal bleeding during the first trimester of pregnancy, the internal cervical os being closed, were referred to the hospital. Twenty-five women (5th and 6th week of gestation) with positive serum concentrations of beta-hCG were admitted to the study without regard to sonogram results. In other 25 women (7th-10th week of pregnancy) and 6 women (greater than or equal to 11th week of pregnancy) fetal heart action and movement could be demonstrated by ultrasound. The patients were prescribed bed rest and vaginal suppositories twice daily, containing either 25 mg progesterone or only polyethylene glycol. The code was not broken until after completion of the study. Serial serum determinations of beta-hCG, estradiol-17 beta (E2), progesterone, and ultrasound were performed. Four patients had to be omitted from final analysis (two tubal pregnancies, one intrauterine infection, one sectio parva). Three of 26 patients progesterone (11%) and five of 26 patients with placebo (19%) had an abortion, which represented no significant difference. Frequency of abortion was increased in women more than 30 years old, in women with previous abortions and after ovulation induction. Progesterone treatment resulted in a significant elevation of serum progesterone concentrations (p less than 0.01), while beta-hCG and E2 were unchanged. The results of this study confirm that pregnancy outcome is favorable in women with bleeding and normal hormone concentrations without hormonal treatment and unfavorable in women with reduced beta-hCG and E2-concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.
Natural methods of family planning make use of the naturally occurring signs and symptoms of the fertile and infertile phases of the menstrual cycle. Recognizable signs and symptoms occur cyclically, and women can be taught to recognize them. Changes take place in basal body temperature, cervical mucus, and the cervix uteri. Basal body temperature rises about .2 degrees C (.4 degrees F) immediately after ovulation when the blood levels of progesterone increase. Following menstruation, cervical mucus is composed of cense cellular matter that forms an impenetrable barrier (typeG). As the cycle progresses under the influence of increasing estrogen, there is a predominance of characteristically lumpy opaque mucus (type L). A few days before ovulation, the characteristically thin slippery crystal clear stretchy mucus is produced (type S). Fertile mucus is composed of a combination of L-type and S-type mucus. Estrogen casuses changes to take place in the muscle and connective tissue of the cervix. As estrogen levels rise during the pre-ovulatory phase, the cervix softens and the cervical os opens. A woman can be aware of these changes by gently palpating the cervix with her finger tip. These signs and symptoms which reflect accurately the rise and fall of the hormones estrogen and progesterone are the basis of fertility awareness on which natural methods of family planning are based. In addition to knowing when ovulation takes place, it is also necessary to know the length of time the ovum can be fertilized after ovulation and the life span of the sperm in the female genital tract before ovulation. In fertile mucus, sperm will live an average of 3 days, but it must be understood that it is possible for sperm to survive for 5 days if conditions are right. To make allowances for sperm survuval, the fertile phase starts when follicular development begins and estrogen levels start to rise. The life span of the ovum is less than 24 hours. Natural family planning methods--including the temperature method, the ovulation method (Billings), the calandar method (rhythm), and the sympto-thermal method are explained.
The incidence of congenital anomalies in infants born to 382 women treated with P was noted. Only five anomalies occurred in the infants born to women who had taken P. This study supports the data of Rock et al. by demonstrating a similar low incidence of birth defects in a much larger series of patients who also took a much higher dosage of P. Similarly, because only 1 of 189 patients treated with both P and 17-OHP developed anomalies, the data supports the study by Katz et al., suggesting no increase in anomalies related to 17-OHP therapy.
Rigorous criteria were used to select women with severe premenstrual syndrome for inclusion in an 8-month double-blind placebo-controlled clinical trial of progesterone vaginal suppositories. Following a control month without treatment, progesterone (200 mg in polyethylene glycol base) or placebo was self administered twice daily by vaginal suppository for a minimum of 12 days before the onset of menstruation for 3 months. Crossover to the opposite medication for a further 3 months was followed by a final control cycle without treatment in month 8. Physician contact was minimized throughout the study to avoid any possible positive effects of psychological support which may have confounded past investigations. Detailed self-report questionnaires were completed every 3 days for the duration of the study. Although the attrition rate was high, 20 women completed the trial and their records are analyzed here. The results of this trial indicate that the response to vaginal progesterone in these dosages is, at best, marginal and not significantly different from response with placebo use.
The first study was done in which vaginal hormonal cytograms were correlated with cervical mucus symptoms as charted by women using the ovulation method of natural family planning. Daily vaginal smears obtained by 67 women during 78 menstrual cycles provided the basis of the study. The women had used the ovulation method for at least three cycles and were not breast-feeding. All vaginal smears examined cytologically had a microbiologic diagnosis of lactobacilli. All the vaginal hormonal cytograms revealed ovulatory-type patterns. Karyopyknotic index (KPI) peak correlated with peak mucus day +/-2 days in 74, or 94.9%, of the cases, with a mean of peak mucus at +0.14 days. The average number of mucus days prior to the KPI peak was 6.1. Seven women also provided daily blood specimens for bioassay of luteinizing hormone (LH). KPI peaked with a mean of 0.7 days after the LH peak.
To determine whether changes in circulating levels of neuropeptides are associated with symptoms of premenstrual syndrome (PMS), 20 women with the diagnosis of PMS and 20 asymptomatic subjects were studied. The premenstrual beta-endorphin levels were significantly lower in PMS patients (P = 0.0001). The decrease in beta-endorphin levels during the luteal phase, compared with the follicular phase, in PMS patients was also significant (P = 0.0002). Neurotensin, human pancreatic peptide, vasoactive intestinal polypeptide, gastrin, and bombesin-like immunoreactivity levels did not reveal significant changes between days 7 and 25 in patients with PMS.
Harrison RF, 1985·Eur J Obstet Gynecol Reprod Biol·
Human chorionic gonadotropin was administered intramuscularly in an open study of 32 women whose last three pregnancies had ended in spontaneous abortion. An initial dosage of 10 000 iu on earliest diagnosis of pregnancy was followed up by 5000 IU twice weekly up to wk 12, then once weekly up to wk 16. Only 2 of the 32 patients aborted (6.2%). Using the same regime a further 20 habitual aborters were randomly allocated double-blind to either hCG or placebo. All 10 women on active therapy continued (100%) compared with only 3 on placebo (30%) (P less than 0.01). These results suggest that hCG should be considered as treatment in women with habitual abortion where other specific causes have been ruled out and a potentially treatable hormonal imbalance surmised.
This report presents the outcome of pregnancies of 93 women who conceived while taking progesterone (P) suppositories (n = 42) or P in oil intramuscularly (n = 51). The dosage and duration of treatment varied according to the indication. The total dose (in milligrams) increased with the duration of treatment and ranged from 75 to 13,500 mg. Two of 75 term pregnancies (2.6%) were noted to have congenital anomalies. Both women had been treated with P in oil. No patient treated with P suppositories gave birth to a malformed infant. An increased spontaneous abortion rate (28.6%) was noted among women treated with P suppositories. The authors recommend that a national registry be created to document fetal outcome after P therapy.
We have examined for the presence of subtle hormonal abnormalities in women with long-standing unexplained infertility. For a full cycle serum LH, FSH, progesterone and oestradiol levels were measured about three times a week, and serial ultrasound scans of the ovaries made until the time of apparent ovulation. The results on 45 cycles in 35 women with unexplained infertility and in three normal volunteers are presented. Normal ovulatory cycles were defined by a length of 26-32 d, and progressive follicular maturation followed by disappearance or abrupt reduction in size of a follicle within 48 h of the recorded LH peak, followed by progressive and sustained rise in serum progesterone levels to more than 25 nmol/l and a luteal phase length of greater than or equal to 13 d. Thirty spontaneous cycles (28 women) were clearly normal while 15 spontaneous cycles (12 women) were abnormal. Abnormalities included luteinization of an unruptured follicle (eight cycles), absence of follicular development (two cycles), poor follicular development (two cycles), persistence of a large ovarian cyst from the preceeding cycle (two cycles) and one aluteal cycle. Six of the abnormal cycles were characterized hormonally by inappropriate elevation of serum LH levels throughout. If this study had been based only on serial ultrasound scans, all results on abnormal cycles might have been misinterpreted. If it had been conducted only with (multiple) progesterone determinations and the level of greater than 25 nmol/l had been taken as indicative of ovulation nine clearly abnormal cycles would have been considered as normal. We conclude that the combination of the hormonal and ultrasound assessment of ovulation increases our confidence for confirmation of normality and reveals various ovulatory disorders which are possibly due to an endocrinological defect or defects.
Endometrial biopsy specimens were obtained from 107 normally menstruating infertile women 2 to 3 days before the anticipated onset of menses and were day-dated according to histologic criteria. A simultaneous blood sample was obtained for measurement of progesterone (P) and beta-subunit of human chorionic gonadotropin. Of 98 biopsies which could be accurately dated, 56 were in-phase (IP) and 42 were out-of-phase (OOP). Mean serum P levels were significantly lower in women with OOP biopsies undertaken more than 4 days before the onset of menses. A sharp decline in serum P levels was observed in women with IP but not OOP biopsies, so that on the final premenstrual day serum P levels were significantly higher than normal in women with OOP biopsies. Pregnancy continued without interruption in two of six patients who underwent biopsy in the cycle of conception. One patient had an ectopic pregnancy; and the three remaining pregnant patients, all with subnormal P values, aborted. The study suggests that there is a high frequency of minor abnormalities in luteal function in normally menstruating, infertile women for whom tubal and male factors were normal. The frequency of subclinical pregnancy (2 of 107) was lower than anticipated from earlier studies.
Luteal phase abnormalities in early menstrual cycles after pregnancy have been shown to cause confusion in the practice of natural family planning (NFP) for some patients and to restrict severely the number of late infertile days available to others. The cause of the abnormalities is uncertain but appears to be related to the nursing status of the patient.
Pregnancy Complications · Premature Rupture of Membranes
The plasma concentrations of medroxyprogesterone acetate (MPA) in 14 women administered the progestagen for threatened abortion during the first 6 weeks of pregnancy were measured by specific radioimmunoassay. Treatment (52 nmol orally every 6 h) was continued to 18 weeks of gestation. The mean plasma concentration of MPA rose rapidly during day 1 of treatment to 14.1 +/- 1.84 nmol/l. It reached 21.5 +/- 2.3 nmol/l by 7 days and subsequently stabilized at around 26.8 +/- 5.0 nmol/l by the end of week 2. Urinary steroid profiles were determined by gas-liquid chromatography and mass spectrometry for six of the MPA-treated women and compared with those of six untreated women of similar gestational age. No differences were detected between the two groups of women, suggesting that the administration of MPA during pregnancy did not alter qualitatively or quantitatively the metabolism and excretion into urine of progesterone and oestrogens.
Barely 13 years after its initial discovery, the hypothalamic luteinizing-hormone releasing hormone (LHRH) appears to be claiming a large territory in clinical medicine. "There's almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogues," predicts William F. Crowley, MD, associate professor of medicine at Harvard University Medical School, Boston. He points out that this polypeptide hormone (also known as gonadotropin-releasing hormone or GnRH) is already providing new treatments for several human diseases and "represents one of the examples where an investment in basic science has profound clinical applications." Crowley, who is also chief of reproductive endocrinology at the Massachusetts General Hospital in Boston, discussed the therapeutic implications of LHRH and its analogues at the Seventh International Congress of Endocrinology in Quebec City. So far, he says, the ability of LHRH to either stimulate or suppress reproductive processes has been applied
Fifteen women with moderate to severe premenstrual symptoms, defined and graded according to a recently developed scoring system, took part in a double blind study of the effect of progesterone on premenstrual symptoms. The dosage was 100 mg progesterone twice daily delivered in vaginal pessaries. The women were improved with a statistically significant decrease in their scores by progesterone as well as by placebo treatment. There was no statistically significant difference between the two regimes.
Blood and urine specimens from 27 premenopausal breast cancer patients and 62 healthy controls have been compared with respect to concentration of testosterone and progesterone in blood and of testosterone and androstanediol in urine, measured in the luteal phase of the menstrual cycle. There was a strong positive association between the concentration of the two androgens, either in blood or urine, and breast cancer risk. A strong association was also observed with decreasing levels of progesterone. The association was statistically significant (p for trend less than 0.01) for each hormone; the rate ratios were 10.2 for serum testosterone (highest category), 5.6 for serum progesterone (lowest category), 8.4 for urinary testosterone (highest category), and 5.2 for androstanediol (highest category). The rate ratio for women presenting both high serum testosterone and low progesterone was 21.8 (4.1 to 116.1). Considering the exposure to at least one of three androgens at the highest level and low progesterone, the rate ratio was as high as 90.2 (8.2 to 989.7). This study provides evidence for the hypothesis that increased androgenic activity is an important risk indicator for breast cancer, particularly when associated with anovulation, as indicated by low serum progesterone level.
Interesting data on infertile human membranous mucus compared with infertile filamentous mucus have emerged from previous studies using scanning electron microscopy (SEM). The aim of this study was to obtain more information about the infertility of membranous mucus being independent of ovarian hormone stimulus. All different types of mucus, progressively secreted during the menstrual cycle by endocervical muciparous cells, were collected from the cervical canal of a fertile woman with a long menstrual cycle and specifically with a long infertile preovulatory period. The most significant results concern the identification of the cycle phase characterized by the presence of membranous mucus alone, i.e. the infertile preovulatory phase and the hormonal bases of membranous mucus infertility. The conclusion is reached that each ovarian hormone pattern stimulates the secretion of a specific type of mucus during the menstrual cycle.
Normal probability plots were used to assess the homogeneity of a population of 327 luteal phases from apparently ovulatory menstrual cycles. The length of the luteal phase was defined as the interval (in days) following but not including, the luteinizing hormone peak, up to and including the day before onset of menstruation. A small sub-set of the population consisted of cycles with abnormally short luteal phases but the majority of the data followed a normal frequency distribution which gave a mean (+/- SD) for normal luteal phase length of 14.13 (+/- 1.41) days. It was estimated that all cycles with a luteal phase less than or equal to 9 days were abnormal, and that 74%, 22% and 2% respectively of cycles with luteal phases of 10, 11 and 12 days were also abnormal. The total incidence of short luteal phases defined as above was 5.2%.
The ovulation method makes women aware of certain changes in their cervical mucus. These modifications help to distinguish the beginning and end of the cycle's fertile period and indicate the time of maximum fertility. In addition to pinpointing the date of ovulation, the method permits the user to know she is not fertile when there is no ovulation. The principle of the method is the state of "basic infertility" which preceeds follicular development. The method cannot be implemented with success unless it is properly acquired. After some preliminary considerations regarding the fertile period, ovluation detection and periodic abstinence, some clinical and hormonal observations are compared in 2 basic studies in order to show to what extent cervical mucus reflects ovarian activity. The application of the method requires an understanding of the "basic infertility profile" and 2 sets of rules regarding the 1st days and the peak sign which indicate respectively the beginning and end of the fertile period. The criteria of an ideal birth control method and the importance of proper teaching are also dealt with. With regard to Natural Family Planning, 2 problems are pointed out--incomplete terminology in data collection and absence of a positive and detailed approach to periodic abstinence. (author's modified)
Serum testosterone, progesterone, luteinizing hormone, prolactin, and sex hormone-binding globulin levels were measured in 55 normal controls, in 31 patients with hyperplastic alterations of breast epithelium, and in 23 patients with breast cancer. All patients and controls were premenopausal, and they were comparable for age, weight, and body surface. In the controls, the mean level of testosterone [0.47 +/- 0.16 (S.D.) ng/ml] was lower and the mean level of progesterone (17.63 +/- 8.11 ng/ml) was higher than in breast cancer patients [testosterone level, 0.62 +/- 0.22 ng/ml (p less than 0.005); progesterone level, 11.4 +/- 8.0 ng/ml (p less than 0.005)] and in patients with breast epithelial hyperplasia [testosterone level, 0.55 +/- 0.2 ng/ml (p less than or equal to 0.05); progesterone level, 13.9 +/- 8.6 ng/ml (p less than 0.05)]. No difference was found in the mean circulating levels of luteinizing hormone, prolactin, or sex hormone-binding globulin between controls and patients. These results confirm previous findings of increased urinary testosterone excretion in women with anovulatory menstrual cycles and epithelial hyperplasia or cancer of the breast and strongly support the hypothesis that androgens play an important role in both induction and development of breast cancer.
Twenty-two infertile women with repeated deficient results in the postcoital test received clomiphene citrate or tamoxifen. The patterns of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol (E2), and progesterone were examined during the follicular and periovulatory phases of the menstrual cycle, as were the cervical mucus characteristics. Under clomiphene treatment, an overproduction of E2 was observed (P less than 0.01), which did not result in an improvement of the cervical mucus characteristics. The pH of the endocervical mucus was lower (P less than 0.01). Under tamoxifen treatment, the serum E2 levels were higher (P less than 0.05) and normalized. Higher spermatozoa penetration meter scores were observed during the preovulatory and periovulatory periods, whereas the pH of the endocervical mucus was not lowered. These data support that tamoxifen may be preferential to clomiphene in treating this kind of infertile woman.
A single dose of micronized oral progesterone was administered to 15 pregnant women immediately prior to elective cesarean section. Levels of progesterone, 17 beta-estradiol, and estrone were measured in the plasma, in the placenta, and at different sites in myometrium obtained during the surgical procedure. Results were compared to those observed in a control group of women who did not receive progesterone. Progesterone levels demonstrated a marked increase in plasma and in the whole myometrium 150 minutes after administration. The levels then decreased rapidly to control values in 1 hour. The concentrations of progesterone in the placenta did not show any changes. No difference appeared in 17 beta-estradiol levels in the plasma or the myometrium, whereas an increase was observed in the placenta. Estrone levels did not change in the plasma, but they decreased in the myometrium and in the placenta.
Basal body temperature (BBT) charts from three menstrual cycles of 20 normal women and 20 women with biopsy-proven luteal phase defect (LPD) were reviewed. Mean luteal phase length in the normal women was 13.4 days, and that of the women with LPD was 11.8 days (P less than 0.05). Six (30%) of the LPD patients had luteal phases of less than 11 days according to BBT, and five of these patients had severely out-of-phase endometrial biopsies. None of the normal patients had luteal phases of less than 11 days. There was no significant difference in the mean rate of postovulatory BBT rise between the two groups. It is suggested that the slope of postovulatory temperature shift is not helpful in the diagnosis of LPD but that evidence of a luteal phase of less than 11 days on BBT does indicate a high likelihood of LPD.
The premenstrual symptom complex many women experience in a moderate to severe form can be divided into four subgroups. Because there is more than one syndrome and nervous tension is one of the most common symptoms, the term premenstrual tension syndromes (PMTS) is used. The most common subgroup, PMT-A, consists of premenstrual anxiety, irritability and nervous tension, sometimes expressed in behavior patterns detrimental to self, family and society. Elevated blood estrogen and low progesterone have been observed in this subgroup. Administration of vitamin B6 at doses of 200-800 mg/day reduces blood estrogen, increases progesterone and results in improved symptoms under double-blind conditions. Women in this subgroup consume an excessive amount of dairy products and refined sugar, and progesterone may be of value in them. The second-most-common subgroup, PMT-H, is associated with symptoms of water and salt retention, abdominal bloating, mastalgia and weight gain. The severe form of PMT-H is associated with elevated serum aldosterone. Vitamin B6 at high dosage suppresses aldosterone and results in diuresis and clinical improvement. Vitamin E helps the breast symptoms. Methylxanthines and nicotine should be curtailed and sodium limited to 3 gm/day. PMT-C is characterized by premenstrual craving for sweets, increased appetite and indulgence in eating refined sugar followed by palpitation, fatigue, fainting spells, headache and sometimes the shakes. PMT-C patients have increased carbohydrate tolerance and low red-cell magnesium. Adequate magnesium replacement results in improved glucose tolerance tests and decreased PMT-C symptoms. Deficiency of the prostaglandin PGE1 may also be involved in PMT-C. PMT-D is the least common but most dangerous because suicide is most frequent in this subgroup. The symptoms are depression, withdrawal, insomnia, forgetfulness and confusion. In ten PMT-D patients the mean blood estrogen was lower and the mean blood progesterone higher than normal during the midluteal phase. Elevated adrenal androgens are observed in some hirsute PMT-D patients. Two PMT-D patients with normal blood progesterone and estrogens had high lead levels in hair tissue and chronic lead intoxication. This subgroups needs careful medical attention when the symptoms are severe. Therapy should be individualized according to the results of the evaluation.
All forms of birth control require some motivation, and motivation calls for understanding. If a woman learns to interpret her own cycles, her understanding of her body will be enhanced, and this could have benefits in all aspects of her fertility control. Professional nurses and health visitors are frequently expected to explain the intrigues of the menstrual cycle whether it be in family planning clinics, on gynecology wards, or in a client's home. When information about the monthly cycle is linked with the signs women observe in their own bodies, knowledge will result. With accurate knowledge about the span of the fertile phase, it should be within most women's grasp to control their own fertility, whether they use this knowledge alone or together with some mechanical contraceptive method. The endocrine hormones which control each menstrual cycle come from the pituitary gland and the ovaries, and they work in a feedback system, triggering each other. The start of the cycle is day 1 of the period when the pituitary gland starts the production of follicle stimulating hormone (FSH). This is taken in the bloodstream to the ovary where, as its name implies, it stimulates the ripening of follicles, each of which contains an egg cell. Operating in a feedback system, estrogen is carried back to the pituitary gland where it then causes a lessening in the production of FSH and stimulates the release of the luteinizing hormone (LH). LH proceeds back to the ovary and together with estrogen suppresses the growth of all the follicles except one, which then matures to release an egg at ovulation. If the egg is not fertilized, the pituitary gland detects the high level of progesterone and ceases production of LH, which causes the corpus luteum to die away. The 1st phase of the cycle leading up to ovulation is known as the follicular phase, and its length can vary considerably from month to month. The 2nd phase, leading up to menstruation, is the luteal phase, and its length does not vary more than 12-16 days, normally 14. There are 3 main observations that women can make each month: daily temperature; the cervical mucus; and a "calendar" assessment, and after a few months the likely course of the cycle is evident. Each of these 3 ways of interpreting cycles are reviewed in detail. If the motivation and understanding is there, most women can become adept at reading the signs each month. While still learning, it is important to seek advice from those who understand the methods and can ensure accurate interpretation. Encouraging women to discover how their bodies work is not aimed at discouraging the use of mechanical or chemical contraceptive methods. It is simply a way to enhance a woman's understanding of her body which could bring her positive physical and emotional benefits. Practically, if more women could read their body cycles, there would most likely be an increase in motivation to use contraception and an associated reduction in unwanted pregnancies.
The authors examined the effect of three months' treatment with spironolactone in 34 women with polycystic ovary syndrome. In all patients a significant decrease in hirsutism was noted as well as restoration of a regular although anovulatory menstrual pattern. Plasma luteinizing hormone and follicle-stimulating hormone levels remained unchanged after spironolactone treatment; however, prolactin levels were lowered in both women with normal and those with elevated basal levels. Plasma testosterone, androstenedione, and dehydroepiandrosterone sulfate levels were decreased after three months of therapy. No side effects were observed. Plasma electrolytes and liver function tests were normal during the entire time of treatment. This therapy is recommended as initial nontoxic but effective treatment for women with polycystic ovary syndrome who are hirsute and have menstrual disturbances.
Ovarian hormones have been implicated in a number of neoplastic conditions. Chronic anovulation syndrome, a spontaneous biologic experiment of unopposed secretion of estrogen by the ovaries, was identified in a cohort of 1270 patients, and the risk of these patients having neoplasia was studied. Of the 1270 patients studied, 30 had a subsequent malignancy develop; the expected number was 29.8. When the individual types of subsequent malignancy were analyzed, the endometrium was the only site at increased risk. The relative risk of developing carcinoma of the endometrium after the diagnosis of chronic anovulation syndrome is 3.1 (95% confidence interval 1.1 to 7.3). The long-term risk of developing adenocarcinoma of the endometrium might be considered when treating patients who have this syndrome.
The human individual responds as an entire organism to the effect of endurance training. Exercise physiologists have long documented cardiovascular, musculo-skeletal and metabolic effects of conditioning. Only recently are we beginning to understand that there are hormonal and hypothalamic changes which occur with conditioning. These hormonal changes probably serve similar adaptive functions as do the other conditioning responses. Careful controlled studies need to be performed of individuals prior to, early in conditioning, and following extended periods of conditioning looking at hypothalamic function, body morphometric characteristics, psychiatric and psychological testing and menstrual cycle data in order to better understand hormonal conditioning. When hormone changes occurring with endurance training are approached in this light, the complex inter-related alterations will begin to form a pattern. Further studies are needed to document the dynamic and reversible nature of these hormonal adaptations.
Fourteen normal women (self-selected from 180 women enrolled) in a marathon training clinic kept basal body temperature (BBT), mileage, and weight records for 48 cycles before the marathon. Entry criteria were: Age 20-45, gynecologic age greater than 5 years, no hormone use, or weight change in 3 months. The women were 35.2 +/- 5.6 years in age, 22.6 +/- 5.1 years gynecologic age, runners of 4.1 +/- 2.5 years with premenstrual symptoms, previous pregnancy 4/14, no infertility and 2/14 remote amenorrhea. BBT records were obtained and analyzed by Vollman's criteria (1977). There was no weight loss. 32/48 cycles were biphasic but only 16 were normal in the length of the premenstrual phase (PreM = luteal, nl 10 - 16 d) with a mean of 11.1 +/- 1.2 days. The other 16 biphasic cycles had short PreM phase of 6.4 +/- 1.8 days. Monophasic (M = anovulatory) cycles occurred in 16/48 records. Cycles which were abnormal (Short PreM and M) differed only in that usual run length was longer (9.6 - 9.9 miles) than in normal cycles (7.9 +/- 2.4 miles). Marathon training may be associated with normal length but M and short PreM type cycles.
The importance of predicting human ovulation for either optimizing or avoiding conception has been considered from an endocrine, morphological and clinical view point. Of the biochemical markers in peripheral blood, a knowledge of the LH peak is the most clearly defined, with a two to four fold increase above baseline levels for a relatively short 24-30 hour preovulatory period. Ovulation is considered to occur 28-36 hours after the beginning of the LH rise or 8-20 hours after the LH peak. Daily assessment of the rise in preovular oestrogen reflects Graafian follicle development but the rise is less distinct and spread over 3-4 days with marked day to day fluctuations. LH induces a marked reduction in oestrogen production some 12 hours prior to ovulation and at the same time induces a two to three fold increase in progesterone production above baseline levels. While these changes in themselves are not great enough for day to day discrimination, a knowledge of their reciprocal relationship may be. The preovular rise in FSH is relatively small compared to LH and the radioimmunoassay technique has not generally been refined to be as rapid and reliable. Monitoring the day to day growth of the preovular follicle ultrasonically is both linear and potentially predictable but there is a wide range of its final diameter (17-26 mm) prior to ovulation making prediction inaccurate. With further refinements in ultrasonic resolution, detection of intrafollicular changes of the cumulus oophorus and granulosal cell layer configuration and thickness may give a closer prediction of the time of ovulation. At a clinical level a knowledge of menstrual cycle length in association with body messages which herald ovulation are useful and may forewarn that ovulation in terms of days is approaching. Such markers as preovulation pain, the detection of periovular cervical mucus and the change in physical character and position of the cervix are reliable signs of preovulation for many well motivated and informed women for either promoting or avoiding conception. A knowledge of the basal body temperature is not a prospective guide to ovulation, but once the thermal shift is established in association with loss of periovular mucus symptoms, the fertile period can be considered to have passed. Because we do not have a precise and simple marker of human ovulation, it is necessary that the most suitable marker of preor postovulation is chosen for the particular need in a given individual.
A significant portion of human infertility is presumably due to defective ovulation, including patients who fail to conceive despite medical induction of ovulation, those who fail despite repeated timely donor inseminations, and those with "infertility of unknown etiology". All point out the inadequacy of standard criteria for normal ovulation. This investigation correlates preovulatory serum estradiol and gonadotropin concentrations with dominant follicle growth measured ultrasonographically and serum progesterone levels. The data indicate a 35% incidence of cycles with significantly abnormal serum estradiol levels, decreased dominant follicle size, and abnormal progesterone levels despite biphasic basal body temperature curves and normal cycle length. If these cycles represent inadequate or abnormal ovulation, they can be distinguished from adequate cycles prior to follicle rupture and may benefit the treatment of human infertility.
This study evaluates the effect of treatment with Proluton-Depot (hydroxyprogesterone hexanoate) in early pregnancy, and the final outcome of pregnancy and fetal status. One hundred and fifty patients received intramuscular injection of Proluton-Depot from 6 weeks to 8 weeks to 16 weeks to 18 weeks gestation. The outcome of this treated group was compared with a similar number of 150 patients with similar problems, but the second group received no hormonal treatment. There was no evidence to suggest that Proluton-Depot had any adverse effect on the infant or the final outcome of pregnancy.
Rats which were subjected to ovariectomy on day 18 of pregnancy and were treated with 17 beta-estradiol underwent delivery prematurely at 0900 +/- 1.9 hours on the morning of day 18. All animals had in plasma and uterine tissue a precipitate and highly significant progesterone withdrawal and a corresponding significant increase in prostaglandin F and prostaglandin F metabolite. Progesterone replacement therapy given to a second group of castrated animals prevented progesterone withdrawal and premature labor, because the hormonal profile in plasma and uterine tissue of these animals was identical with that of the intact pregnant vehicle controls. Electron microscopy of longitudinal and circular myometrial layers showed a precipitate and highly significant increase in the number, size, and area of gap junctions in the uteri of the group undergoing premature delivery. In the uteri of the progesterone-treated and vehicle control groups (both intact pregnant), gap junctions were conspicuously scarce. Thus the extensive regulatory imbalance, provoked by progesterone withdrawal, induced a significant increase in myometrial gap junctions. This structural change established contacts between individual myometrial cell which could transform the multibillion cell community of the uterus into a syncytium, to generate low-resistance pathways to the flow of current and thus promote the propagation of trains of electrical discharge in support of labor.
Cancer and Fertility · Hormone Sensitive Cancer and Reproductive Care
In order to investigate the nature of the association of involuntarily delayed first birth and risk of breast cancer, 1083 white women who had been evaluated and treated for infertility from 1945-1965 were followed prospectively through April 1978 to ascertain their breast cancer incidence. These women were categorized as to the cause of infertility into two groups, those with endogenous progesterone deficiency (PD) and those with nonhormonal causes (NH). Women in the PD group had 5.4 times the risk of premenopausal breast cancer compared to women in the NH group. This excess risk could not be explained by differences between the two groups in ages at menarche or menopause, history of oral contraceptive use, history of benign breast disease or age at first birth. Women in the PD group also experienced a 10-fold increase in deaths from all malignant neoplasms compared to the NH group. The incidence of postmenopausal breast cancer did not differ significantly between the two groups.
27 healthy young Italian women were studied to evaluate their ability to identify symptomatically the potentially fertile phase of the menstrual cycle by self observation of their cervical mucus pattern as described in the Ovulation Method Billings. The women's observations were correlated with daily plasma levels of FSH, LH, estradiol-17 beta and progesterone. Ovulation was considered to occur on the day following the LH peak. The hormonal assays revealed that 2 of the 34 cycles studied were anovulatory. 24 of the 27 subjects in the study group demonstrated their ability to recognize the onset of the mucus discharge and the peak symptom from the first cycle after teaching, another two from the second cycle. The only other subject contributed an anovulatory cycle in which the hormonal assay confirmed the accuracy of her mucus observations. In the study, the mean interval between the time of ovulation as assessed and the peak symptom recorded by the subjects was 0.0 days, with a range from -2 to +1 days. The mean time interval from the first recorded symptom to the estimated day of ovulation was 6.0 days, with a range from 3 to 10 days. The study shows that young Italian women can be taught to recognize their cervical mucus pattern as described in the Ovulation Method Billings. The accuracy of their observations is demonstrated by the hormonal assays. The study also confirms the conclusion reached in earlier similar studies that there is a direct correlation between the cervical mucus symptom and the potentially fertile phase of the cycle. Research is currently being conducted on a larger number of couples employing the Ovulation Method Billings to actually regulate their fertility.
The luteinized unruptured follicle syndrome is a frequent phenomenon, occurring in half of our women with regular cycles and infertility. Progesterone concentrations and 17 beta-oestradiol concentrations were assayed in peritoneal fluid of women during the luteal phase. Up to day 20 of the cycle, the concentrations were significantly higher in women with an ovulation stigma than in women without an ovulation stigma on their corpus luteum. The range of concentrations was sufficiently different in the early luteal phase to be used diagnostically, the only limitation being the presence of a cystic corpus luteum. We suggest that the assay of progesterone and 17 beta-oestradiol in peritoneal fluid should be done in all women with infertility and biphasic basal body temperature charts in order to diagnose the luteinized unruptured follicle syndrome.
Healthy volunteers with regular ovarian function, women taking oral contraceptives, and infertile patients being treated with clomiphene were studied longitudinally from day 7 of the cycle to menstruation. The main objective was to determine whether ovulation or failure to ovulate could be detected accurately by the use of ultrasound. The ovaries were scanned with a Kretz Combison 100 sector scanner every 1 to 3 days for morphologic changes consistent with follicle development, ovulation, and development of the corpus luteum. The morphologic changes were correlated with daily urinary hormone profiles. The estimated times of ovulation according to ultrasound and luteinizing hormone peak overlapped by 24 hours in 19 of 23 normal cycles and in 5 of 6 cycles of patients treated with clomiphene. Both techniques indicated that three of three women taking oral contraceptives did not ovulate. The ultrasound studies indicated a wide range in the diameter of the preovulatory follicle, which precludes follicular diameter as a single index for prediction of ovulation. However, by measuring the maximal diameter of the follicle and observing the morphologic changes within the ovary from follicle to corpus luteum, it was possible to detect ovulation in more than 80% of cycles studied. This technique was found to be quick, inexpensive, and efficient.
Four points on the basal body temperatures (BBT) curve have been correlated with the estimated time of ovulation (ETO), as determined by indirect hormonal parameters, in 74 menstrual cycles from 24 subjects. Only 10 of 66 hormonally
The volume of peritoneal fluid was measured after laparoscopic aspiration in 303 women. Contamination with blood was estimated at 4.2 per cent by haemoglobin assay. In 120 women with regular menstrual cycles, the volume of peritoneal fluid increased progressively during the follicular phase, was highest during the early luteal phase (20.0 +/- 6.3 ml) and declined thereafter. In 89 women with moderate and mild endometriosis the amounts of peritoneal fluid were similar, but 9 women with severe endometriosis had lower (P less than 0.05) volumes during the luteal phase. Women with inactive ovaries had uniformly low amounts of peritoneal fluid: 4.2 +/- 2.3 ml in 31 women taking combined oral contraceptive pills; 4.7 +/- 5.8 ml in 17 women taking 5 mg of lynoestrenol daily and 1.2 +/- 1.9 ml in 20 postmenopausal women with an inactive endometrium. In contrast, two postmenopausal women with proliferative endometrium had 7 and 10 ml of peritoneal fluid. Women with active ovaries, 5 with absent or distally occluded Fallopian tubes and 7 without a uterus had normal amounts of peritoneal fluid. The volume of peritoneal fluid was not affected by pelvic varicose veins, a visible corpus luteum or an ovulation stigma. Peritoneal fluid appears to be predominantly an ovarian exudate, neither an exudate from the pelvic peritoneum nor a tubal secretion.
One hundred and forty-nine patients presenting with infertility underwent two hundred and ten endometrial biopsies as part of a routine infertility evaluation. The initial biopsy was out of phase in 44 (29.5%), confirmed by subsequent biopsy to yield a total of 28 (19%) patients with luteal phase inadequacy. Of 44 patients taking clomiphene citrate, 13 (29.5%) had out-of-phase biopsies. Although hyperprolactinemia, recurrent miscarriages, extremes of reproductive life, and clomiphene citrate administration have been associated with an increased incidence of the defect, in this series a predisposing cause could not be detected in approximately one-half of the patients. The routinely obtained endometrial biopsy provides a safe, reproducible, and adequate means of providing histologic evidence for normal endometrial development for subsequent implantation.
Progesterone and human chorionic gonadotrophin (HCG) in serum and pregnandiol in urine were measured in 64 patients admitted to hospital because of threatened abortion. Blood samples were taken and urine specimens collected at regular intervals during admission and after discharge during the rest of the pregnancy. A reference range was worked out for each hormone based on the hormone values obtained from the pregnancies proceeding to term. The predictive significance of values within and below the reference range was determined, for the initial sample and for serial samples. An association between hormone levels and outcome of pregnancy was observed but it is concluded that both single and serial determinations of progesterone and pregnandiol and serial determinations of HCG are unsatisfactory for the evaluation of threatened abortion. However, an initial progesterones value below the reference range and HCG values below 10,000 mIU/ml between the 8th and 15th week of pregnancy was in every case always followed by spontaneous abortion. A hormonal test of fetoplacental origin is recommended for monitoring threatened abortion.
It is commonplace for gynecologists to refer to "midcycle" ovulation of women. This concept has often led to the routine diagnosis of ovulatory status on day 14 of what is expected to be a 28-day menstrual cycle. For example, the postcoital test in an infertile patient, or intercourse to achieve pregnancy in a normally fertile patient, is often timed around day 14 under the assumption that ovulation is occurring then. Advocates of natural family planning (NFP) have criticized the concept of "midcycle" ovulation, because their clinical experience suggests that the natural irregularity of menstrual-cycle length militates against ovulation's occurring with any great frequency on day 14.
This report analyzes the relationship of day 14 and the actual midcycle of the menstrual cycle to each other and to indirect hormonal parameters that more directly estimate the time of ovulation.
Patients with premenstrual syndrome recorded their symptoms daily using menstrual distress questionnaires. These were analysed by a least mean square method of fitting sine waves. After recording an untreated cycle, patients were given progesterone 200 mg b.d. and placebo in a double-blind crossover manner; 75 per cent of patients were then given progesterone 400 mg b.d. and placebo in a similar manner. Treated cycles were rated by both daily menstrual distress questionnaires and retrospective self-assessment. Both rating methods showed there was no significant difference between progesterone and placebo in reducing symptoms of premenstrual syndrome, and in the majority of cases placebo was more effective, although never significantly so.
Daily (12-hour) urine collections taken throughout the menstrual cycle were obtained from 30 young women who by genetic analysis were at risk for familial breast cancer, and from 30 control women carefully matched for age, height, and reproductive history. Steroids in the urine were extracted by glucuronidase hydrolysis, and the primary glucocorticoid, androgen, and estrogen hormones and their metabolites were measured by radioimmunoassay. Highly significant differences were observed only in the case of estrone and estradiol, with the high-risk subjects exhibiting lower values that the controls. This endocrine abnormality in young women at risk for breast cancer may be a potential discriminant for identifying women at risk for the disease in the population at large.
This study was designed to test the assumption that women with regular menstrual cycles and premenstrual symptoms are ovulatory. 40 women aged 20-40 years were selected as probably ovulatory on the basis of their recent histories of regular menstrual cycles consistently accompanied by premenstrual molimina. Each subject recorded menses and (BBT) basal body temperature for 1-3 consecutive menstrual cycles during which luteal phase serum (P) progesterone concentrations were determined by radioimmunoassay. All subjects were rated ovulatory or anovulatory by each of several espoused P criteria which confirmed 39/40 subjects (98%) to be ovulatory by a 3 ng/ml criterion; 38/40 subjects (95%) by a 5 ng/ml criterion; and 36/40 (90%) by a 15 ng/ml criterion. Thus P measurements confirmed the clinical impression of ovulation in 90-98% of subjects depending on which P criterion was selected. BBT correlated well with P measurements in that 61/66 cycles (92%) displayed a biphasic BBT pattern 2/66 cycles (3%) displayed a monophasic BBT pattern and 3/66 cycles (5%) were uninterpretable. Only 1 subject was not ovulatory in either of 2 consecutive cycles by even the most liberal P criterion and both cycles were abnormally long and would have been suspected of being anovulatory on clinical grounds. We conclude that patients presenting with a history of regular menstrual cycles accompanied by premenstrual molimina are identifiable as ovulatory without the necessity of measuring luteal phase serum P concentrations. (Authors modified)
12 normal ovulatory women were studied during 17 menstrual cycles. The first day on which the women had increasing quantities of 0.1 ml or more clear cervical mucus (IQCCM) was closely related to the time of ovulation as monitored by basal body temperature and radioimmunoassay of serum-luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. The results show that the time of ovulation can be predicted clinically without specialized tests by observing the day of onset of IQCCM.
Pregnancy Complications · Premature Rupture of Membranes
Patients with two or more previous spontaneous second trimester abortions and vaginal cytology indicating a poor progestational response in current pregnancies were selected for treatment with Provera (medroxyprogesterone acetate) and/or Delalutin (17 alpha-hydroxyprogesterone caproate). Serum was examined serially for progesterone (P) and estradiol (E) by radioimmunoassay. Serum from 174 untreated patients with no known complications ranging from 6--40 weeks gestation provided normal distribution data. Of 14 progestagen-treated patients, four aborted during the second trimester. These all had chronically low (greater than 50% of observations were less than 1 standard deviation of the normal population) or falling P/E ratios. The rest delivered normal full-term infants although five of the 10 had chronically low P, seven had chronically low P/E ratios, and in one other P/E was falling. Chronically high E contributed to the low P/E ratio in three cases. Thus, these selected cases with poor obstetrical histories demonstrated steroid patterns outside the +/- 1 standard deviation range, although the steroid levels were still within the normal range. Serum progesterone and estradiol analysis may eventually be useful in identifying patients who will best respond to progestagen treatment.
Pip: The only way to be sure of avoiding pregnancy is for a couple to abstain from sexual intimacy during the fertile phase of the woman's cycle. Billings showed by reference to hormonal parameters that after competent instruction in the ovulation method women can identify the fertile phase of their cycle. If abstinence during the fertile phase is replaced by coitus combined with barrier methods, the pregnancy rate will be higher. The hormonal monitoring has revealed that the Peak Symptom as defined in the ovulation method is the most accurate biological marker of the time of ovulation. The cervical mucus pattern reflects the estrogen levels during follicular ripening from its commencement, and the Peak Symptom reflects a sharp cut-off effected by the elevation of the progesterone level at the time of ovulation. This means that once the mucus begins to be observed as a warning of the approach of ovulation, the woman needs to follow the changing characteristics on a daily basis in order to be certain that she recognizes ovulation.
The observation of the "Peak" mucus symptom in women using the ovulation method of natural family planning has been correlated with the estimated time of ovulation, as evaluated by indirect hormonal parameters. In 65 cycles of the 73 studied in 24 patients, there was hormonal confirmation of ovulation; in eight cycles, anovulation or luteal dysfunction was suspected. In the 65 normal cycles, 64 exhibited a Peak symptom. In those cycles, ovulation was estimated to occur from 3 days before to 3 days after the Peak symptom with a mean of 0.31 days before the Peak symptom. In 95.4% of these cycles, ovulation was estimated to occur from 2 days before to 2 days after the Peak symptom. The variation between cycles of the same patient ranged from 0 to 4 days with a mean of 1.8 days. The beginning of the mucus symptom preceded the estimated time of ovulation by an average of 5.9 days.
The only way to be sure of avoiding pregnancy is for a couple to abstain from sexual intimacy during the fertile phase of the woman's cycle. Billings showed by reference to hormonal parameters that after competent instruction in the ovulation method women can identify the fertile phase of their cycle. If abstinence during the fertile phase is replaced by coitus combined with barrier methods, the pregnancy rate will be higher. The hormonal monitoring has revealed that the Peak Symptom as defined in the ovulation method is the most accurate biological marker of the time of ovulation. The cervical mucus pattern reflects the estrogen levels during follicular ripening from its commencement, and the Peak Symptom reflects a sharp cut-off effected by the elevation of the progesterone level at the time of ovulation. This means that once the mucus begins to be observed as a warning of the approach of ovulation, the woman needs to follow the changing characteristics on a daily basis in order to be certain that she recognizes ovulation.
Estriol was administered for a six-month period as estrogen replacement therapy to 52 symptomatic postmenopausal women. Assays of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone, and estradiol were performed before and during therapy. During this period of administration, vaginal cytology, cervical mucus, and endometrial studies were performed. Clinical effectiveness was directly related to dosage (2 to 8 mg/day). Estriol (8 mg/day) failed to induce endometrial proliferation and proved a poor suppressor of FSH and LH. This agent's capacity to relieve vasomotor instability and improve vaginal maturation without notable side effects is sufficient reason to include this drug in the management of the postmenopausal syndrome.
Plasma levels of progesterone (P), oestradiol (OE2), unconjugated oestriol (OE3) and total OE3 were measured in blood samples taken from patients with fetal growth retardation, pre-eclampsia and other complications of pregnancy. The levels were compared with the 24-hour urinary excretion levels of total oestrogen (OE) in these patients, and with the plasma levels found in 31 normal pregnant patients from whom blood samples were taken serially from 21 weeks gestation onwards. There was good correlation between plasma unconjugated and total OE, levels, and urinary OE levels (r = 0.77). In 12 patients with fetal growth retardation and no other abnormality, levels of all hormones were significantly lower than normal; unconjugated OE3, total OE3, and urinary OE levels were significantly less than 1 SD below the normal mean. In 22 patients with mild or moderate pre-eclampsia who were delivered of normal birth weight infants none of the hormone levels were significantly different from normal. In 12 patients with mild or moderate pre-eclampsia in association with fetal growth retardation OE2, unconjugated OE3 and urinary OE levels were significantly lower than normal, and total OE3 levels were significantly less than 1 SD below the normal mean. In 12 patients with severe pre-eclampsia, OE2, levels were significantly less than 1 SD below the normal mean and unconjugated OE3, total OE3, and urinary OE levels were significantly less than 2 SD below the normal mean. In studies of diurnal and day-to-day variation the coefficients of variation for P were respectively 12.7 per cent and 14.2 per cent, for OE2, 11 per cent and 12.7 per cent, for unconjugated OE3, 15.6 per cent and 14.1 per cent, and for total OE3, 15 per cent and 15.8 per cent. It was concluded that measurements of plasma total OE, and urinary OE were probably of comparable value and that the plasma estimation had much to commend it.
Following Fraenkel's discovery, demonstrating that the rabbit corpora lutea are indispensable in pregnancy maintenance, Corner and Allen showed (1) in a series of now classic studies that luteectomy predictably terminates pregnancy, except when progesterone is provided as substitution therapy. Despite the clarity of these demonstrations and the accumulation of complementary data over 40 years (2, 3, 4), many investigators held the view that the studies in the rabbit model failed to establish a basic biological law of broad …
The cervical canal mucus is important to human fertility since conception can only occur if sperm pass through the contents of the cervical canal to reach the ovum. The biophysical properties of the cervical mucus and their relation to sperm migration are, therefore, curcial. A variety of laboratory experimentation methods have been used in studies of cervical mucus: 1) sperm migration measurements; 2) reheological studies; 3) cell countings; 4) crystallization studies; 5) Nmr: 6) EPR; and 7) photoelectron spectroscopy. Cervical mucus is the end result of complicated biosynthetic processes occurring in the epithelial cells of the cervical mucosa; this biosynthesis is regulated by many factors. Type E, characteristic for estrogenic stimuli on mucus biosynthesis, and type G, for gestagenic stimulation, are the 2 main types of cervical secretions. The 2 types always occur together, in differing proportions. For example, at normal ovulation there is a 97:3 ratio of type E to type G; at normal corpus luteum, the ratio is 10:90. The string variety of type E seems to aid in conveying sperm from the vagina while the loaf variety is inactive. The very low viscosity of the string variety intermicellar fluid permits very rapid sperm swimming. Not much is known regarding cervical mucus pathology or therapy.
An endometrial biopsy and a blood sample for progesterone determination obtained simultaneously in the midluteal phase of the cycles of 55 infertile women were compared for reliability for confirmation of presumptive ovulation and evaluation of luteal function. Progesterone levels of 3 ng/ml or greater were found in 90.5% of the cycles. Secretory endometrium was identified in 81% of the cycles. Thirty-three cycles yielded sufficient information to compare the two methods for evaluation of luteal function. Histology and progesterone levels were consistent with each other and the presumed time of ovulation in only 11 cycles. Histology was inconsistent with the presumed time of ovulation in 20 cycles, while progesterone was inconsistent in only two cycles. Additional samples for progesterone determinations were obtained during the biopsy cycles of 15 patients who presented adequate data for evaluation of luteal function. A single, well-timed progesterone determination appeared adequately to reflect the data obtained from serial samples in the same cycle. These results support the thesis that a single, well-timed serum progesterone determination is superior to a single endometrial biopsy as a screening method for confirmation of presumptive ovulation and for evaluation of luteal function.
The ovulation method of natural family planning is described in detail as taught in the ovulation method centers with an account of its development in Australia and the underlying philosophy. Hormonal studies supporting its scientific bases are given including recent work on the hormonal events of the menstrual cycle. The teaching of the method for the avoidance and achievement of pregnancy is outlined including special circumstances such as lactation premenopause stress situations abnormal vaginal discharges and formal oral contraceptive use. The failure rate of the ovulation method has been shown by a number of surveys as between that of the pill and the IUD. It is the fastest spreading method of natural family planning currently in use in 50 countries.
Fifteen years have passed since our group first proposed the use of clomiphene citrate as an ovulation-inducing agent. Our 15-year experience with over 2,000 patients has not dampened our enthusiasm for this drug. The benefits have far outweighted the minor side effects or the possibility of multiple births. Serious birth defects were minimal and have been no greater than what one may expect in the general population. Clomiphene citrate has been a boon to womankind and deserves the confidence of both patient and physician: it is a drug with a record of utility and with but minor risks.
Nine healthy fertile women were studied during 29 menstrual cycles. A cervical mucus grading system, assessed by the patient and used in conjunction with basal body temperature, was correlated with plasma levels of luteinizing hormone (LH), oestradiol and plasma progesterone. The results show that a patient can be taught to predict the time of ovulation by observing the changes in the cervical mucus.
Plasma concentration of estrogen and progesterone were measured during the last 6 days of the menstrual cycle in women with premenstrual tension, and compared with a group of healthy women. Those women with anxiety as the main symptom (PMT-a) had significantly higher estrogen levels on days 5-2 before the onset of menstruation. On days 6-4 they had lower levels of progesterone. Estrogen-progesterone ratios were significantly higher on days 6-3 before menstruation. The PMT-a group also showed increases in body wt. during the last days of the menstrual cycle.
The levels of prostaglandins in the human endometrium throughout the normal menstrual cycle were measured by bioassay. The identity of prostaglandin F2alpha and prostaglandin E2 in endometrial tissue extracts was established by combined gas chromatography/mass spectrometry. The levels of prostaglandin F2alpha and prostaglandin E2 are low during the proliferative phase of the cycle (10-25 ng/100 mg tissue). Prostaglandin F2alpha rises significantly during the luteal phase to levels of 65-75 ng/100 mg of tissue. Prostaglandin E2 levels are similar to prostaglandin F2alpha levels in the proliferative phase but remain lower during the luteal phase. The prostaglandin E2 level is highest at menstruation (52 ng/100 mg tissue). The implications of these findings are discussed in relation to the menstrual process and to the steroid hormonal changes during the cycle.
Ten ovulating women were studied to assess the interrelationships of various systemic, hormonal, and reproductive tract changes during normal menstrual cycles. Samples of blood, 24 hour urine specimens, vaginal smears, and cervical mucus were obtained every 2 days preand post-menstrually and daily in mid-cycle. Endometrial biopsies were performed at the onset of or immediately before menstruation, and the basal body temperature was recorded. Data for 10 cycles were fed into a computer, and mean reciprocal relationships were determined. The results were: (1) All endometrial biopsies reflected the late secretory phase; (2) there was a simultaneous mid-cycle surge of luteinizing hormone (LH) and folliclestimulating hormone (FSH), and serum concentrations of FSH and LH were significantly lower in the luteal phase compared to the follicular phase; (3) urinary peaks of estrone, estradiol and total estrogens occurred on the day before and that of estriol occurred on the day of the LH surge; (4) serum progesterone began to rise just before the LH peak, reached a high level 7 days after the LH peak, declined precipitately on Day 9, and rose again on Day 10, to decrease slowly until the onset of menstruation; (5) a significant relationship was observed between the LH peak and the basal body temperature; (6) urinary pregnanediol levels closely paralleled serum progesterone concentrations; (7) vaginal cytology revealed a karyopyknotic index peak the day following the LH peak; (8) properties of cervical mucus showed a remarkable relationship to the ovulatory estrogen peak.
Measurement and Statistics · Instrument Development and Validation
A method to measure plasma progesterone by gas-liquid chromatography is presented. The procedure allows for the preparation of a plasma progesterone extract clean enough for accurate submicrogram quantification by gas-liquid chromatography. In a gas chromatograph equipped with a hydrogen flame detector, the instrument modifications and operating conditions as outlined make possible the measurement of 0.001 μg (1 ng.) of progesterone standard on a stable recorder base line. In biologic samples the sensitivity of the assay is in the order of 0.01 μg (10 ng.) of progesterone.
239 women received medroxyprogesterone during their pregnancies; they received no other hormone therapy. Of the 203 who went to term 172 were treated prior to the 12th week; the latter are discussed. Average daily dose varied from 5-50 mg or more orally with or without injectable supplements. Sex distribution of infants was 92 male to 82 female there were 2 sets of twins 1 stillborn and 1 newborn with congenital heart disease. The authors report a case of transient masculization of a female infant born with an enlarged clitoris which persisted until age 6 months. Masculization of the female fetus may occur if the fetus is subjected to some source of androgen prior to the 12th week of gestation after which the female generative tract is well differentiated and not likely to be affected. Other studies have reported up to 18% masculization using exogenous hormones with abnormalities as extreme as labial fusion and cloacal formation necessitating surgical correction.
Pregnancy Complications · Premature Rupture of Membranes
Study of 54 habitual aborters with low or normal pregnanediol excretion, in a double-blind trial, revealed the spontaneous-salvage rate and the possible benefit of therapy with medroxyprogesterone acetate. The salvage rate in the placebo group with the worst prognosis (never a term pregnancy, low pregnanediol in the current pregnancy) was ten of 13, and the salvage rate in the other placebo groups showed no statistically significant difference. In view of this high spontaneous salvage rate, the numbers required to demonstrate a therapeutic effect of progestin administration are prohibitively large. This indicates the need for new criteria to pinpoint cases with a poor prognosis, and it raises the question whether habitual abortion is a disease entity or a statistical coincidence.
Measurement and Statistics · Instrument Development and Validation
A modification of Short's method for the determination of plasma progesterone is described, which allows the estimation of 0.5–1.0 μg per sample. The reliability of the method is tested and plasma levels in cord and peripheral blood during pregnancy are reported.
While investigating the use of progesterone for the relief of premenstrual syndrome (Greene and Dalton, 1953) a high incidence of toxaemia of pregnancy (19.1 %) was recognized among sufferers from this syndrome. A further investigation, undertaken to ascertain the incidence of premenstrual syndrome in those who had previously suffered from toxemia of pregnancy, revealed that 86% of the 237 women thus affected at one time or another during the previous twelve years also suffered from premenstrual syndrome (Dalton, 1954). Furthermore, direct questioning and a scrutiny of records of these patients showed that before the full development of the signs of toxaemia–that is, oedema, hypertension, and albuminuria–most had earlier in the pregnancy experienced a symptomatic stage characterized by relatively minor afflictions–for example, lethargy 43 %, headache 48%, visual aura 37%, vertigo 29%, nausea and vomiting 16%, irritability 14%, depression 9%, and backache 6%. In fact, only 7% disclosed freedom from these symptoms during a toxaemic pregnancy. Of the 237 women, 92 (38.8%) had experienced both a normal and a toxaemic pregnancy, and 72 (78 %) contrasted the sense of well-being associated with a normal pregnancy with the malaise and minor symptoms characteristic of the toxaemic condition. The striking feature of these early minor symptoms of toxaemia was their close resemblance to those of premenstrual syndrome noted in an earlier investigation (Greene and Dalton, 1953), most patients confirming that the minor symptoms during their toxaemic pregnancy were similar, though of increased severity, to those experienced in the premenstruum, irrespective of whether the onset of premenstrual syndrome had preceded or followed the toxaemic pregnancy. Apart from the similarities of these minor symptoms in the two conditions, other points in common were noted. For example, day-to-day observations of sufferers of premenstrual syndrome had shown that, apart from minor symptoms, some developed oedema, hypertension, and albuminuria during the premenstruum, with spontaneous improvement during menstruation. This appeared to be analogous to the spontaneous resolution of oedema, hypertension, and albuminuria following delivery. Furthermore, if symptoms remain untreated either in premenstrual syndrome or in toxaemia both diseases may culminate in fits, epileptic in the one case, eclamptic in the other. In an earlier investigation one of the reasons for using progesterone in the treatment of premenstrual syndrome had been that some patients suffering from this condition were symptom-free during pregnancy. It was considered that the corpus luteum and placenta supplied enough progesterone during pregnancy to keep these patients symptom-free. Others were not only unrelieved of their premenstrual symptoms during pregnancy, but, as already indicated, developed symptoms closely resembling those of the premenstruum and culminating in toxaemia. It was therefore thought possible that the development of toxaemia might in such cases arise from failure of the corpus luteum and placenta to produce sufficient progesterone. In the light of similarities between premenstrual syndrome and toxaemia, and the fact that treatment of the former with progesterone not only relieved the symptoms (Greene and Dalton, 1953) but also prevented the development of edema, hypertension, and albuminuria in the premenstruum (Dalton, 1954, 1955), it was decided to carry out a trial, employing large doses of progesterone in patients disclosing early minor symptoms of toxaemia, in an attempt to arrest full development of that condition.
Pregnancy Complications · Premature Rupture of Membranes
Of 900 biopsies made with a small suction curet 457 from 329 women were analyzed to show the progression of the endometrium from the high-estrogen early-proliferative phase, immediately following menstruation, through the late proliferation occurring about Day 12 foll owing menstruation. Classifications from Days 14 to 27 are much easier to make because the 1st sign of progestin effect causes significant change. On Day 15 vacuolization of the cytoplasm and beginning migration of the nuclei toward the surface of the cells is seen, leaving a lucid zone underlying the nuclei. On Day 17 this zone is well-marked and the nuclei above it are lining up to lie later each beside the other near the middle of the cell. On Day 19 the row of nuclei has sunk distally near to the base of all the cells. On Day 18 a beginning edema of the stroma is seen, first in patches; by Day 21 it is generalized and the last vestige of the zona pellucida has disappeared. On Day 21 the process of secretion, which began about Day 17, is well advanced. From Day 21 on the signs of hormonal action are seen not primarily in the gla nds but in the stroma and vascular system. Edema has become generalized by Day 21; on Day 23 the stroma cells are larger, more thick-walled, and more numerous; by Day 25 the edema is replaced by masses of contiguous large cells with large pale nuclei and much cytoplasm; and on Day 26 size of the stroma cells has extended so that almost all the interglandu lar cells are contiguous. On Day 27 this solidification of the most sup erficial stroma becomes complete, the glands are widely dilated, the epithelium approaches the cuboidal, the vascular system is highly developed, and the arterioles and venules are engorged with blood. Late on Day 27, just before menstruation, lymphocytes and polymorphonuclear leukocytes appear in great numbers and erythrocytes appear in clumps. T he whole predeciduum is infiltrated, the stroma nuclei become pale, neutrophils appear in large numbers, the tissue disintegrates, and menstruation occurs. Understanding of this normal process can aid in clinical diagnosis of menstrual disorders. A series of biopsies taken with a small surgical curet does little tissue damage and can reveal hormonal imbalance, thin stroma associated with menopause or hypoplastic endometrium, and such pathological conditions as tuberculous endometritis and cancer of the endometrium. In the 3 cases in which a woman with unsuspected early pregnancy was biopsied, no harm was done. This study showed amenorrhea is usually due to deficient follicular development but may be present even if a proliferative endometrium shows a high degree of follicle activity; in the absence of pregnancy there is never a persistent corpus aluteum.