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.
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.
In many animals, olfactory cues are key for recognizing their sex, kinship, and reproductive status. In humans, it has been proposed that males find female body odors attractive during the ovulatory phase, coinciding with peak fertility. However, the molecular and physiological foundations of this attractiveness remain unclear. In this study, we combined sensory evaluation with gas chromatography-mass spectrometry for chemical analysis and identified volatile compounds that fluctuate across menstrual cycle phases. We identified three ovulatory phase-increasing compounds that mitigate the basal unpleasant axillary odor, resulting in the ovulatory-phase body odor being perceived as the most pleasant by males. Additionally, these compounds alleviated hostility and stress induced by the basal axillary odor, leading to relaxation in males and an enhanced positive impression of female facial images. Our results suggest that several ovulatory phase-increasing compounds may contribute to the positive effects of ovulatory female odor on males, as proposed in previous research.
Cycle Across the Lifespan · Cycle and General Health
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.
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.
Frey Nascimento A et al., 2025·BMJ Evid Based Med·
Open Access
To investigate the efficacy and safety of open-label placebos (OLP) in premenstrual syndrome (PMS).
Randomised controlled trial.
Switzerland, 2018-2020. 150 women (18-45 years of age) with PMS or premenstrual dysphoric disorder. Random assignment (1:1:1) to treatment as usual (TAU), OLP without treatment rationale (OLP-), or OLP with treatment rationale (OLP+). OLP consisted of two placebo pills per day for 6 weeks. Primary outcomes were PMS symptom intensity and interference between groups across three menstrual cycles (MC1-MC3); adverse events (ie, safety) were measured at weeks 3 and 6 after the start of the intervention. Secondary outcomes were psychological and somatic subscales of PMS symptom intensity, and adherence. From 2 August 2018 to 3 December 2020,
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.
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.
Adolescent heavy menstrual bleeding(HMB), menorrhagia or abnormal uterine bleeding commonly occur in adolescent women. The differential diagnosis can be challenging. The pneumonic: PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified), is commonly used but it does not stratify as to the likelihood of a disorder. We have sought to develop a probability-based differential diagnosis for Adolescent HMB, menorrhagia or abnormal uterine bleeding. A comprehensive literature search was conducted using PubMed, EMBASE, and SCOPUS databases. Case series describing adolescents from 10-19 years of age with HMB, menorrhagia or abnormal uterine bleeding was acceptable if: more than 10 patients were included; editorials, case reports, and secondary sources such as review articles, or book chapters were excluded. No language filter was used, but an English abstract was required. The etiology of HMB, menorrhagia or abnormal uterine bleeding, and the country of origin was extracted from articles that met inclusion criteria. Cumulative rate estimates were determined by Bayesian probability modeling. Seventeen full text articles were reviewed in detail; 2,770 patients were included. The most frequent causes of HMB were Ovarian Uterine Disorders (23.7%; 95% CredI 22-25.5%), Coagulation Disorders (19.4%; 95% CredI 17.8-21.1%), and Platelet Disorders (6.23%; 95% CredI 5.27-7.27%) with 45.9% (95% CredI 43.8-47.%9) of the cases of indeterminate origin. The leading causes of HMB in healthy adolescent females were varied. The sub-analysis identified distinct etiologies, suggesting that multiple factors must be considered in the evaluation of HMB. While PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified) provides us with a comprehensive picture of the possible causes of HMB in females, this systematic review assigns probabilities to the etiologies of HMB in adolescent females, providing physicians with a more focused and efficient pathway to diagnosis.
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.
Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with gynecological diseases. However, the causal relationship between gut microbiota and menstrual disorders remains to be determined. We obtained summary data of gut microbiota from the global consortium MiBio-Gen's genome-wide association study (GWAS) dataset and data on menstrual disorders from the IEU Open GWAS project. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were used to examine the causal association between gut microbiota and menstrual disorders. Thorough sensitivity studies were performed to confirm the data's horizontal pleiotropy, heterogeneity, and robustness. Through MR analysis of 119 kinds of gut microbiota and 4 kinds of clinical phenotypes, it was discovered that 23 different kinds of gut microbiota were loosely connected to menstrual disorders. After FDR correction, the results showed that only Escherichia/Shigella (p = 0.00032, PFDR = 0.0382, OR = 1.004, 95%CI = 1.002-1.006) is related to menstrual disorders. According to our MR Analysis, there are indications of a causal relationship between menstrual disorders and gut microbiota. This finding could lead to new discoveries into the mechanisms behind menstrual disorders and clinical research involving the microbiota.
Observational studies have demonstrated associations between menstrual disorders, dysmenorrhea, and cardiovascular disease (CVD). However, it remains unclear whether these associations are causal. This study is to investigate whether menstrual disorders and dysmenorrhea causally affect the risk of CVD. The summary data for menstrual disorders (excessive menstruation and irregular menses) and dysmenorrhea were obtained from FinnGen study, summary data for CVD were obtained from UK Biobank and meta-analysis. The inverse-variance-weighted method was mainly used in the Mendelian randomization for causality analysis. Sensitivity analyses were performed by several methods under different model assumptions. Genetic liability to excessive menstruation was associated with higher risk of atrial fibrillation (odds ratio (OR), 1.078 [95% confidence interval (CI), 1.015-1.145]; P=0.014), but a lower risk of hypertension (OR, 0.994 [95% CI: 0.989-0.999]; P=0.016). Irregular menses was associated with higher risk of atrial fibrillation (OR, 1.095 [95% CI: 1.015-1.182]; P=0.02), hypertension (OR, 1.007 [95% CI: 1.000-1.013]; P=0.047), myocardial infarction (OR, 1.172 [95% CI: 1.060-1.295]; P=0.02), ischemic heart disease, (OR, 1.005 [95% CI: 1.000-1.010]; P=0.037) and coronary heart disease (OR, 1.004 [95% CI: 1.001-1.008]; P=0.026). Dysmenorrhea was associated with higher risk of atrial fibrillation (OR, 1.052 [95% CI: 1.014-1.092]; P=0.008) and Ischemic stroke (cardioembolic) (OR, 1.122 [95% CI: 1.002-1.257]; P=0.046). After Benjamini-Hochberg correction, irregular menses was associated with higher risk of myocardial infarction. We confirmed a causal relationship of excessive menstruation, irregular menses and dysmenorrhea on cardiovascular outcomes independent of sex hormone levels, with an emphasis on the link between irregular menses and myocardial infarction. These clinical features can be utilized as markers to identify women at higher risk of developing CVD in the future, recommending early clinical intervention of menstrual diseases.
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.
Cycle Across the Lifespan · Cycle and General Health
Menstrual characteristics are important signs of women's health. Here we examine the variation of menstrual cycle length by age, ethnicity, and body weight using 165,668 cycles from 12,608 participants in the US using mobile menstrual tracking apps. After adjusting for all covariates, mean menstrual cycle length is shorter with older age across all age groups until age 50 and then became longer for those age 50 and older. Menstrual cycles are on average 1.6 (95%CI: 1.2, 2.0) days longer for Asian and 0.7 (95%CI: 0.4, 1.0) days longer for Hispanic participants compared to white non-Hispanic participants. Participants with BMI ≥ 40 kg/m2 have 1.5 (95%CI: 1.2, 1.8) days longer cycles compared to those with BMI between 18.5 and 25 kg/m2. Cycle variability is the lowest among participants aged 35-39 but are considerably higher by 46% (95%CI: 43%, 48%) and 45% (95%CI: 41%, 49%) among those aged under 20 and between 45-49. Cycle variability increase by 200% (95%CI: 191%, 210%) among those aged above 50 compared to those in the 35-39 age group. Compared to white participants, those who are Asian and Hispanic have larger cycle variability. Participants with obesity also have higher cycle variability. Here we confirm previous observations of changes in menstrual cycle pattern with age across reproductive life span and report new evidence on the differences of menstrual variation by ethnicity and obesity status. Future studies should explore the underlying determinants of the variation in menstrual characteristics.
Read P et al., 2022·Science & medicine in football
This study assesses how female footballers perceive how their menstrual cycle impacts their physical and psychological performance, informing future research and intervention. Semi-structured interviews, developed using piloting and peer review took place with fifteen elite female footballers from two English WSL clubs (age: 25.2 [18-33]). Data was audio recorded, transcribed verbatim, and analysed thematically using NVivo. All players (100%) perceive their menstrual cycle to negatively impact performance. Analysing 27,438 words of data revealed five themes: A) symptoms, B) preparation, C) performance, D) recovery, and E) management. Over half (53%) of players experienced decreased appetite and sleep quality prior to performance during menstruation. Competitive performance was perceived to be most negatively impacted during menses (54 references) following by the pre-menstrual stage (23 references). During menstruation, the most impacted physical performance indicators were power (93%) and fatigue (87%). Psychologically, confidence, focus, and reaction to criticism were commonly affected (66.7%). Players reported missing training (13.3%) and matches (13.3%) due to severity of impact. Recovery was affected during the pre-menstrual (26.7%) and menstrual (66.7) stages. Players self-manage symptoms using over the counter (66.7%) and prescription (26.7%) medication, some prophylactically prior to competition (46.7%). This first attempt to ascertain player perception in football exposes a clear negative impact on performance. The complex interplay of biopsychosocial and logistical factors, lack of awareness and education highlight the need for further research. Intervention is necessary and immediate initiation would be prudent, starting with simple measures such as basic self-management advice, education, and provision of sanitary products.
Najmabadi S et al., 2022·Hum Reprod Open·
Open Access
Does sexual intercourse enhance the cycle fecundability in women without known subfertility? Sexual intercourse (regardless of timing during the cycle) was associated with cycle characteristics suggesting higher fecundability, including longer luteal phase, less premenstrual spotting and more than 2 days of cervical fluid with estrogen-stimulated qualities. Human females are spontaneous ovulators, experiencing an LH surge and ovulation cyclically, independent of copulation. Natural conception requires intercourse to occur during the fertile window of a woman's menstrual cycle, i.e. the 6-day interval ending on the day of ovulation. However, most women with normal fecundity do not ovulate on Day 14, thus the timing of the hypothetical fertile window varies within and between women. This variability is influenced by age and parity and other known or unknown elements. While the impact of sexual intercourse around the time of implantation on the probability of achieving a pregnancy has been discussed by some researchers, there are limited data regarding how sexual intercourse may influence ovulation occurrence and menstrual cycle characteristics in humans. This study is a pooled analysis of three cohorts of women, enrolled at Creighton Model FertilityCare centers in the USA and Canada: '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 cycle phase lengths, bleeding and cervical mucus patterns and estimated the fertile window in 2564 cycles of 530 women, followed for up to 1 year. Participants were US or Canadian women aged 18-40 and not pregnant, who were heterosexually active, without known subfertility and not taking exogenous hormones. Most of the women were intending to avoid pregnancy at the start of follow-up. Women recorded daily vaginal bleeding, mucus discharge and sexual intercourse using a standardized protocol and recording system for up to 1 year, yielding 2564 cycles available for analysis. The peak day of mucus discharge (generally the last day of cervical fluid with estrogen-stimulated qualities of being clear, stretchy or slippery) was used to identify the estimated day of ovulation, which we considered the last day of the follicular phase in ovulatory cycles. We used linear mixed models to assess continuous cycle parameters including cycle, menses and cycle phase lengths, and generalized linear models using Poisson regression with robust variance to assess dichotomous outcomes such as ovulatory function, short luteal phases and presence or absence of follicular or luteal bleeding. Cycles were stratified by the presence or absence of any sexual intercourse, while adjusting for women's parity, age, recent oral contraceptive use and breast feeding. MAIN Most women were <30 years of age (75.5%; median 27, interquartile range 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators and nulliparous (70.9%). Cycles with no sexual intercourse compared to cycles with at least 1 day of sexual intercourse were shorter (29.1 days (95% CI 27.6, 30.7) versus 30.1 days (95% CI 28.7, 31.4)), had shorter luteal phases (10.8 days (95% CI 10.2, 11.5) versus 11.4 days (95% CI 10.9, 12.0)), had a higher probability of luteal phase deficiency (<10 days; adjusted probability ratio (PR) 1.31 (95% CI 1.00, 1.71)), had a higher probability of 2 days of premenstrual spotting (adjusted PR 2.15 (95% CI 1.09, 4.24)) and a higher probability of having two or fewer days of peak-type (estrogenic) cervical fluid (adjusted PR 1.49 (95% CI 1.03, 2.15)). LIMITATIONS Our study participants were geographically dispersed but relatively homogeneous in regard to race, ethnicity, income and educational levels, and all had male partners, which may limit the generalizability of the findings. We cannot exclude the possibility of undetected subfertility or related gynecologic disorders among some of the women, such as undetected endometriosis or polycystic ovary syndrome, which would impact the generalizability of our findings. Acute illness or stressful events might have reduced the likelihood of any intercourse during a cycle, while also altering cycle characteristics. Some cycles in the no intercourse group may have actually had undocumented intercourse or other sexual activity, but this would bias our results toward the null. The Creighton Model FertilityCare System (CrM) discourages use of barrier methods, so we believe that most instances of intercourse involved exposure to semen; however, condoms may have been used in some cycles. Our dataset lacks any information about the occurrence of female orgasm, precluding our ability to evaluate the independent or combined impact of female orgasm on cycle characteristics. Sexual activity may change reproductive hormonal patterns, and/or levels of reproductive hormones may influence the likelihood of sexual activity. Future work may help with understanding the extent to which exposure to seminal fluid, and/or female orgasm and/or timing of intercourse could impact menstrual cycle function. In theory, large data sets from women using menstrual and fertility tracking apps could be informative if women can be appropriately incentivized to record intercourse completely. It is also of interest to understand how cycle characteristics may differ in women with gynecological problems or subfertility. Funding for the research on the three cohorts analyzed in this study was provided by the Robert Wood Johnson Foundation #029258 (Creighton Model MultiCenter Fecundability Study), the Eunice Kennedy Shriver National Institute of Child Health and Human Development 1K23 HD0147901-01A1 (Time to Pregnancy in Normal Fertility) and the Office of Family Planning, Office of Population Affairs, Health and Human Services 1FPRPA006035 (Creighton Model Effectiveness, Intentions, and Behaviors Assessment). The authors declare that they have no conflict of interest. N/A.
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.
To evaluate variations in micronutrient biomarker concentrations and deficiencies across the menstrual cycle in a cohort of healthy women. This prospective cohort study was conducted among healthy women of reproductive age living in the State College area, Pennsylvania, (n = 45). Data collection occurred at the early follicular phase, the late follicular phase, and the midluteal phase. Fasting blood samples were collected to measure micronutrient biomarkers. At the early follicular phase, the mean ± SD concentrations for zinc, copper, magnesium, and retinol were 81.8 ± 16.2 µg/dL, 80.1 ± 12.8 µg/dL, 17.9 ± 1.4 mg/L, and 39.4 ± 9.3 µg/dL, respectively. The geometric mean (95% CI) for manganese, iron and ferritin concentrations were 1.51 [1.21, 1.87] µg/L, 106.7 [90.8, 125.4] µg/dL, and 26.4 [20.5, 34.0] µg/L, respectively. Mean concentrations of zinc and magnesium declined by 6.6% (p = 0.009) and 4.6% (p < 0.001) from the early follicular phase to the midluteal phase, respectively. Other biomarkers remained relatively constant across the cycle. At the early follicular phase, the prevalence of low serum concentrations for zinc, copper, magnesium, manganese, iron, and ferritin was 22%, 7%, 29%, 13%, 14%, and 28%, respectively. Also, in early follicular phase, 36% had anemia, and 13% specifically had iron deficiency anemia. The prevalence of magnesium deficiency was significantly higher at the midluteal phase vs. the early follicular phase (p = 0.025). Our study suggests that while many micronutrient concentrations are relatively constant across the menstrual cycle in healthy women, zinc and magnesium decline, and the prevalence of magnesium deficiency increases. Supplemental data for this article is available online at.
Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.
LEARNING After participating in this activity, learners should be better able to:• Discuss and outline the general and overlapping effects of the menstrual cycle on women's mental health. A growing body of research demonstrates menstrual cycle-dependent fluctuations in psychiatric symptoms; these fluctuations can therefore be considered as prevalent phenomena. Possible mechanisms underlying these fluctuations posit behavioral, psychological, and neuroendocrine influences. Recent reviews document cyclic exacerbation of symptoms and explore these mechanisms in the context of specific and often single disorders. The question remains, however, as to whether there are general and overlapping effects of the menstrual cycle on women's mental health. To address this gap, we synthesized the literature examining the exacerbation of a variety of psychiatric symptoms across the menstrual cycle in adult women. Results show that the premenstrual and menstrual phases are most consistently implicated in transdiagnostic symptom exacerbation. Specifically, strong evidence indicates increases in psychosis, mania, depression, suicide/suicide attempts, and alcohol use during these phases. Anxiety, stress, and binge eating appear to be elevated more generally throughout the luteal phase. The subjective effects of smoking and cocaine use are reduced during the luteal phase, but fewer data are available for other substances. Less consistent patterns are demonstrated for panic disorder, symptoms of posttraumatic stress disorder, and borderline personality disorder, and it is difficult to draw conclusions for symptoms of generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and trichotillomania because of the limited data. Future research should focus on developing standardized approaches to identifying menstrual cycle phases and adapting pharmacological and behavioral interventions for managing fluctuations in psychiatric symptoms across the menstrual cycle.
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.
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.
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.
Cycle Across the Lifespan · Cycle and General Health
Dorani F et al., 2021·Journal of psychiatric research
This is the first study to assess the prevalence of symptoms of premenstrual dysphoric disorder (PMDD), episodes of postpartum depression symptoms (PPD) after first childbirth, and climacteric mood symptoms in Attention-Deficit/Hyperactivity Disorder (ADHD). 209 consecutive women (18-71 years) with ADHD completed the PMDD chapter of the Neuropsychiatric Interview Plus version 5.0.0 to assess PMDD, the Edinburgh Postnatal Depression Scale to assess PPD, and the Greene Climacteric Scale to assess climacteric symptoms. Comorbid psychiatric disorders, medication use, and chronobiological sleep characteristics were also assessed. The prevalence of PMDD and PPD were high in ADHD, compared to the general population. PMDD symptoms were associated with less use of contraceptives. Antidepressants were associated with more PMDD symptoms. The following GCS scores were significant increased: anxiety, depression, and sexual dysfunction, vasomotor and somatic complaints. No significant differences were found in sleep characteristics or current comorbidity between the groups with and without PPD or PMDD, or increased climacteric scores. The prevalences of PMDD, PPD and climacteric scores were high in women with ADHD. This is the first study in women with ADHD that suggests that female ADHD patients suffer from significant PMDD symptoms, experience PPD during the first child birth, and experience more severe climacteric symptoms.
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.
DeVilbiss EA et al., 2020·Paediatr Perinat Epidemiol·
Attaining pregnancy is conditional upon a series of complex processes, including adequately timed intercourse, ovulation, fertilisation, and implantation. Anovulation is a first-line treatment target for couples with difficulty conceiving and is frequently examined in studies of fecundability. To identify whether sporadic anovulation is an important determinant of cumulative pregnancy rates and time to pregnancy among fertile women with regular menstrual cycles. We simulated cumulative pregnancy rates and time to pregnancy for 12 consecutive menstrual cycles among 100 000 women based on data-driven probabilities of implantation, fertilisation, ovulation, and intercourse occurring in the fertile window. We assumed anovulation probabilities of 1%, 8%, or 14.5% and intercourse averaging once per week, every other day, or daily. The model incorporated reductions in implantation and fertilisation rates for successive cycles of non-pregnancy. After 12 cycles, a reduction in the per cycle incidence of anovulation from 14.5% to 1% resulted in a 4.0% higher cumulative pregnancy rate (86.7% vs 90.7%) and similar time to pregnancy (1-cycle median difference). In contrast, increasing mean unscheduled sexual intercourse frequency from weekly to every other day was associated with a 5-cycle median reduction in time to pregnancy (weekly: 7 cycles; every other day or daily: 2 cycles) and a 28.9% increase in the cumulative pregnancy rate (weekly: 59.9%, every other day: 88.8%; daily: 91.6%). In presumed fertile women with regular menstrual cycles, routine investigation of anovulation may not be an informative outcome in studies of fecundability, and routine testing to ensure ovulation and treatment of anovulation are unlikely to be medically necessary. While biomarkers or cervical fluid may help time intercourse to the fertile window, time to pregnancy can also be improved through increasing the frequency of unscheduled intercourse. These findings need corroboration in large preconception time to pregnancy studies.
Creatine is an amino acid derivative synthesized from arginine, glycine and methionine. It serves as the substrate for the creatine kinase system, which is vital for maintaining ATP levels in tissues with high and fluctuating energy demand. There exists evidence that the creatine kinase system operates in both the endometrial and myometrial layers of the uterus. While use and regulation of this system in the uterus are not well understood, it is likely to be important given uterine tissues undergo phases of increased energy demand during certain stages of the female reproductive cycle, pregnancy, and parturition. This review discusses known adaptations of creatine metabolism in the uterus during the reproductive cycle (both estrous and menstrual), pregnancy and parturition, highlighting possible links to fertility and the existing knowledge gaps. Specifically, we discuss the adaptations and regulation of uterine creatine metabolite levels, cell creatine transport, de novo creatine synthesis, and creatine kinase expression in the various layers and cell types of the uterus. Finally, we discuss the effects of dietary creatine on uterine metabolism. In summary, there is growing evidence that creatine metabolism is up-regulated in uterine tissues during phases where energy demand is increased. While it remains unclear how important these adaptations are in the maintenance of healthy uterine function, furthering our understanding of uterine creatine metabolism may uncover strategies to combat poor embryo implantation and failure to conceive, as well as enhancing uterine contractile performance during labor.
Cycle Across the Lifespan · Cycle and General Health
Grieger JA et al., 2020·Journal of medical Internet research
There is increasing information characterizing menstrual cycle length in women, but less information is available on the potential differences across lifestyle variables. This study aimed to describe differences in menstrual cycle length, variability, and menstrual phase across women of different ages and BMI among a global cohort of Flo app users. We have also reported on demographic and lifestyle characteristics across median cycle lengths. The analysis was run based on the aggregated anonymized dataset from a menstrual cycle tracker and ovulation calendar that covers all phases of the reproductive cycle. Self-reported information is documented, including demographics, menstrual flow and cycle length, ovulation information, and reproductive health and diseases. Data from women aged ≥18 years and who had logged at least three cycles (ie, 2 completed cycles and 1 current cycle) in the Flo app were included (1,579,819 women). Of the 1.5 million users, approximately half (638,683/1,579,819, 40.42%) were aged between 18 and 24 years. Just over half of those reporting BMIs were in the normal range (18.5-24.9 kg/m2; 202,420/356,598, 56.76%) and one-third were overweight or obese (>25 kg/m2; 120,983/356,598, 33.93%). A total of 16.32% (257,889/1,579,819) of women had a 28-day median cycle length. There was a higher percentage of women aged ≥40 years who had a 27-day median cycle length than those aged between 18 and 24 years (22,294/120,612, 18.48% vs 60,870/637,601, 9.55%), but a lower percentage with a 29-day median cycle length (10,572/120,612, 8.77% vs 79,626/637,601, 12.49%). There were a higher number of cycles with short luteal phases in younger women, whereas women aged ≥40 years had a higher number of cycles with longer luteal phases. Median menstrual cycle length and the length of the follicular and luteal phases were not remarkably different with increasing BMI, except for the heaviest women at a BMI of ≥50 kg/m2. On a global scale, we have provided extensive evidence on the characteristics of women and their menstrual cycle length and patterns across different age and BMI groups. This information is necessary to support updates of current clinical guidelines around menstrual cycle length and patterns for clinical use in fertility programs.
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.
Gnoth C et al., 2020·Archives of gynecology and obstetrics
Many physicians and other healthcare professionals are often asked questions on interfering factors for conception by couples with a desire for children. Such possible disturbances include, for example, the very common minor diseases, stress and also sexual intercourse during the suspected implantation period. Non-scientifically based statements about disturbances in conception cycles, as found in many layman publications and on the internet, can strongly unsettle couples with a desire for children and force them into corset of rules of conduct. Therefore, a systematic scientific evaluation of the impact of disturbances on conception is urgently needed. A search for possible disturbances in natural conception cycles together with up to three of the respective pre-cycles in a large cycle database from users of the symptothermal method of natural family planning in Germany was performed. Disturbances were qualified by scientific panel decision and analysed statistically with their effects on the chances of spontaneous conception. Mixed logistical regression models and survival time analyses were used. A total of 237 women with a total of 747 cycles could be included in the analysis. In 61% of all 237 conception cycles, disturbances occurred. The statistical analysis shows that disturbances in natural conception cycles unexpectedly increase the likelihood of pregnancy by an overall factor of 1.32 (95% CI 1.04-1.70). Sexual intercourse in the window of implantation does not decrease the chances of conception. Relaxation states at the time of ovulation and/or during the implantation period have no representable effect and do not increase the chance of pregnancy. Couples trying to conceive should at least be informed that disturbances in conception cycles, such as minor diseases, stress or sexual intercourse during the implantation period do not interfere with conception. Relaxation has no effect in favour of success. This takes away the guilty feeling of couples, fearing that they possibly did something wrong in cycles without the desired pregnancy.
Tully L et al., 2020·Obstet Gynecol Sci·
Open Access
Premenstrual syndrome (PMS) affects millions of women. While over-the-counter products have helped with the physical symptoms of PMS, emotional symptoms have been less well supported. The objective of this trial was to measure the effect of an oxaloacetate/vitamin C combination on the major emotional symptoms of PMS, including depression, anxiety, perceived stress, aggression, and suicidal ideation. Forty-eight women experiencing PMS completed a baseline survey comprising the Beck's Depression Inventory, Cohen Perceived Stress Scale, Generalized Anxiety Disorder Test, and Buss-Perry Aggression Questionnaire. After baseline measurements, participants were randomly assigned to take either 2 capsules of 100 mg oxaloacetate/150 mg ascorbic acid, or 2 capsules of rice flour (placebo) for their entire menstrual cycle. At menstruation, the women completed the 4 surveys again. The women then switched capsules in a cross-over design and continued the study for an additional menstrual cycle. The final assessment was repeated at menstruation. Statistical analysis of the 4 surveys was performed to examine efficacy. Oxaloacetate/vitamin C supplementation during PMS significantly improved depression, perceived stress, anxiety, aggression, and suicidal ideation. The mean improvement in depression was 54.1%, 35.8% for perceived stress, 51.43% for generalized anxiety, and 17.8% for aggression. Suicidal ideation was reduced by 47.9%. All results were highly significant. A combination of oxaloacetate and vitamin C supplementation helped to alleviate depression, anxiety, perceived stress, aggression, and suicidal ideation symptoms associated with PMS. ClinicalTrials.gov Identifier: NCT03509714.
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.
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.
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.
Cycle Across the Lifespan · Cycle and General Health
Some authorities have found that, when the mean follicular diameter is >25 mm, the follicle is considered large, and these authorities are convinced that large follicles are biomarkers to ovarian pathology. Several studies have been carried out to determine the optimal maximum follicular size (MFS) that will be adequate before the use of human chorionic gonadotropin trigger to induce ovulation. None of these studies have considered the woman's age as a factor. An in vitro fertilization-based study has also shown that large leading follicles did not result in higher percentage of matured oocytes, and they even result in a lower live birth rate; however, we note that the ages of the women were not specifically mentioned in connection with the problems of large follicle. Subjects and We set out in this study to evaluate the relationship between the MFS and the woman's age both in our control group (fertile women) Group (A) and in the women attending fertility clinic Group (B). Using the Creighton Model Fertility Care System and NaProTECHNOLOGY, it was possible to determine when to start follicular tracking and also determine ultrasound diagnosis of ovulation by recording the MFS and the reduced size. In both Group A and Group B, we discovered that the MFS reduces as woman's age increases. We also discovered that the average MFS in the Group B was higher for age compared with the Group A (P = 0.0043). There was also an association between these bigger follicles for age and low mid-luteal progesterone. This is probably the first study that describes the association of follicular size and woman's age and its possible link with ovulation defects. Recommendation: We have proposed that this phenomenon of large matured maximum follicle for age could be a contributory factor to infertility and miscarriages. We propose further studies to verify this hypothesis. Despite the high percentage of complete rupturing of follicles in the AB cycles in the Group (B) there are very high proportion having low mid luteal (P+7) Progesterone. This may be due to pathologies associated with big follicles for woman's age. The E2/Pg ratio study in luteal phase strongly suggested that the women in Group (B) that may have fertility challenge are those in subgroup of AB in Group (B). Therefore matured follicular size should be considered with the woman's age. If the follicles grows bigger away from the range for a woman's age it may be the marker for infertility or reproductive health challenges.
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.
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.
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.
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.
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.
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.
Rafieian-Kopaei M et al., 2017·Electronic physician
Vitex agnus-castus, also called vitex is aboriginal to the Mediterranean region, with long leaves, tender stem, flowers and ripening seeds. The aim of this study was to overview premenstrual, postmenstrual and infertility disorder of Vitex agnus-castus. This review article was carried out by searching studies in PubMed, Medline, Web of Science, and IranMedex databases. The initial search strategy identified about 87 references. In this study, 43 studies were accepted for further screening, and met all our inclusion criteria (in English, full text, therapeutic effects of Vitex agnus-castus and dated mainly from the year 2009 to 2016). The search terms were Vitex agnus-castus, premenstrual, postmenstrual, infertility disorder properties and pharmacological effects. Vitex agnus-castus was shown to contribute to the treatment of premenstrual syndrome (PMS). Moreover, the result of the present study showed that this valuable plant is helpful in alleviation of pain resulting from postmenstrual disease. Furthermore, it was found that Vitex agnus-castus is beneficial in infertility disorder. Vitex agnus-castus (AC) is a phytopharmaceutical compound and is shown to be widely used to treat PMS and PMDD. In addition, it was shown to be beneficial in post-menstrual cases and it can also contribute to treatment of infertility cases in both men and women. Dopaminergic compounds available in this plant help to treat premenstrual mastodynia as well as other symptoms of the premenstrual syndrome.
The topic of how the menstrual cycle is a vital sign which could signal pathophysiologic process has received considerable attention in the past decade. The current recommendations of various academic groups will be discussed as well as the FertilityTMM Care method of charting and the Naprotechnology approach to evaluating abnormalities of the menstrual cycle. Two clinical scenarios seen in adolescent medicine, PCOS and AUB, will be analyzed looking at the pathophysiology of these clinical scenarios and their management. The approach will be one that conducts an evaluation to try to find the underlying problem and aims to restore the normal physiology of the menstrual cycle.
The American Academy of Pediatrics, the American College of Obstetrics and Gynecology and the New York Academy of Sciences have published academic statements during the past ten years emphasizing the need for providers to teach patients how to chart and the important clinical ramifications of using this charting as a vital sign. In 2006 the American Academy of Pediatrics published in the Pediatrics Journal a recommendation titled: "Menstruation in Girls and Adolescents: Using the Menstrual Sign as a Vital Sign." In 2015, the American College of Obstetrics and Gynecology published a Committee Opinion emphasizing the need to teach women the charting of their menses and the important pathophysiologic process that could be detected with the charting.
James AH, 2016·Hematology American Society of Hematology Education Program·
Open Access
Heavy menstrual bleeding (HMB), which is the preferred term for menorrhagia, affects approximately 90% of women with an underlying bleeding disorder and approximately 70% of women on anticoagulation. HMB can be predicted on the basis of clots of >=1 inch diameter, low ferritin, and 'flooding' (a change of pad or tampon more frequently than hourly). The goal of the work-up is to determine whether there is a uterine/endometrial cause, a disorder of ovulation, or a disorder of coagulation. HMB manifest by flooding and/or prolonged menses, or HMB accompanied by a personal or family history of bleeding is very suggestive of a bleeding disorder and should prompt a referral to a hematologist. The evaluation will include the patient's history, pelvic examination, and/or pelvic imaging, and a laboratory assessment for anemia, ovulatory dysfunction, underlying bleeding disorder, and in the case of the patient on anticoagulation, assessment for over anticoagulation. The goal of treatment is to reduce HMB. Not only will the treatment strategy depend on whether there is ovulatory dysfunction, uterine pathology, or an abnormality of coagulation, the treatment strategy will also depend on the age of the patient and her desire for immediate or long-term fertility. Hemostatic therapy for HMB may serve as an alternative to hormonal or surgical therapy, and may even be life-saving when used to correct an abnormality of coagulation.
Premenstrual disorders affect up to 12% of women. The subspecialties of psychiatry and gynecology have developed overlapping but distinct diagnoses that qualify as a premenstrual disorder; these include premenstrual syndrome and premenstrual dysphoric disorder. These conditions encompass psychological and physical symptoms that cause significant impairment during the luteal phase of the menstrual cycle, but resolve shortly after menstruation. Patientdirected prospective recording of symptoms is helpful to establish the cyclical nature of symptoms that differentiate premenstrual syndrome and premenstrual dysphoric disorder from other psychiatric and physical disorders. Physicians should tailor therapy to achieve the greatest functional improvement possible for their patients. Select serotonergic antidepressants are first-line treatments. They can be used continuously or only during the luteal phase. Oral contraceptives and calcium supplements may also be used. There is insufficient evidence to recommend treatment with vitamin D, herbal remedies, or acupuncture, but there are data to suggest benefit from cognitive behavior therapy.
Wesselink AK et al., 2016·Ann Epidemiol·
Open Access
The aim of this study was to evaluate the association between menstrual cycle characteristics in early life and adulthood and fecundability. Pregnancy Study Online (PRESTO) is an Internet-based preconception cohort study of pregnancy planners from the United States and Canada. During the preconception period, we enrolled 2189 female pregnancy planners aged 21-45 years who had been attempting conception for ≤6 cycles. Women self-reported menstrual cycle characteristics via an online baseline questionnaire, and pregnancy status was ascertained through bimonthly follow-up questionnaires. Proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Compared with usual menstrual cycle lengths of 27-29 days, cycle lengths of <25 (FR = 0.81, 95% CI: 0.54-1.22) and 25-26 days (FR = 0.92, 95% CI: 0.75-1.14) were associated with reduced fecundability. Compared with women who reached menarche at the age of 12-13 years, those who reached menarche at <12 years had reduced fecundability (FR = 0.87, 95% CI: 0.76-0.99). Women whose cycles never regularized after menarche (FR = 0.93, 95% CI: 0.81-1.06) had slightly reduced fecundability compared with women whose cycles regularized within 2 years of menarche. Bleed length and heaviness of bleeding were not appreciably associated with fecundability. Menstrual cycle characteristics, specifically cycle length and age at menarche, may act as markers of fertility potential among pregnancy planners.
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.
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.
Hapangama DK et al., 2016·Women's health (London, England)·
Open Access
Heavy menstrual bleeding (HMB) is a common gynecological complaint with multiple etiologies and diverse pathophysiological origins. This review discusses HMB with reference to the recently proposed PALM-COEIN classification system for abnormal uterine bleeding, initially describing the endometrial events in normal menstruation followed by discussion of the perturbations of normal endometrial shedding that can result in HMB. Our present understanding of the mechanisms of menstrual bleeding as well as many of the pathological aberrations of HMB is incomplete. Further research into the pathophysiology of HMB is urgently needed, as clear knowledge of the mechanisms of this disorder will provide new therapeutic targets to formulate more effective treatments.
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.
Bonnesen B et al., 2015·Acta Obstet Gynecol Scand·
Very few studies describe the obstetric and neonatal outcome of spontaneous pregnancies in women with irregular menstrual cycles. However, menstrual cycle irregularities are common and may be associated with increased risk, and women who develop pregnancy complications more frequently recollect irregular menstrual cycles before the time of conception in case-control studies. MATERIAL AND This retrospective cohort study compares obstetric and neonatal outcomes in spontaneous singleton pregnancies in 3440 primiparous Danish women stratified according to menstrual cycle regularity. All pregnancies delivered after 22 weeks of gestation and had a nuchal translucency examination at Copenhagen University Hospital Hvidovre between 1 January 2009 and 31 December 2010. Menstrual cycle irregularity was defined as more than 7 days' deviation between self-reported and ultrasound examination-based gestational age. Outcome measures were gestational diabetes, hypertension, preeclampsia, preterm premature rupture of membranes, preterm birth, prolonged pregnancy, birthweight, umbilical artery pH <7.1, APGAR <7 after 5 min, admission to neonatal intensive care unit and stillbirth. Women with more than 7 days' deviation between self-reported and ultrasound examination-based gestational age were compared with women with a deviation of 7 days or less. Irregular menstrual cycle before conception increases the risk of preeclampsia (7.9% vs. 5.2%, p < 0.05) and low birthweight (6.0% vs. 3.6%, p < 0.05) in spontaneous pregnancies, but reduces the risk of prolonged pregnancy (1.4% vs. 4.7%, p < 0.001). Irregular menstrual cycle before conception is associated with increased risk of adverse obstetric and neonatal outcome.
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.
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.
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.
Over 100 million women currently use oral contraceptive pills (OCPs) worldwide. However, little is known about the effects of OCPs on arterial stiffness and hemodynamics. Furthermore, whether arterial stiffness and hemodynamics vary throughout the natural menstrual cycle remains controversial. Herein, we estimated the effect of the natural menstrual cycle and OCP use on arterial stiffness and hemodynamics. Healthy, nonsmoking women, aged 18-30 years, were recruited if they had regular menstrual cycles and never used OCPs (OCP nonuser group), or were using low-dose OCPs for at least 6 months (OCP user group). Using applanation tonometry, three assessments of arterial stiffness and central and peripheral hemodynamics were performed in a randomized order: during the early follicular (days 3-6), late follicular (days 14-16), and luteal (days 22-26) phases. Within group and between group comparisons were performed using general linear models. Sixty women (21.7 ± 2.8 years) were recruited. Compared with OCP nonusers, OCP users had significantly increased aortic and peripheral SBPs during the active OCP use, but not during the inert tablet phase. No differences in arterial stiffness were noted. OCP use was associated with significant increases in aortic and peripheral blood pressures, but not with increased arterial stiffness. Given the widespread OCP use, future longitudinal studies are needed to confirm our findings and assess the long-term effect of OCPs on arterial stiffness and hemodynamics.
The purpose of this study was to test whether men perceive changes in their female partner's attractiveness as a function of her fertility status. We further tested how both male and female self-perception varies in relation to female fertility status. This study benefits from the use of transvaginal ultrasonography to detect fertility during the regular cycle and the use of a within-subjects design in which romantic couples were followed both across the cycle and during hormonal contraceptive use. We find that men rated their female partner as more attractive near to ovulation (when fertile) as compared to during the luteal cycle phase or during hormonal contraceptive use. Moreover, our results point to a presently unrecognized negative consequence of hormonal contraceptive use on male self-perception, with men rating themselves lower in attractiveness when their partner was using hormonal contraceptives than when she was regularly cycling. In contrast, there was no difference across measures in female self-reported attractiveness. Results are discussed in terms of their potential impact on within-couple social dynamics.
Cycle Across the Lifespan · Cycle and General Health
Glueck CJ et al., 2013·Metabolism: clinical and experimental
We determined whether simple, clinical information on late and early menarche could help identify adult women with metabolic syndrome (MetS) and oligomenorrhea. We carried out a 26-year prospective follow-up of 272 suburban schoolgirls from ages 5-22 to 30-46. Early menarche (≤10 years, 5.2% of girls) and late menarche (≥16 years, 6.7% of girls) were both associated with oligomenorrhea (≥42 days) in adulthood, 29% and 11%, vs. 5% for normal menarche (11-15 years), p=.004. Early menarche was characterized by high childhood BMI (LS mean±SE: 21.2 ±1.0 kg/m2) and by high childhood and adult MetS (15%, 36%). Girls with late menarche had the lowest childhood BMI (18.1±1.0), no childhood MetS, and the highest adult MetS (47%). Increasing age at menarche was associated with uniformly decreasing childhood BMI and MetS, but with a U-shaped pattern of BMI (p = .05), MetS (p=.008), and oligomenorrhea (p=.02) in adulthood. Change to MetS from median ages 13 to 38 was associated with early-late menarche (OR=3.11, 95% CI 1.37-7.07, p=.007). MetS in adulthood was associated with childhood MetS (OR=8.03, 95% CI 2.57-25.08, p=.0003) and with early-late menarche (OR =3.43, 95% CI 1.44-8.15, p=.005). Menarche age had a curvilinear ('U' shaped) relationship with MetS and oligomenorrhea in adulthood. Late menarche and early menarche are risk factors for adult oligomenorrhea, MetS, and cardiometabolic abnormalities. Girls with early (≤ age 10) and with late menarche (≥ 16) represent a group at high risk for adult cardiometabolic abnormalities and oligomenorrhea that is easily identifiable by physicians.
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.
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.
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.
Fertility awareness constitutes fundamental knowledge for every woman and is an important tool for health professionals. The objective of this review is to show how fertility awareness can be useful in the assessment of a woman's health. The main techniques for detecting ovulation are explained, and then the events that characterize a normal menstrual cycle are discussed. The relevance of cervical mucus from the perspective of female fertility is highlighted. Finally, the usefulness of fertility awareness 1) to identify fertile and infertile periods, 2) to help to detect several pathologies, and 3) in regards to how it exerts an important role in the success of programs in education for affectivity and sexuality are discussed.
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.
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.
White CP et al., 2011·Obstet Gynecol Int·
Open Access
We report menstrual and mid-cycle patterns of self-reported "fluid retention" in 765 menstrual cycles in 62 healthy women. Self-reported "fluid retention," commonly described as bloating, is one element of the clinical assessment and diagnosis of premenstrual symptoms. These daily diary data were collected as part of an observational prospective one-year study of bone changes in healthy women of differing exercise characteristics. Ovulation was documented by quantitative basal temperature analysis, and serum estradiol and progesterone levels were available from initial and final cycles. Fluid retention scores (on a 0-4 scale) peaked on the first day of menstrual flow (mean ± 0.9 ± 0.1), were lowest during the mid-follicular period, and gradually increased from 0.22 ± 0.05 to 0.50 ± 0.09 over the 11 days surrounding ovulation. Mid-cycle, but not premenstrual, fluid scores tended to be lower in anovulatory cycles (ANOVA P = 0.065), and scores were higher around menstruation than at midcycle (P < 0.0001). Neither estradiol nor progesterone levels were significantly associated with fluid retention scores. The peak day of average fluid retention was the first day of flow. There were no significant differences in women's self-perceived fluid retention between ovulatory and anovulatory cycles.
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.
Schweiger BM et al., 2011·Reproductive biology and endocrinology : RB&E
Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.
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.
Fathizadeh N et al., 2010·Iranian journal of nursing and midwifery research
Since premenstrual syndrome (PMS) can cause suicide, dissociation of familial relationships, abnormalities in the daily work and inter-personal relationships in the patients, and bring about direct and indirect economic burden for the society, it is important to resolve the problems of the patients. The objective of the current study is to determine the effect of magnesium (Mg), combination of vitamin B6 and Mg, and the placebo on the severity of PMS in the patients affected by the disease referred to the health centers of Isfahan University of Medical Sciences during 2009-2010. The participants were randomly assigned to two intervention groups and one control group. The study was carried out for four months in ten selected health centers in Isfahan. To confirm the PMS diagnosis in patients, they were asked to fill out the PMS daily symptom record form for two months and then, when the diagnosis was confirmed, the participants were randomly assigned to one of the three groups of the study (Mg, Mg plus vitamin B6, and placebo). Medical intervention was carried out in two menstrual cycles and the results of pre- and post-test were compared. After the intervention, the mean score of PMS significantly decreased in all the three groups (p < 0.05). The decrease was the greatest in the Mg plus vitamin B6 group, and was the least in the placebo group. The findings indicated that Mg plus vitamin B6 and placebo has the greatest and the least effect on the mean score of PMS, respectively.
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.
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.
Hickey M et al., 2009·Womens Health (Lond)·
Open Access
Abnormal uterine bleeding imposes major medical, social and financial problems for women, their families and the health services. Abnormal uterine bleeding refers to the regularity, frequency, duration and volume of bleeding. Irregular menstrual bleeding is most common at the extremes of reproductive life, in the initial 12-18 months after menarche and 5-6 years before the menopause begins. In Australia, the estimated cost of investigating and managing heavy menstrual bleeding alone is approximately AUS $6 million per annum. This article addresses the common causes of irregular bleeding in preand peri-menopausal women and presents an investigational approach.
Bryant GA et al., 2009·Biology letters·
Open Access
Recent research has documented a variety of ovulatory cues in humans, and in many nonhuman species, the vocal channel provides cues of reproductive state. We collected two sets of vocal samples from 69 normally ovulating women: one set during the follicular (high-fertility) phase of the cycle and one set during the luteal (low-fertility) phase, with ovulation confirmed by luteinizing hormone tests. In these samples we measured fundamental frequency (pitch), formant dispersion, jitter, shimmer, harmonics-to-noise ratio and speech rate. When speaking a simple introductory sentence, women's pitch increased during high- as compared with low-fertility, and this difference was the greatest for women whose voices were recorded on the two highest fertility days within the fertile window (the 2 days just before ovulation). This pattern did not occur when the same women produced vowels. The high- versus low-fertility difference in pitch was associated with the approach of ovulation and not menstrual onset, thus representing, to our knowledge, the first research to show a specific cyclic fertility cue in the human voice. We interpret this finding as evidence of a fertility-related enhancement of femininity consistent with other research documenting attractiveness-related changes associated with ovulation.
Menstruation is widely viewed as serving no purpose other than to reinitiate the endometrial cycle in the absence of pregnancy. Yet, it is striking that cyclic endometrial decidualization followed by menstrual shedding is confined to the few species, including human beings, where placenta formation entails deep trophoblast invasion of maternal tissues and its vasculature. Both menstruation and pregnancy are inflammatory conditions that cause a degree of physiological ischemia-reperfusion tissue injury, albeit much more so in pregnancy. Thus, the emergence of cyclic menstruation may not have been an evolutionary coincidence but serves to protect uterine tissues from the profound hyperinflammation and oxidative stress associated with deep placentation, a process known as preconditioning. The concept of menstrual preconditioning provides a novel paradigm for understanding how reproductive disorders impact on pregnancy outcome. For example, endometriosis could be viewed as a disorder of exaggerated menstrual preconditioning that confers protection against placentation-related disorders, such as preeclampsia.
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.
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.
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.
Cycle Across the Lifespan · Cycle and General Health
Young patients and their parents often are unsure about what represents normal menstrual patterns, and clinicians also may be unsure about normal ranges for menstrual cycle length and amount and duration of flow through adolescence. It is important to be able to educate young patients and their parents regarding what to expect of a first period and about the range for normal cycle length of subsequent menses. It is equally important for clinicians to have an understanding of bleeding patterns in girls and adolescents, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate young patients' conditions appropriately. Using the menstrual cycle as an additional vital sign adds a powerful tool to the assessment of normal development and the exclusion of pathological conditions.
Conception, as defined by the fertilisation of an ovum by a sperm, marks the beginning of human development. Currently, a biomarker of conception is not available; as conception occurs shortly after ovulation, the latter can be used as a proxy for the time of conception. In the absence of serial ultrasound examinations, ovulation cannot be readily visualised leaving researchers to rely on proxy measures of ovulation that are subject to error. The most commonly used proxy measures include: charting basal body temperature, monitoring cervical mucus, and measuring urinary metabolites of oestradiol and luteinising hormone. Establishing the timing of the ovulation and the fertile window has practical utility in that it will assist couples in appropriately timing intercourse to achieve or avoid pregnancy. Identifying the likely day of conception is clinically relevant because it has the potential to facilitate more accurate pregnancy dating, thereby reducing the iatrogenic risks associated with uncertain gestation. Using data from prospective studies of couples attempting to conceive, several researchers have developed models for estimating the day-specific probabilities of conception. Elucidating these will allow researchers to more accurately estimate the day of conception, thus spawning research initiatives that will expand our current limited knowledge about the effect of exposures at critical periconceptional windows. While basal body temperature charting and cervical mucus monitoring have been used with success in field-based studies for many years, recent advances in science and technology have made it possible for women to get instant feedback regarding their daily fertility status by monitoring urinary metabolites of reproductive hormones in the privacy of their own homes. Not only are innovations such as luteinising hormone test kits and digital fertility monitors likely to increase study compliance and participation rates, they provide valuable prospective data that can be used in epidemiological research. Although we have made great strides in estimating the timing and length of the fertile window, more work is needed to elucidate the day-specific probabilities of conception using proxy measures of ovulation that are inherently subject to error. Modelling approaches that incorporate the use of multiple markers of ovulation offer great promise to fill these important data gaps.
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.
Two main types of cervical mucus have been described during the menstrual cycle: oestrogenic and progestative. Each category shows diverse morphological and functional features from the reproductive point of view. Traditionally, this change has been approached by analysing morphological patterns. In fact, a mesh model has been described for cervical mucus, structurally composed of fibrillar subunits with a parallel orientation, together with another model in a characteristic network shape with canalicular units, but the real model is not clear. The objective of our work was to study the different morphological structures of the mucus, as related to the day of follicular rupture (considered as day 0) determined by ultrasound. Cervical mucus samples were obtained from the cervical canal with an ASPIRETTEtrade mark from day -4 to day +1 of the menstrual cycle. Samples were fixed and dried by critical point. The ultrastructure was examined with scanning electron microscopy. The presence of three types of oestrogenic and one type of progestative cervical mucus was confirmed in this period. Our paper shows different types of ultrastructure in the oestrogenic mucus in relation to ovulation, which would help to understand the interaction between male gametes and cervical mucus in migration through the female genital tract.
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.
Cycle Across the Lifespan · Cycle and General Health
Labad J et al., 2005·The Journal of clinical psychiatry
The aim of our study was to assess whether there is a relationship between reproductive cycle events and the initiation or changes in symptoms of obsessive-compulsive disorder (OCD). Forty-six female outpatients meeting DSM-IV criteria for OCD completed a semistructured interview at our OCD unit to assess the relationship between reproductive cycle events and OCD. Dates of data collection were from January 2001 to December 2003. In our sample, OCD onset occurred in the same year as menarche in 22% (N = 10), at pregnancy in 2% (N = 1), at postpartum in 7% (N = 3), and at menopause in 2% (N = 1). Worsening of preexisting OCD was reported by 20% of patients (9/45) at premenstruum, 8% (1/12) at pregnancy, 50% (6/12) at postpartum, and 8% (1/12) at menopause. The number of premenstrual mood symptoms, which included anxiety, irritability, mood lability and depressed mood, was associated with both premenstrual worsening of OCD (OR = 5.1, p < .01) and onset or worsening of OCD at postpartum (OR = 2.7, p < .05). Patients with an onset or worsening of OCD at postpartum also more frequently reported pre-menstrual worsening of OCD and previous history of major depressive disorder, including postpartum depression (p < or =.05 for all). In a substantial number of patients, the onset or worsening of OCD was related to reproductive cycle events, especially at menarche and postpartum. Certain women with OCD seem to be vulnerable to worsening of OCD at different reproductive periods that imply hormonal fluctuations, and premenstruum and post-partum were the 2 reproductive events with a greater vulnerability. Those patients whose OCD symptoms appeared to be related to reproductive events also exhibited a greater history of mood symptoms (premenstrual depression and major depressive episodes).
Shankar M et al., 2004·BJOG : an international journal of obstetrics and gynaecology
To determine the prevalence of von Willebrand disease in women presenting with menorrhagia. Systematic review of studies evaluating the prevalence of von Willebrand disease in women with menorrhagia. Hospital outpatient clinics (mainly gynaecological) and population surveys. Women presenting with menorrhagia. Relevant studies were extracted from MEDLINE search, bibliographies of identified articles and published proceedings of meetings and conferences. Number of women with von Willebrand disease. Eleven studies were included, totalling 988 women with menorrhagia. One hundred and thirty-one women were diagnosed to have von Willebrand disease with prevalences in individual studies ranging from 5% to 24%. The overall prevalence was 13% (95% CI 11-15.6%). The prevalence was higher in the European studies-18% (95% CI 15-23%) compared with that in North American studies-10% (95% CI 7.5-13%). This difference (P= 0.007) is likely to be the result of differences in the studies, which include method of recruitment of study population, method of assessing menstrual blood loss ethnic composition of study population, criteria for diagnosis and use of race- and ABO blood group-specific values for von Willebrand factor. The prevalence of von Willebrand disease is increased in women with menorrhagia and is the underlying cause in a small but significant group of women with menorrhagia across the world. Testing for this disorder should be considered when investigating women with menorrhagia, especially those of Caucasian origin, those with no obvious pelvic pathology or with additional bleeding symptoms.
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.
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, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
CrMS charting features -- Peak day definition, pre-Peak mucus quality and duration, post-Peak phase length, and premenstrual spotting -- are systematically compared against sonographic and endocrine findings to demonstrate that prospective cycle observations reliably identify specific ovulation disorder categories. This clinical validation shows that the CrMS chart functions as a non-invasive biomarker map capable of directing targeted ultrasound and hormonal investigation, and that treatment guided by the classification improves ovulatory and fertility outcomes.
Menárguez M et al., 2003·Human reproduction (Oxford, England)
This study was conducted on human cervical mucus using light microscopy (LM) and scanning electron microscopy (SEM). The objective was the morphological characterization of the different mucus types, with samples taken from the lumen of the cervix and from the different secretory zones of the cervical mucosa. A total of 230 samples from 195 women were spread out on slides and air dried. The phenomenon of 'ferning' was observed and assessed in these samples using both LM and SEM. Further samples from the lumen of the cervix and the different secretory crypts were spread out on cover slips and fixed with glutaraldehyde (2.5%) to be studied by SEM. The results show the presence of four different morphological mucus types, namely L, S, P and G, in both types of sample using dried and fixed techniques. Mucus from the lumen of the cervix appears to be a morphologically heterogeneous entity. It contains different types of secretions, the proportions of which vary throughout the menstrual cycle. The different mucosal types show different types of crystallization, different patterns of ultrastructure (probably related to the arrangement of the glycoprotein network) and are produced in different secretory zones of the crypts in the cervix.
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 describe severity of emotional and physical symptoms in a large diverse sample; to examine demographic, health status, and behavioral correlates of symptom severity; and to describe use of medications and alternative remedies for premenstrual symptoms. A total of 1194 women, ages 21-45, selected from members of a large northern California health maintenance organization, completed daily ratings of symptom severity for two menstrual cycles. An empirically derived algorithm defined symptom severity groups as minimal (n = 186), moderate (n = 801), severe (n = 151), or premenstrual dysphoric disorder (n = 56). Symptom severity as a continuous variable was defined by the two-cycle mean symptom ratings in the luteal phase. Demographic, health status, and behavioral factors and use of treatments for premenstrual symptoms were assessed by self-report. Luteal phase symptom-specific ratings were generally significantly greater in the premenstrual dysphoric disorder group than in the other groups (P <.001). Symptom severity score increased with each comorbidity and decreased with each year of age. Symptom severity was also inversely associated with oral contraceptive use (emotional symptoms) and better perceived health (physical symptoms). Hispanics reported greater severity of symptoms, and Asians less, relative to whites. Use of herbal and nutritional supplements for premenstrual symptoms steadily increased from 10.8% in the minimal group to 30.4% in the premenstrual dysphoric disorder group (P <.01). The degree of premenstrual symptom severity varies in the population, is relatively constant within each woman over two consecutive cycles, particularly for emotional symptoms, and is influenced by age, race/ethnicity, and health status.
Investigators examined whether premenstrual dysphoric disorder (PMDD) poses a risk for major depressive disorder (MDD). In an initial study, women rated premenstrual symptoms and functional impairment daily for two menstrual cycles. A semistructured diagnostic interview was given to obtain psychiatric histories and differentiate PMDD from premenstrual exacerbations of other disorders. Participants in this pilot study were eight women with PMDD and a random subgroup without PMDD (n = 9) initially. Another semistructured interview was given to diagnose psychiatric disorders occurring during a two-year follow-up interval. In all, seven of the eight women with PMDD developed MDD within two years, including all those who had never had MDD before. The odds that a woman with PMDD developed MDD were 14 times the odds that a woman without PMDD developed MDD ( p <.05). Premenstrual dysphoric disorder may be a prodrome of or causal risk factor for MDD. Preliminary evidence for the diagnostic validity of PMDD is provided.
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 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.
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.
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 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.
Sveinsdóttir H et al., 2000·Acta Obstet Gynecol Scand·
The prevalence of significant symptom change (symptom cyclicity) prospectively rated over multiple menstrual cycles has not been established in a non-clinical population. Seventy-three women charted 57 symptoms over 2-6 menstrual cycles each. Symptoms, and summarized symptom scores within seven symptom groups, were tested for changes between the follicular phase and the luteal phase of each cycle. Recurrent symptom cyclicity over multiple cycles within individuals was ascertained and the stability between cycles of mean symptom scores for both the follicular phase and the luteal phase. Forty-five percent of the participants experienced cyclicity over multiple cycles in at least one symptom and 23% in at least one symptom group. Eighteen percent of the participants consistently reported a higher symptom score during the luteal phase compared to the follicular phase (a PMS-like pattern) in all symptoms in which they experienced a change. The remaining 27% experienced a varying direction of change in the same symptom between cycles, or consistently experienced a lower symptom score during the luteal phase (a reverse PMS-like pattern) of the cycles they charted. Recurrent cyclicity was experienced by 16% of the participants in one symptom; in two symptoms by 15%; in 3 8 symptoms by 14%; in one symptom group by 19% and in two symptom groups by only 4% of participants. Average symptom severity did not vary significantly between cycles. Due to the varied direction of symptom severity change over multiple cycles, prospective daily ratings are necessary to achieve a true picture of menstrual related symptom cyclicity in the general population.
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.
Is Menstruation Obsolete? argues that regular monthly bleeding is not the “natural” state of women, and that it actually places them at risk of several medical conditions of varying severity. The authors maintain that while menstruation may be culturally significant, it is not medically meaningful. Moreover, they propose that suppressing menstruation has remarkable health advantages. Because of cultural changes, shorter durations of breast feeding, and birth control, the reproductive patterns of modern women no longer resemble that of their Stone age ancestors. Women have moved from the age of incessant reproduction to the age of incessant menstruation. Consequently, they often suffer from clinical disorders related to menstruation: anemia, endometriosis, and PMS, just to name a few. The authors encourage readers to recognize what has gone previously unnoticed that this monthly discomfort is simply not obligatory. They present compelling evidence that the suppression of menstruation is a viable option for women today, and that it can be easily attained through the use of birth control pills. In fact, they reveal that contraceptive manufacturers, knowing that many women equate menstruation with femininity and that without monthly bleeding would fear that they were pregnant, engineered pill dosage regimens to ensure the continuation of their cycles. Indeed, throughout history societies have assigned menstruation powerful meaning, and Is Menstruation Obsolete? presents a fascinating history of how menstruation inspired doctors to try therapeutic bleeding for a variety of ailments, and how this therapy remained dominant in Western medicine until the early 20th century. Is Menstruation Obsolete? offers women a fresh view of menstruation, providing them with the information they need to make progressive choices about their health. This is a message whose time has come.
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.
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 evaluate the expression of alpha6 and beta4 integrin subunits on surface and glandular endometrium throughout the menstrual cycle and during early pregnancy. Second Department of Obstetrics and Gynecology, University of Catania, Catania, Italy. PATIENT(S): Thirty-two women. Nineteen of the women regularly menstruated in different phases of the cycle, and 13 were in the sixth to ninth week of gestation and required voluntary abortion. INTERVENTION(S): Endometrial specimens collected during endometrial biopsy, hysterectomy, or voluntary abortion. MAIN OUTCOME MEASURE(S): Immunohistochemical staining for alpha6 and beta4 integrin subunits in endometrial tissues. RESULT(S): Both subunits (poorly expressed in preimplantation days) reached a significant peak on the endometrial surface during the implantation window, which tended to disappear in the postimplantation phase. On glandular endometrium they exhibited an opposite trend, showing high levels in the preimplantation and postimplantation days, whereas their expression decreased during the implantation window. The two subunits tended to disappear in early pregnancy. CONCLUSION(S): alpha6 and beta4 integrin subunits are uniformly distributed and highly expressed on the endometrial surface during the implantation window; they decreased dramatically in the postimplantation phase. These results could suggest involvement of integrin-extracellular matrix components in blastocyst-endometrium interaction during the early stages of implantation.
To investigate and compare the diagnoses and treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) from the perspectives of psychiatrists and obstetricians/gynecologists (OB/GYNs) in Japan. Between December 2021 and February 2022, a web-based survey was conducted among the members of the Japanese Association of Neuro-Psychiatric Clinics. Data from 262 psychiatrists who responded to the aforementioned survey were compared with data from 409 OB/GYNs from a survey conducted in 2021 among members of the Japanese Society of Obstetrics and Gynecology. Overall, 79.8% of psychiatrists and 97.3% of OB/GYNs were involved in practicing PMS/PMDD diagnosis and treatment. Most psychiatrists believed that PMS should be treated by OB/GYNs (74.4%) and PMDD by psychiatrists (75.6%). Only vague medical interviews were conducted by 86.6% of psychiatrists, and only 9.7% maintained a two-cycle symptom diary. Psychiatrists mostly prescribed selective serotonin/serotonin and noradrenaline reuptake inhibitor (SSRI/SNRI) continuous dosing (91.1%), followed by Kampo medicines, especially Kamishoyosan (73.3%); only 2.8% chose oral contraceptive pills, unlike OB/GYNs, while SSRI continuous (32.8%) and luteal phase dosing (20.6%) and Kampo medicine (42.1%) were the most common first-line treatments. Lifestyle guidance was prescribed by 63.6% of psychiatrists, followed by cognitive behavioral therapy (13.8%) and the symptom diary observation method (11.1%), which were similar to OB/GYNs' choices. Many Japanese psychiatrists and OB/GYNs do not base PMS/PMDD diagnoses on prospective monitoring methods using specific diagnostic criteria and therefore do not provide evidence-based treatment. Moreover, a tendency of being biased toward treatments in which the department specialized was observed.
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.
To assess menstrual blood loss and other menstrual characteristics prospectively in women with and without endometriosis. Three hundred fifteen premenopausal women undergoing laparoscopy for various reasons were asked to complete a pictorial blood loss assessment chart devised by Higham et al to evaluate menstrual flow on which the monthly score has been demonstrated to correlate directly with uterine blood loss measured by the alkaline hematin method. In addition, cycle length and flow duration were recorded. The women also were asked to grade dysmenorrhea severity using a 100-mm visual analogue and a 0-3-points verbal rating scale. One hundred sixty-three women had endometriosis, and 152 did not. The latter group comprised 59 women with a normal pelvis, 36 with nonendometriotic ovarian cysts, 29 with chronic pelvic inflammatory disease, and 28 with miscellaneous conditions. The median [interquartile range] pictorial blood loss assessment chart score was 110 [66.5-156.5] in women with endometriosis and 84 [56-129] in those without the disease (P = .007); 87 out of 163 (53%) women with endometriosis had a menstrual chart score equal to or greater than 100 compared with 56 out of 152 (37%) of those without (chi 2(1) = 8.02, P = .005; difference = 16%, 95% confidence interval, 6%, 28%). Menstrual flow duration was slightly longer in women with endometriosis (mean difference, 0.33 days). Dysmenorrhea visual analogue and verbal rating scores were significantly higher in the endometriosis than the nonendometriosis group. According to a visual chart, women with endometriosis had heavier menstrual flow and a significantly higher rate of abnormal menstrual scores that those without the disease.
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,
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.
The optimal timing of sexual intercourse in relation to the day of ovulation in order for pregnancy to result is a topic of broad interest. Of obvious relevance to fecundability, on the one hand, a...
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.
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.
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 assess the efficacy of alprazolam in the treatment of two groups of patients diagnosed with late luteal phase dysphoric disorder (LLPDD). The first group met only the diagnostic criteria for LLPDD. The second group experienced LLPDD and mild symptoms of anxiety and depression during the follicular phase. A double-blind, placebo-controlled crossover design was used. Patients were treated with alprazolam and placebo for 3 months each and completed daily measures of anxiety, tension, depression, irritability, and feelings of being out of control. The response to alprazolam differed significantly by group. For the first group, alprazolam (0.25 mg three times a day) relieved the severity of tension (P = .001), irritability (P = .005), anxiety (P = .008), and feelings of being out of control (P = .012) more than placebo. Few side effects were reported; the incidence (P = .001) and severity (P = .001) of side effects were dose-related. Alprazolam and placebo did not differ for the second group, and the incidence and severity of side effects were unrelated to dose. Alprazolam benefits women diagnosed solely with LLPDD. It is not recommended for patients who experience LLPDD as well as symptoms of mild anxiety or depression during the follicular phase.
We measured plasma Cu. Zn and Mg levels in 40 women suffering from premenstrual tension syndrome (PMTS) and in 20 control subjects by atomic absorption spectrophotometer. Mean plasma Cu, Zn and Mg levels, the Zn/Cu ratio were 80.2 +/- 6.00 micrograms/dl, 112.6 +/- 8.35 micrograms/dl, 0.70 +/- 0.18 mmol/l, and 1.40 +/- 0.10 in the PMTS group; and 77.0 +/- 4.50 micrograms/dl, 117.4 +/- 9.50 micrograms/dl, 0.87 +/- 0.10 mmol/l, and 1.51 +/- 0.05 in the control group respectively. The mean Mg level and the Zn/Cu ratio were significantly lower in PMTS patients than in the control group. Plasma Mg and Zn levels were diminished significantly during the luteal phase compared to the follicular phase in PMTS group. Mg deficiency may play a role in the etiology of PMTS.
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.
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.
Cervical mucus is produced throughout the menstrual cycle. Sperm migration, however, is possible only during the periovulatory period of the cycle. Cervical mucus is also produced during the amenorrhoeic post-partum period. Post-partum mucus is very similar to luteal phase mucus except that it can allow sperm migration. In this study, mucus samples obtained from all these periods were classified according to their capacity to allow sperm migration. The biochemical characteristics of mucus samples that did (peri-ovulatory and 40% of post-partum samples) and did not (luteal and 60% of post-partum samples) allow sperm migration were then compared. Mucus samples with positive sperm migration showed the highest percentage of water and lowest protein and glycoprotein concentration (per ml of mucus). In addition, post-partum mucus samples with positive sperm migration showed lower concentrations of proteins and glycoproteins than post-partum mucus samples that did not allow sperm migration. However, the amount of glycoproteins per mg of protein was similar between post-partum samples that were positive and negative for sperm migration. These data suggest that the carbohydrate composition of the glycoproteins is playing a key role in the ability of cervical mucus to accept spermatozoa.
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.
Cycle Across the Lifespan · Cycle and General Health
Munster K et al., 1992·British Journal of Obstetrics and Gynaecology
To investigate the current epidemiology of menstrual patterns among women of fertile age. Cross-sectional postal questionnaire study. County of Copenhagen, Denmark. 3743 women, aged 15-44, selected at random from a Danish county, who were asked to provide information on menstrual pattern during the preceding year, 1981. The response rate was 78%. Information from non-responders was obtained via telephone interviews. In women with regular menstrual cycles, the 5th-95th centile range of usual cycle length decreased from 23-35 days in the 15-19 years age group to 23-30 days in the 40-44 years age group. Only 0.5% of regular menstruating women had a usual cycle length of less than 21 days and 0.9% had a usual cycle length of greater than 35 days. At least one cycle length of less than 21 days was experienced by 18.6%, whereas 29.5% had at least one cycle of greater than 35 days. Menstrual cycle variation of greater than 14 days was present in 29.3% of all women. Cycle length variation of greater than 14 days was 2.7 times more frequent in women from lower social groups (controlled by age). The study confirmed the normally used definitions of polymenorrhoea (cycle length less than 21 days) and oligomenorrhoea (cycle length between 36 and 90 days), as these very short or long menstrual cycle lengths were very seldom recorded for a longer period. However, the high frequency in a normal population of large menstrual cycle length variation challenges the view that an intra-individual variation of greater than 5 days should be regarded as a sign of disease in the woman.
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.
Three-hour oral glucose tolerance tests were performed on days 5 and 25 of ovulatory menstrual cycles in 26 women. The women were divided into normal (n = 9) and premenstrual syndrome (PMS) (n = 17) categories. Ovulation was confirmed by basal body temperature records and plasma progesterone levels. There were no statistically significant changes in the plasma glucose or insulin levels between the two tests in either group. Except for a higher two-hour plasma insulin concentration on the day 5 test in normal women, no statistically significant carbohydrate differences were noted between the groups. The data suggest that alterations in carbohydrate metabolism are not important in PMS.
Laser ablation of the endometrium was performed on 18 patients for menorrhagia. The patients were evaluated for the premenstrual syndrome (PMS) preoperatively and again at three and six months postoperatively. An improvement in both the severity and duration of PMS symptoms was noted postoperatively, and the reduction in menstrual bleeding was correlated with the reduction in PMS symptoms.
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.
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.
Whole-blood serotonin levels in 14 subjects with well documented premenstrual syndrome and 13 age-matched controls were compared. Serotonin levels of premenstrual syndrome subjects were significantly lower during the last ten days of the menstrual cycle. No significant differences were noted in levels of serum estradiol and progesterone. Decreased serotonin is known to be associated with depression in humans, and nonhuman primates have exhibited abnormal behavioral profiles when given serotonin antagonists. The present observation suggests that the physiologic basis of premenstrual syndrome involves an alteration in serotonin metabolism.
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.
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.
World Health Organization Task Force on Adolescent Reproductive Health, 1986·Journal of Adolescent Health Care
During a two-year study, 670 girls (aged 11-15 years) submitted menstrual diaries that started at the onset of their first menstrual bleeding (Group I), and 802 girls (aged 11-15 years) who had already experienced menarche prior to the study (Group II) kept similar diaries. The two groups were recruited in three centers: Colombo (urban), Peradeniya (rural), both in Sri Lanka, and Hong Kong. The mean duration of bleeding episodes was 4.7 days (SD 1.8) in Group I and 4.9 days (SD 1.4) in Group II. The median length of the first cycle after menarche was 34 days, with 38.3% of the cycles being longer than 40 days. By the 5th cycle the median length was 31 days, similar to that of Group II. The establishment of cycle regularity was defined by three successive cycles within the range of 10 days with none of the three cycles shorter than 20 or longer than 40 days. This regularity was achieved by 19% of the Group I girls in the first three cycles and by 67% of these girls during the entire study period, compared to 89% in Group II.
In recent years increasing interest has focused on the symptoms that accompany normal ovulation. 'Identifying the accuracy ofthese symptoms as indicators of ovulation is of practical importance both to the subfertile couple trying to maximise the chance of conception and to the couple using" natural fiaily planiing" to prevent conception. Until recently it has not been possible to assess the accuracy of the symptoms because of difficulties in assessing the exact time of ovulation. Ovarian ultrasonography has now been shown to allow accurate …
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.
Plasma and erythrocyte magnesium were measured in 105 patients with premenstrual syndrome (PMS) using a simple atomic absorption spectroscopy method. The erythrocyte magnesium concentration for the patients with PMS was significantly lower than that of a normal population. The plasma magnesium did not show this difference. The significance of this apparent cellular deficiency of magnesium is discussed.
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.
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.
Blood was found in the peritoneal fluid in 90% of women with patent tubes at laparoscopy during perimenstrual time. If the fallopian tubes were occluded, then only 15% of patients had evidence of blood in the pelvis. Also, 90% of patients with endometriosis and eight of nine women on oral contraceptives had bloody fluid during the menstrual period. The present observations indicate that retrograde menstruation through the fallopian tubes into the peritoneal cavity is a very common physiologic event in all menstruating women with patent tubes.
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%.
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.
One hundred thirty-seven premenopausal women with premenstrual tension underwent laparoscopy for bleeding, pain and/or infertility. Endometriosis was the associated gynecologic disease observed most frequently (66 patients). Other associated disorders were primary dysmenorrhea (31), poststerilization syndrome (24), chronic pelvic inflammatory disease (8) and leiomyoma uteri (8). Screening for prolactin and thyroid-stimulating hormone in patients with galactorrhea (74) revealed one patient with pituitary microadenoma and two with primary hypothyroidism. The midluteal progesterone levels were significantly decreased, whereas the midluteal estradiol 17 beta levels were significantly elevated. Because of the frequent association of premenstrual tension with other gynecologic diseases, screening for premenstrual tension in all premenopausal women is recommended.
In a double-blind, randomized dose-response study, 75 women with benign breast disease were administered a written questionnaire in which they scored the severity of premenstrual syndrome (PMS) symptoms before and after two months of treatment with placebo or alpha-tocopherol (150, 300, or 600 IU/day). Controlling for age and pretreatment scores, alpha-tocopherol had a significantly greater effect than placebo, improving three of the four classes of PMS symptoms. These findings suggest that vitamin E supplementation may be of value in women with severe PMS symptoms.
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.
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.
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.
In this report, the ultrastructure of eM was studied by cryo-scanning electron microscopy (cryo-scan), which enabled us to observe the sample while it still contained water. … It was then placed in a specially made chamber which was part of the cryo-scanning electron microscope model JSM-50A (JEOL, Tokyo). The eM was examined after etching and coating with gold. A human cervical mucus specimen as observed by cryo-scan. The 3-dimensional netlike structure was characteristic (original magnification x 10,000).
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.
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)
Evrard JR et al., 1976·American Journal of Obstetrics and Gynecology
A prospective study was done on 326 nulliparous women who ceased oral contraception. Follow-up was obtained on 311. The mean age was 20.3 years (SD 2.5). Eighty-nine per cent began menstruating within 60 days after stopping therapy, and only 7 took 180 days or longer to menstruate. Late menarche strongly correlated with post-pill amenorrhea (PPA), but continuous length of time on oral contraceptives and type of oral contraceptive showed no significant relationship. The incidence of PPA was 2.2 per cent. All women did eventually menstruate spontaneously, the longest period of amenorrhea being 540 days. The less the number of years between menarche and the beginning of oral contraceptives, the longer it took these patients to menstruate.
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.
Accurate timing of ovulation is especially necessary (1) in artificial insemination in order to avoid wastage of donor semen; (2) in cases where the husband is relatively infertile and it is necessary to conserve his semen. While many physicians rely upon the basal body temperature curve for timing ovulation, the interpretation of such curves is varied. Some physicians believe ovulation occurs prior to the lowest point in the temperature cycle, while others believe that ovulation occurs either at the low point or following the thermal shift. We have been disappointed in our ability to interpret the basal body temperature curve for accurate timing of ovulation, and have placed greater reliance upon concurrent phenomena, such as changes in the quantity and viscosity of cervical mucus and the cyclic changes observed in the vaginal smear. Although the relationship between the occurrence of a profuse, thin cervical mucus discharge and the optimal time of fertility in the human has been recognized for the past century, in our opinion this relationship requires further evaluation.
In his excellent review, "Cervical mucus: Cyclic variations and their clinical significance," Shettles quotes Robin who, in 1848, noted the viscous nature of human cervical secretions; and Smith who, in 1865, concluded that conception is most likely when the mucus contents of the cervix are in the most fluid condition. J. Marion Sims, who invented a vaginal speculum and first described the postcoital examination in 1868, observed that the test is positive for motile spermatozoa when the cervical mucus becomes clear and translucent, and about the consistency of the white of egg. Although these observations on human cervical mucus have been well documented, they have been almost disregarded by gynecologists. The significance of the cyclical outpouring of cervical mucus has been rediscovered in the past few years and has aroused great interest in students of sterility.
The optimal time of fertility in domestic animals is the period of heat or estrus. In 1925, Woodman and Hammond showed that during estrus, bovine cervical mucus is fluid and capable of being drawn out into threads, whereas in diestrus the mucus is thick. Seguy and Vimeux, and Seguy and Simonnet called attention to the optimal conditions of longevity of human spermatozoa in the fluid, glairy mucus of the cervix at midcycle. They postulated that these changes in cervical mucus were associated with ovulation and could be compared to the period of estrus in subprimate mammals. They correlated these changes with visual evidence of ovulation at laparotomy. Subject: ively, many women observe an increased sticky, mucoid discharge which is typical at midcycle and which is present over a period of days. On occasion this discharge is blood-tinged and may be compared to the distinct bloody mucoid discharge present in the domestic animal "in heat."
This mucus can be seen exuding from the cervix at midcycle and it may be aspirated from the endocervix and actually weighed, as reported by Viergiver and Pommerenke. Clift demonstrated certain rheologic properties of cervical mucus, especially flow elasticity and Spinnbarkeit. Flow elasticity, or elastic recoil of mucus, is measured by an instrument described by Blair. The use of the Blair capillary viscometer is a cumbersome method which we discontinued. We have had no experience with the new modification of the viscometer described by Clift, Glover, and Blair. Spinnbarkeit is easily tested, and we have found it to be a very practical objective method for determining viscosity of cervical mucus. In performing this test (Fig. 1), a vaginal speculum is inserted, exposing the cervix. A glass cannula is inserted into the endocervix and by means of gentle suction, a quantity of endocervical mucus is obtained. This mucus is blown onto a glass slide and a cover slip is placed on it. The mucus adheres to both the slide and the cover slip, and by withdrawing the cover slip, a thread of mucus is formed which can be measured in centimeters (Fig. 2). Usually, the cover slip is withdrawn several times, and the average length of the thread is ascertained. It is our purpose to show the relationship of Spinnbarkeit to other cyclic phenomena occurring during the menstrual cycle, such as basal body temperatures, vaginal smears, quantity of cervical mucus, and longevity of spermatozoa (Fig. 3).
Cervical mucus at midcycle is increased in amount, acellularity, water content, and fluidity. Furthermore, cervical mucus at this time is well supplied with carbohydrate and presumably amino acids. From a teleologic standpoint, we may conclude that because of these characteristics the sperm, on deposition in the vagina, find an environment propitious for their nutrition and migration through the cervical canal.
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.
Stein IF et al., 1935·American Journal of Obstetrics and Gynecology·
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Metabolic and Endocrine Agents · GLP-1 Receptor Agonists
Carmina E et al., 2026·Journal of clinical medicine
Irregular menses and chronic anovulation are key components of Polyendocrine Metabolic Ovarian Syndrome (PMOS), but available treatments generally only mask the clinical problem, which presents itself again when the drugs are stopped. Because reduction of body weight in these patients is often associated with improvement of menstrual cycles, we evaluated the effects of treatment with semaglutide, a GLP-1 agonist that has emerged as an effective treatment for obesity. A total of 96 women with PMOS and body mass index (BMI) > 25 kg/m2 completed a six-month treatment protocol with semaglutide using an individualized dose-escalation regimen. Body weight, fasting glucose, insulin levels, insulin resistance (HOMA-IR), and ovulatory function were assessed before and after treatment. After six months of treatment, mean body weight decreased significantly (-11.3 ± 5%, p < 0.01). Before treatment, 83% of PMOS patients presented with oligomenorrhea and anovulatory cycles. Following treatment, ovulatory cycles were observed in 52.5% of previously anovulatory women. The results were particularly good in overweight patients, with almost 95% of these PMOS patients achieving menstrual cycle normalization and ovulation, but also in patients with mild obesity. Results were less favorable in PMOS patients with moderate or severe obesity, but 25% of these patients achieved menstrual ovulatory cycle normalization when treated with semaglutide. This study represents an important therapeutic advancement, suggesting that women with PMOS and excessive body weight should be considered for treatment with GLP-1 receptor agonists before proceeding to therapies specifically aimed at inducing normal cycles and ovulation.
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.
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.
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.
Several studies have evaluated the reliability of using temperature sensors placed in different locations on the body to identify the day of ovulation. However, such demonstrations are lacking for axillary temperature wearable devices. This study aimed to evaluate the accuracy with which an axillary temperature armband sensor (Tempdrop) identifies the day of ovulation and the fertile window, using the Clearblue Connected Ovulation Test System as the reference method. A total of 194 cycles were analyzed from 125 women that participated in the study between April 2023 and June 2024. The performance parameters were high: the sensitivity (96.8% (95% CI 95.6; 97.7)), specificity (99.1% (98.8; 99.4)), accuracy (98.6% (98.2; 98.9)), positive predictive value (96.8% (95.6; 97.7)) and negative predictive value (99.1% (98.8; 99.4)). Furthermore, the results revealed a remarkably clear and better-than-expected change in temperature around the time of ovulation. This axillary temperature wearable sensor is an effective alternative to urine ovulation tests for determining the timing of ovulation. Another advantage is that it provides a clear temperature curve that can be used to evaluate the quality of the luteal phase.
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.
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.
Nutrition and Metabolic Health · Body Weight and Composition
Brito J et al., 2025·Journal of applied physiology (Bethesda, Md. : 1985)·
Open Access
Understanding changes to gut microbiota composition in response to hormonal birth control (HBC) may provide insight into the microbial mechanisms underlying the metabolic effects of HBC, for example, altered short-chain fatty acid (SCFA) production. Athletes' unique physiological demands may interact with these microbial mechanisms in distinct ways; however, there is limited research on HBC and gut microbiota diversity and composition across different menstrual cycle phases in physically active females. A pilot cohort of physically active females using HBC (oral contraceptives, hormone-based intrauterine devices, or arm implants) and a control group not using HBC (n = 12 per group; 22 ± 2 yr, 24 ± 4 kg/m2 vs. 22 ± 4 yr, 23 ± 4 kg/m2; Ps ≥ 0.496) provided fecal samples alongside self-reported menstrual phase and circulating sex hormones. α-diversity (microbial richness and evenness) was assessed using the Shannon index whereas β-diversity (microbial composition differences) was analyzed using PERMANOVA based on Bray-Curtis dissimilarity. Circulating estrogen and luteinizing hormone increased from early (days 1-5) to mid-cycle (days 12-17) in both groups (time effect Ps ≤ 0.01), with greater changes in Control (Ps ≤ 0.046) than HBC (Ps ≥ 0.231). Although no menstrual phase effect was observed on either diversity measure (Ps ≥ 0.473), β-diversity differed between Control and HBC groups (P = 0.015), reflecting distinct gut microbiota profiles irrespective of menstrual phase. Seven taxa linked to SCFA production were less abundant in the HBC group (unadjusted Ps ≤ 0.046), though significance was lost after adjusting for multiple comparisons. These findings suggest that in physically active females, hormonal contraception influences gut microbial composition, which may have downstream effects on metabolism and performance.NEW & NOTEWORTHY This study is the first to investigate interactions between hormonal contraception and the gut microbiota in a cohort of physically active young females across the menstrual cycle. Our findings suggest that hormonal contraception may influence gut microbiota composition, potentially through a reduced relative abundance of short-chain fatty acid-producing taxa. Experimental studies are needed to confirm these associations and explore their potential implications for metabolism, health, and performance.
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.
Pedersen ES et al., 2024·Paediatr Perinat Epidemiol·
Open Access
The use of fertility indicators to predict ovulation has largely been studied for contraceptive purposes, while less so as fertility-promoting tools. To investigate the association between fertility indicators and fecundability in Danish women trying to conceive. Web-based preconception cohort study. We analysed data from 11,328 females aged 18-49 years trying to conceive without fertility treatment for ≤6 menstrual cycles, from the Danish SnartGravid.dk and SnartForældre.dk cohorts (2007-2023). Participants reported the use of fertility indicators (counting days since the last menstrual period, cervical fluid monitoring, urinary ovulation testing, feeling ovulation, using a smartphone fertility app and measuring basal body temperature [BBT]). Time to pregnancy was measured in menstrual cycles ascertained by self-reported pregnancy status. We estimated fecundability ratios (FR) and 95% confidence intervals (CI) using proportional probabilities regression models adjusted for age, socio-economic position, health indicators, reproductive history and gynaecological factors. Fertility indicators were used by 63.3% of participants at study entry. Counting days was the most common (46.9%), while measuring BBT was the least (3.0%). Other indicators ranged from 17.0% to 23.6%, with 69.7% using more than one indicator. Compared with non-use, use of any fertility indicator was associated with greater fecundability (adjusted FR 1.14, 95% CI 1.08, 1.19). Cervical fluid monitoring showed the strongest association (aFR 1.46, 95% CI 1.03, 2.07), followed by urinary ovulation testing (aFR 1.35, 95% CI 1.16, 1.58) and counting days (aFR 1.18, 95% CI 1.09, 1.29). Feeling ovulation and fertility apps were modestly associated with fecundability, while measuring BBT was not associated. Sensitivity analysis restricting to ≤2 cycles of attempt time and two cycles of follow-up showed an aFR for any indicator use of 1.21 (95% CI 1.13, 1.31). In this Danish preconception cohort, use of fertility indicators was associated with a higher fecundability, varying by type of indicator.
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.
Globally, polycystic ovarian syndrome (PCOS) affects approximately 10% of fertile women, leading to great health and economic burden. PCOS is a heterogenous illness that can cause infertility, irregular menstrual cycles, acne, and hirsutism, among other symptoms. The clinical diagnosis is primarily a diagnosis of exclusion if one or more of the three primary symptoms, namely, oligo- or anovulation, hyperandrogenism, and polycystic ovarian morphology, are present. Obesity and PCOS are often coexisting disorders that may be bidirectionally causally related. Phenotypic heterogeneity throughout the reproductive lifespan, such as the overlap of PCOS symptoms with regular fluctuations in a woman’s menstrual cycle and metabolism during the menarche and menopausal transition, further complicates diagnosis. PCOS etiology is mostly unknown and complex, likely due to the fact that it is a group of disorders with overlapping metabolic and reproductive problems. Evidence-based, common, standardized guidelines for PCOS diagnosis and treatment are urgently needed. Genomics and clinical data from populations across diverse ages and ethnicities are urgently needed to build efficient machine learning models for the stratification of PCOS. PCOS subtype-specific strategies for early screening, an accurate diagnosis, and management throughout life will optimize healthcare resources and reduce unnecessary testing. This will pave the way for women to be able to take the best possible care of their own health using the latest clinical expertise combined with their unique needs and preferences.
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.
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.
Sleep deprivation is known to be a risk factor for premenstrual syndrome and primary dysmenorrhea in adults. However, it has rarely been investigated in adolescents. The aim of this study was to investigate whether sleep pattern, duration, and quality independently affect premenstrual syndrome and primary dysmenorrhea in adolescent girls. An additional purpose was to investigate the sleep status in Korean adolescent girls during the COVID-19 pandemic. A cross-sectional survey study was conducted in 519 high school girls aged 15 to 18 years in Gyeonggido, South Korea, in 2021 during the COVID-19 lockdown. Menstrual pain intensity and menstrual symptoms were assessed using the visual analogue scale (VAS) and Cox menstrual symptom scale (CMSS), respectively. Premenstrual syndrome was assessed by the premenstrual symptoms screening tool (PSST). Sleep was assessed by the Pittsburgh Sleep Quality Index (PSQI). The known risk factors of dysmenorrhea, including menstrual and lifestyle characteristics and stress, were assessed as covariates. During the pandemic, approximately 68% of girls slept 7 h or less, while about 60% reported poor sleep quality. Additionally, 64% of participants had a bedtime later after 1AM, and 34% woke up later after 8AM. Late bedtime significantly affected VAS (P = 0.05), CMSS severity and frequency (both P < 0.01), and PSST symptom (P < 0.01). Waking up late affected CMSS severity (P < 0.05), PSST symptom (P = 0.05), and PSST function (P < 0.05). However, the significance of these effects disappeared after controlling for covariates. Sleeping less than 5 h affected CMSS frequency (P < 0.05) and PSST symptoms (P < 0.001). After controlling for covariates, the significance of the effect on PSST symptom remained (P < 0.05). General sleep quality and PSQI components, including subjective sleep quality, sleep latency, sleep disturbance, use of sleeping medication, and daytime dysfunction, significantly affected CMSS frequency and severity and PSST symptom after controlling for covariates (P < 0.05, P < 0.01, or P < 0.001). The multiple regression analysis revealed that among sleep characteristics, sleep quality was the most important risk factor of premenstrual syndrome and dysmenorrhea. Our study result heightens the importance of healthy sleep hygiene, especially sleep quality in the management of premenstrual syndrome and dysmenorrhea in adolescent girls.
Five to ten percent of women experience period pains that disrupt their lives yet 4 in 5 women believe that their claims for their dysmenorrhea are not taken seriously. Within the process of seeking support and understanding about their pain, they face various barriers that prevent them from finding the answers they deserve. Semi-structured interviews were conducted with 8 women aged 20-28 to discuss their experiences with dysmenorrhea throughout their time since menarche. Using Scheper-Hughes and Lock understanding of the mindful body, this research explores women's experiences of dysmenorrhea through their physical body (relationship with the body and needing control), the social body (cultural concepts and comparisons to others) and the body politic (medicalisation, the medical team and the transvaginal ultrasound). The impact of these aspects of their mindful bodies developed arguments showing how different actors had an impact on preventing them obtaining the patient-centred care they required without resistance. More must be done to honour the experience of pain women have regarding their periods, especially by healthcare professionals. There must be consistency in the way women are approached for their dysmenorrhea to prevent discrepancies of support. This must be done with clearer guidance on what is offered to women with dysmenorrhea, especially in the primary care setting.
Diagnostic Criteria and Classification · Staging and Classification Systems
Jain V et al., 2023·International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
Abnormal uterine bleeding (AUB) is common, often debilitating, and may affect over 50% of reproductive-aged women and girls. Whereas AUB is a collection of symptoms that include intermenstrual bleeding and abnormalities in period duration, cycle length, and regularity, it is heavy menstrual bleeding (HMB) that is most contributory to iron deficiency and related anemia. It is apparent that AUB, in general, and HMB, in particular, remain underrecognized and underreported. FIGO created two systems for assessing and classifying AUB. FIGO System 1 defines the bleeding pattern using four primary descriptors: frequency, duration, regularity, and flow volume. FIGO System 2 provides a structured classification system of possible causes of AUB, using the acronym PALM-COEIN. "PALM" refers to structural causes of AUB (Polyp, Adenomyosis, Leiomyoma, Malignancy), and "COEI" refers to nonstructural causes (Coagulopathy, Ovulatory dysfunction, Endometrial, and Iatrogenic). The "N" is reserved for those entities that are currently not otherwise classified. Using FIGO System 1 as a gateway to FIGO System 2 streamlines the investigation of reproductive-aged women and girls with AUB. Understanding the pathogenesis of the FIGO System 2 "PALM-COEIN" causes helps interpret investigations and the onward management of AUB. Numerous evidence gaps exist concerning AUB; however, if researchers and trialists universally adopt FIGO Systems 1 and 2 for the assessment and diagnosis of AUB, clear translatable research findings can be applied globally.
Yu O et al., 2023·American journal of obstetrics and gynecology
Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age, yet US incidence estimates do not exist, and prevalence estimates vary widely. A population-based US study estimated the incidence, prevalence, and trends of polycystic ovary syndrome by age, race and ethnicity, and diagnosing provider type. A retrospective cohort study of patients enrolled in Kaiser Permanente Washington from 2006 to 2019 was conducted. All members identified as female, aged 16 to 40 years with at least 3 years of enrollment and at least 1 healthcare encounter during that time, were eligible for inclusion. Individuals were excluded if they had a history of oophorectomy or hysterectomy. Polycystic ovary syndrome cases were identified using the International Classification of Diseases diagnosis codes (International Classification of Diseases, Ninth Revision, 256.4 or International Classification of Diseases, Tenth Revision, E28.2). Individuals with a polycystic ovary syndrome diagnosis before study entry were excluded from incidence rate estimations. The incidence rates were adjusted by age using direct standardization to the 2010 US census data. Temporal trends in incidence were assessed using weighted linear regression (overall) and Poisson regression (by age, race and ethnicity, and provider type). Prevalent cases were defined as patients with a polycystic ovary syndrome diagnosis at any time before the end of 2019. Medical record review of 700 incident cases diagnosed in 2011-2019 was performed to validate incident cases identified by International Classification of Diseases codes using the Rotterdam criteria. Among 177,527 eligible patients who contributed 586,470 person-years, 2491 incident polycystic ovary syndrome cases were identified. The mean age at diagnosis was 26.9 years, and the mean body mass index was 31.6 kg/m2. Overall incidence was 42.5 per 10,000 person-years; the rates were similar over time but increased in individuals aged 16 to 20 years from 31.0 to 51.9 per 10,000 person-years (P=.01) and decreased among those aged 26 to 30 years from 82.8 to 45.0 per 10,000 person-years (P=.02). A small decreasing temporal trend in incidence rates was only observed among non-Hispanic White individuals (P=.01). The incidence rates by diagnosing provider type varied little over time. Among the 58,241 patients who contributed person-time in 2019, 3036 (5.2%) had a polycystic ovary syndrome International Classification of Diseases diagnosis code; the prevalence was the highest among the Hawaiian and Pacific Islander group (7.6%) followed by Native American and Hispanic groups. Medical record review classified 60% as definite or probable incident, 14% as possible incident, and 17% as prevalent polycystic ovary syndrome. The overall positive predictive value of polycystic ovary syndrome International Classification of Diseases diagnosis code for identifying definite, probable, or possible incident polycystic ovary syndrome was 76% (95% confidence interval, 72%-79%). Among a cohort of nonselected females in the United States, we observed stable rates of incident polycystic ovary syndrome diagnoses over time. The incidence of polycystic ovary syndrome was 4- to 5-fold greater than reported for the United Kingdom. The prevalence of polycystic ovary syndrome (5.2%) was almost double before the published US estimates (2.9%) based on the International Classification of Diseases codes. Race and ethnicity and provider type did not seem to have a major impact on temporal rates. Incident diagnoses increased over time in younger and decreased in older age groups, perhaps related to shifting practice patterns with greater awareness among practitioners of the impact of polycystic ovary syndrome on long-term health outcomes and improved prevention efforts. Moreover, increasing obesity rates may be a factor driving the earlier ages at diagnosis.
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 and
Accuracy in detecting ovulation and estimating the fertile window in the menstrual cycle is essential for women to avoid or achieve pregnancy. There has been a rapid growth in fertility apps and home ovulation testing kits in recent years. Nevertheless, there lacks information on how well these apps perform in helping users understand their fertility in the menstrual cycle. This pilot study aimed to evaluate and compare the beginning, peak, and length of the fertile window as determined by a new luteinizing hormone (LH) fertility tracking app with the Clearblue Fertility Monitor (CBFM). A total of 30 women were randomized into either a quantitative Premom or a qualitative Easy@Home (EAH) LH testing system. The results of the two testing systems were compared with the results from the CBFM over three menstrual cycles of use. Potential LH levels for estimating the beginning of the fertile window were calculated along with user acceptability and satisfaction. The estimates of peak fertility by the Premom and EAH LH testing were highly correlated with the CBFM peak results (R = 0.99, p < 0.001). The participants had higher satisfaction and ease-of-use ratings with the CBFM compared to the Premom and EAH LH testing systems. LH 95% confidence levels for estimating the beginning of the fertile window were provided for both the Premom and EAH LH testing results. Our pilot study findings suggest that the Premom and EAH LH fertility testing app can accurately detect impending ovulation for women and are easy to use at home. However, successful utilization of these low-cost LH testing tools and apps for fertility self-monitoring and family planning needs further evaluation with a large and more diverse population.
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.
Premenstrual syndrome (PMS) is one of the most common disorders faced by women of reproductive age. More than 200 symptoms of varying severity associated with PMS have been identified. Because of the broad spectrum of action of PMS and its impact on quality of life, symptom relief is the main challenge of treating PMS and premenstrual dysphoric disorder (PMDD). The review aims to analyze and identify the potential impact of dietary and nutritional therapies on PMS and, respectively, for its better management. The study was conducted by accessing Internet databases such as PubMed, ScienceDirect, and Scopus and using relevant keywords such as PMS, symptoms, dietary patterns (DPs), macro and micronutrients, and supplements. The results showed that diet is an essential modulating factor in reducing and managing PMS symptoms. But research on the actual effect of foods and nutrients on PMS is sparse, sporadic, and studied with insufficient scientific rigor. No correlations were identified between the consumption of macronutrients and protein, fat, carbohydrates, and fiber, but the effectiveness of micronutrients, especially calcium, magnesium, vitamin D, B vitamins, and herbal supplements, was demonstrated. Researchers remain unanimous that the evidence is insufficient and limited to support their use as an effective treatment. Nevertheless, the results could contribute to providing quality information to help women and girls make evidence-based decisions regarding premenstrual health and the adoption of dietary and nutritional therapies.
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.
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.
Thyroid and Metabolic Function · Insulin and Metabolism
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.
Belay DG et al., 2022·Front Reprod Health·
Open Access
The timing of the resumption of post-partum menses is important for a woman who intends to avoid subsequent unintended pregnancy, and it has key implications on maternal, neonatal, and child health outcomes. Despite this, information is scant about the time to resumption of post-partum menses and predictors in Ethiopia. Therefore, this study aimed to determine the time it takes to start menses and spatial distribution among post-partum period women in Ethiopia and identify its predictors. A secondary data analysis was conducted based on 2016 Ethiopian Demographic and Health Survey (EDHS). A total weighted sample of 6,489 post-partum women was included in the analysis. STATA 14 was used to weigh, clean, and analyze the data. The shared frailty model was applied since the EDHS data have a hierarchical nature. For checking the proportional hazard assumption, the Schenefold residual test, Log-Log plot, Kaplan-Meier, and predicted survival plot were applied. Akakie Information Criteria (AIC), Cox-Snell residual test, and deviance were used for checking model adequacy and for model comparison. Based on these, the Gompertz inverse Gaussian shared frailty model was the best-fitted model for this data. Variables with a p < 0.2 were considered for the multivariable Gompertz inverse Gaussian shared frailty model. Finally, the adjusted hazard ratio (AHR) with a 95% confidence interval (CI), and a p < 0.05 was reported to identify the significant predictors of time to the resumption of post-partum menses. The median survival time to post-partum menses resumption was 14.6 months. In this study, 51.90% [95% CI: 50.03, 53.76] of post-partum period women had resumed, and the risk of menses resumption was 1.17 times [AHR: 1.17; 95% CI: 1.03-1.33] higher among urban resident, 1.14 times [AHR: 1.14; 95% CI: 1.0-1.24] in women who had attended formal education, and 1.63 times [AHR: 1.63; 95% CI: 1.4-1.7] higher among women who used hormonal contraceptives. However, the risk of post-partum menses resumption was lower among 7-24 months breastfeeding women by 36% [AHR: 0.64; 95% CI: 0.5-0.76], women with child alive by 26% [AHR: 0.74; 95% CI: 0.6-0.85], and multiparous women by 27% [AHR: 0.73; 95% CI: 0.6-0.80]. Almost half of the participants had resumed post-partum menses, with the median survival timing of menses resumption at 14.5 months. Women residing in urban areas, who attended formal education, and using hormonal contraceptives have a shorter time to resume post-partum menses, whereas a woman with an alive child, breastfeeding practice, and multiple parity has a longer time to resume post-partum menses. Therefore, the healthcare providers and program managers should act on the resumption of post-partum menses through health education and promotion to cultivate the 14 months lag period identified by considering the significant factors.
Diagnostic Criteria and Classification · Staging and Classification Systems
Ovulatory disorders are common causes of amenorrhea, abnormal uterine bleeding and infertility and are frequent manifestations of polycystic ovary syndrome (PCOS). There are many potential causes and contributors to ovulatory dysfunction that challenge clinicians, trainees, educators, and those who perform basic, translational, clinical and epidemiological research. Similarly, therapeutic approaches to ovulatory dysfunction potentially involve a spectrum of lifestyle, psychological, medical and procedural interventions. Collaborative research, effective education and consistent clinical care remain challenged by the absence of a consensus comprehensive system for classification of these disorders. The existing and complex system, attributed to the World Health Organization (WHO), was developed more than three decades ago and did not consider more than 30 years of research into these disorders in addition to technical advances in imaging and endocrinology. This article describes the development of a new classification of ovulatory disorders performed under the aegis of the International Federation of Gynecology and Obstetrics (FIGO) and conducted using a rigorously applied Delphi process. The stakeholder organizations and individuals who participated in this process comprised specialty journals, experts at large, national, specialty obstetrical and gynecological societies, and informed lay representatives. After two face-to-face meetings and five Delphi rounds, the result is a three-level multi-tiered system. The system is applied after a preliminary assessment identifies the presence of an ovulatory disorder. The primary level of the system is based on an anatomic model (Hypothalamus, Pituitary, Ovary) that is completed with a separate category for PCOS. This core component of the system is easily remembered using the acronym HyPO-P. Each anatomic category is stratified in the second layer of the system to provide granularity for investigators, clinicians and trainees using the GAIN-FIT-PIE mnemonic (Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious and Inflammatory, Trauma and Vascular; Physiological, Idiopathic, Endocrine). The tertiary level allows for specific diagnostic entities. It is anticipated that, if widely adopted, this system will facilitate education, clinical care and the design and interpretation of research in a fashion that better informs progress in this field. Integral to the deployment of this system is a periodic process of reevaluation and appropriate revision, reflecting an improved understanding of this collection of disorders.
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.
Groenman AP et al., 2022·Autism : the international journal of research and practice
Autism spectrum conditions were once seen as a predominantly male condition, but this has caused research to have little focus on women. Therefore, little is known about menstruation and menopause in autism spectrum conditions. Some smaller studies indicate that autistic individuals might suffer from increased difficulties surrounding these events. This study aimed to investigate whether autistic women experience more frequent premenstrual dysphoric disorder, causing extreme physical, emotional, and functional impairment. In a partly overlapping sample, we also examined whether women with autism spectrum condition experience increased complaints surrounding menopause. We did not find an increased prevalence of premenstrual dysphoric disorder in autism spectrum conditions (14.3%) compared with non-autistic women (9.5%). Those with autism spectrum conditions did experience increased menopausal complaints. These menopausal complaints were associated with higher levels of depression and autistic traits. In non-autistic women, menopausal complaints were associated with increased inattention, hyperactivity/impulsivity (i.e. attention deficit hyperactivity disorder traits), and depression. With this work, we show the important role that major reproductive milestones can have in an autistic woman's life.
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.
Guy M et al., 2022·Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie·
Open Access
This randomized, crossover, double-blind, controlled trial evaluates the efficacy and safety of a preprogrammed transcutaneous electrical nerve stimulation (TENS) device versus placebo (SHAM) in women with primary dysmenorrhea (PD). Forty women suffering from significant dysmenorrhea requiring the use of analgesics and/or non-steroidal anti-inflammatory drugs self-apply to the abdominal or lumbar region depending on the location of the pain, alternately according to randomization, the TENS device then the SHAM (dummy device) or conversely SHAM then TENS. The primary endpoint compares the evolution of pain intensity before and after application of TENS and SHAM. The speed of action, the persistence of the analgesic effect and the therapeutic savings are also evaluated. Adverse events (AEs) are collected. A statistically and clinically significant decrease in the pain of 53% (P<0.0001) is observed during the first 2 applications of TENS versus no analgesic effect (-5%, P=0.318) with SHAM. Over all 197 applications of TENS, the reduction of menstrual pain intensity by more than half is confirmed. The rapid relief, less than 20 minutes in 74% of cases, lasts on average more than 7 hours. A difference in analgesic consumption of -93% is observed in favor of TENS (P<0.01). Seven participants reported 10 non-serious AEs, 2 of which were possibly related to TENS. The TENS device tested represents a well-tolerated, rapidly and lastingly effective non-pharmacological analgesic solution, capable of replacing or being combined with analgesics in the management of PD.
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.
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.
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.
Yang R et al., 2022·Lancet Reg Health West Pac·
Open Access
Polycystic ovary syndrome (PCOS) has become a major international public health concern. However, because of controversy about the diagnostic criteria and patient selection, estimates of its absolute prevalence and change with time vary greatly. We conducted two consecutive nationwide epidemiological surveys of the prevalence of PCOS in representative samples of reproductive-aged women in China in 2010 and 2020. Face-to-face interviews were performed by trained interviewers in each survey. All participants completed a questionnaire and underwent a physical examination, blood sampling, and transvaginal pelvic ultrasound. We assessed hyperandrogenism (H), chronic anovulation (O), and polycystic ovaries (P) to classify the presence of PCOS using the Rotterdam criteria. The prevalence of PCOS among reproductive-aged women was estimated after consideration of differential probabilities of selection and population distribution. We conducted a logistic regression analysis by using the probability of PCOS as a function of the survey year to acquire the trend information across the years. Findings: 28,739 respondents completed the survey, including 15,924 in the previously published 2010 survey and 12,815 in the new 2020 survey. In 2020, 826 participants could be diagnosed as having PCOS, with a weighted prevalence of 7.8% (95%CI: 7.0%, 9.0%) among women aged 20-49 years, leading to an estimate of 24.0 million women of reproductive age affected by this condition in China as a whole. The estimated prevalence in 2020 was higher than that of a decade ago despite identical research methods suggesting a two-thirds increase over the study period. Women with PCOS in 2020 also appeared to have a more severe phenotype overall than those of a decade ago, possibly reflecting a significantly higher prevalence of obesity, hyperandrogenism, and infertility. Interpretation: The prevalence of PCOS in Chinese women has increased significantly over the past 10 years. PCOS is a significant public health problem in women of reproductive age in China and national policy and guidelines should be re-examined in the light of the current data. National Key R&D Program of China and the National Natural Science Foundation of China.
Over the last 5 decades, the fulfillment of maternity wishes in solid organ transplanted women has become a reality. Despite pregnancy contraindication in transplanted women during the early post-transplant period, such a condition can be overcome after 12 months if patients show a good clinical evolution and do not present other general pre-conceptional findings. This article presents the case report of a young female liver transplanted patient that used symptothermal method as a reliable family planning method. After her gestational contraindication was lifted, observation of biological fertility indicators and fertility-guided sexual intercourse helped her fulfill her maternity wish and conceive and carry out a healthy offspring. Based on this case and on the available bibliographic evidence, this paper reviews the potential implications of the use of this kind of approach as a safe and effective alternative to assisted reproduction technology in the management of potential infertility problems in the young female transplanted population, a population which according to literature has higher rates of unsuccessful parenthood and might also be more vulnerable to iatrogenicity of ovarian hyperstimulation process and to multiple pregnancy.
Itani R et al., 2022·Korean journal of family medicine
Primary dysmenorrhea (PD) is a common, disregarded, underdiagnosed, and inadequately treated complaint of both young and adult females. It is characterized by painful cramps in the lower abdomen, which start shortly before or at the onset of menses and which could last for 3 days. In particular, PD negatively impacts the quality of life (QOL) of young females and is the main reason behind their absenteeism from school or work. It is suggested that increased intrauterine secretion of prostaglandins F2α and E2 are responsible for the pelvic pain associated with this disorder. Its associated symptoms are physical and/or psychological. Its physical symptoms include headache, lethargy, sleep disturbances, tender breasts, various body pains, disturbed appetite, nausea, vomiting, constipation or diarrhea, and increased urination, whereas its psychological symptoms include mood disturbances, such as anxiety, depression, and irritability. While its diagnosis is based on patients' history, symptoms, and physical examination, its treatment aims to improve the QOL through the administration of nonsteroidal anti-inflammatory drugs, hormonal contraceptives, and/or the use of non-pharmacological aids (e.g., topical heat application and exercise). Patients must be monitored to measure their response to treatment, assess their adherence, observe potential side effects, and perform further investigations, if needed.
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.
Lora J et al., 2022·Clin. Exp. Obstet. Gynecol.·
Open Access
The principal objective of this study was to correlate biophysical properties of vaginal discharge present in the cervical mucus with the timing of the fertile window. In particular, we produce measures of the viscoelasticity of the cervical secretion using two methods. The first uses only the elasticity extracted from the Creighton Model Fertility Care System (CrMs) scale, calculated P-6 ovulation estimated day (OED) with respect to the peak day of the CrMs. The second uses a numerical method that takes into account the changes in viscoelasticity, but without reference to the peak day calculated using the CrMs model. Using both methods, twelve records were obtained from a single female subject. The methodology used to evaluate the viscoelasticity factor was by measuring the approximate length in centimeters (cm) of the vaginal discharge of cervical discharge. For this, the scale of the stretching graph established by observing the stretching of CrMS was used, taking into account the previous 6 days at peak day P-6. The first method, which we termed CFW (Clinical Fertile Window), uses a measure based on the approximate length (cm) of the maximal stretchiness of the vaginal discharge. The second method we termed SFW (Software-CrMS/strectching) (Software-based Fertile Window). The fertile window was detected correctly in 100% of the cases using either method, and a correlation value of 0.71 was observed between the two methods. We conclude that the assessment of viscoelasticity using SFW algorithm allowed in this pilot study to detect the fertile window and to describe the evolution pattern of cervical discharge throughout the fertile window. Our study provides support for the use of computational methods in detecting the fertile window, taking only into account the time evolution of the cervical discharge throughout the menstrual cycle.
Case-based clinical presentation examining the role of mast cells in the pathophysiology of endometriosis and dysmenorrhea, presented by April Lind, MD (IFMCP, CFCMC, RHRI). Reviews mast-cell mediated inflammation, its relationship to endometriosis-associated pain and abnormal uterine bleeding, and functional-medicine considerations.
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.
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.
Favaro C et al., 2021·J Womens Health (Larchmt)·
Open Access
Time to pregnancy (TTP) is a biomarker of fecundability and has been associated with behavioral and environmental characteristics; however, these associations have not been examined in a large population-based sample of application (app) users. This observational study followed 5,376 women with an age range of 18 to 45 years who used an app to identify their fertile window. We included women who started trying to conceive between September 30, 2017 and August 31, 2018. TTP was calculated as the number of menstrual cycles from when the user switched to "Plan" mode up to and including the cycle in which they logged a positive pregnancy test. We examined associations with several characteristics, including age, gravidity, body mass index, cycle length and cycle length variation, frequency of sexual intercourse, and temperature measuring frequency. Discrete time fecundability models were used to estimate fecundability odds ratios. For the complete cohort the 6-cycle and 12-cycle cumulative pregnancy probabilities were found to be 61% (95% confidence interval [CI]: 59-62) and 74% (95% CI: 73-76), respectively. The median TTP was four cycles. The highest fecundability was associated with an age of less than 35 years, with cycle length variation <5 days and logging sexual intercourse on at least 20% of days added (the proportion of days in which intercourse was logged) (11.5% [n = 613] of entire sample). This group achieved a 6and 12-cycle cumulative pregnancy probability of 88% (95% CI: 85-91) and 95% (95% CI: 94-97), respectively, and a TTP of 2 cycles. Natural Cycles was an effective method of identifying the fertile window and a noninvasive educational option for women planning a pregnancy. Women under age 35 with regular cycles showed a high pregnancy rate.
Zhu TY et al., 2021·Journal of medical Internet research
As a daily point measurement, basal body temperature (BBT) might not be able to capture the temperature shift in the menstrual cycle because a single temperature measurement is present on the sliding scale of the circadian rhythm. Wrist skin temperature measured continuously during sleep has the potential to overcome this limitation. This study compares the diagnostic accuracy of these two temperatures for detecting ovulation and to investigate the correlation and agreement between these two temperatures in describing thermal changes in menstrual cycles. This prospective study included 193 cycles (170 ovulatory and 23 anovulatory) collected from 57 healthy women. Participants wore a wearable device (Ava Fertility Tracker bracelet 2.0) that continuously measured the wrist skin temperature during sleep. Daily BBT was measured orally and immediately upon waking up using a computerized fertility tracker with a digital thermometer (Lady-Comp). An at-home luteinizing hormone test was used as the reference standard for ovulation. The diagnostic accuracy of using at least one temperature shift detected by the two temperatures in detecting ovulation was evaluated. For ovulatory cycles, repeated measures correlation was used to examine the correlation between the two temperatures, and mixed effect models were used to determine the agreement between the two temperature curves at different menstrual phases. Wrist skin temperature was more sensitive than BBT (sensitivity 0.62 vs 0.23; P<.001) and had a higher true-positive rate (54.9% vs 20.2%) for detecting ovulation; however, it also had a higher false-positive rate (8.8% vs 3.6%), resulting in lower specificity (0.26 vs 0.70; P=.002). The probability that ovulation occurred when at least one temperature shift was detected was 86.2% for wrist skin temperature and 84.8% for BBT. Both temperatures had low negative predictive values (8.8% for wrist skin temperature and 10.9% for BBT). Significant positive correlation between the two temperatures was only found in the follicular phase (rmcorr correlation coefficient=0.294; P=.001). Both temperatures increased during the postovulatory phase with a greater increase in the wrist skin temperature (range of increase: 0.50 °C vs 0.20 °C). During the menstrual phase, the wrist skin temperature exhibited a greater and more rapid decrease (from 36.13 °C to 35.80 °C) than BBT (from 36.31 °C to 36.27 °C). During the preovulatory phase, there were minimal changes in both temperatures and small variations in the estimated daily difference between the two temperatures, indicating an agreement between the two curves. For women interested in maximizing the chances of pregnancy, wrist skin temperature continuously measured during sleep is more sensitive than BBT for detecting ovulation. The difference in the diagnostic accuracy of these methods was likely attributed to the greater temperature increase in the postovulatory phase and greater temperature decrease during the menstrual phase for the wrist skin temperatures.
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.
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.
NaProTECHNOLOGY – a chance for offspring or fraud? In the media space in Poland, you can meet the concept of Naprotechnology as an alternative to the in vitro procedure. Often, many myths and untruths appear in the discussion regarding this method of treatment. Naprotechnology is a new look at the health of women and men created by prof. Thomas Hilgers. It takes into account natural fertility biomarkers thanks to observation with the Creighton Model based on the female mucus. At every stage of diagnosis and treatment, Naprotechnology respects human life from the moment of conception and the mutual dignity of the spouses. It also does not use assisted reproductive procedures for ethical reasons. Naprotechnology is part of the broader scientific discipline of restorative medicine in infertility. Thanks to the accurate diagnosis and observation of the cycle, it is possible to correctly diagnose the cause of infertility. A proper diagnosis is the starting point for the implementation of specialized pharmacological and surgical treatment for both women and men. Properly used Naprotechnology and restorative medicine are highly effective in treating marital infertility. W przestrzeni medialnej w Polsce można spotkać pojęcie Naprotechnologii jako alternatywy dla procedury in vitro. Często w dyskusji pojawia się wiele mitów i nieprawdy dotyczących takiego sposobu leczenia. Naprotechnologia, stworzona przez prof. Thomasa Hilgersa, jest nowym spojrzeniem na zdrowie kobiety i mężczyzny. Uwzględnia ona naturalne biomarkery płodności dzięki obserwacji za pomocą Modelu Creighton bazującego na kobiecym śluzie. Na każdym etapie diagnostyki i leczenia Naprotechnologia szanuje ludzkie życie od samego poczęcia oraz wzajemną godność małżonków. Nie stosuje ona też procedur wspomaganego rozrodu z powodów etycznych. Naprotechnologia jest częścią szerszej dyscypliny naukowej, jaką jest przyczynowe leczenie niepłodności. Dzięki dokładnej diagnostyce i obserwacji cyklu możliwe jest postawienie prawidłowej diagnozy dotyczącej przyczyny niepłodności. Właściwa diagnoza jest punktem wyjścia dla wdrożenia specjalistycznego leczenia farmakologicznego i chirurgicznego zarówno wobec kobiety, jak i mężczyzny. Prawidłowo stosowana Naprotechnologia i przyczynowe leczenie niepłodności cechują się wysoką skutecznością leczenia niepłodności małżeńskiej.
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.
Nutrition and Metabolic Health · Eating Disorders and Underfueling
Skorseth P et al., 2020·Orthopaedic journal of sports medicine
Investigations of the female athlete triad (Triad) in high school athletes have found that 36% had low energy availability, 54% had menstrual abnormalities, and 16% had low bone mineral density (BMD). Limited data are available showing the prevalence of these risk factors in high school distance runners or regarding best practice on screening for the Triad in the adolescent population. To (1) evaluate the prevalence of Triad risk factors and iron supplementation in high school distance runners and (2) pilot a screening tool for Triad risk score. Descriptive epidemiology study. The study population included female high school athletes who participated in cross-country/track. Participants completed a survey including questions regarding dietary habits, menstrual history, and bone stress injury (BSI) history. They then underwent evaluation of 25-hydroxyvitamin D, free triiodothyronine (T3), and dual-energy x-ray absorptiometry scan to measure body fat and BMD through use of age-, sex-, and ethnicity-matched Z scores. Triad scores were calculated. Relationships were analyzed using Spearman correlation coefficient. There were 38 study participants (mean age, 16.9 years). Average body mass index was 19.8 kg/m2. Disordered eating or eating disorders were reported in 76.3% of runners; in addition, 23.7% reported delayed menarche, 45.9% had a history of amenorrhea or oligomenorrhea, 42.1% had low BMD (Z score < -1.0), and 15.8% reported prior BSI. Low free T3 was significantly associated with higher Triad risk scores (r S = -0.36; P = .028). More than 42% of athletes were supplementing iron. The prevalence of Triad risk factors in high school distance runners was high. Free T3 was inversely associated with Triad score, which may serve as an indicator of low energy availability. Nearly half of the athletes were using iron supplementation.
Lifespan Health · Cycle as a Lifespan Health Marker
AbstractObjectiveTo evaluate whether irregular or long menstrual cycles throughout the life course are associated with all cause and cause specific premature mortality (age <70 years). Prospective cohort study. Nurses’ Health Study II (1993-2017).Participants79 505 premenopausal women without a history of cardiovascular disease, cancer, or diabetes and who reported the usual length and regularity of their menstrual cycles at ages 14-17 years, 18-22 years, and 29-46 years. Hazard ratios and 95% confidence intervals for all cause and cause specific premature mortality (death before age 70 years) were estimated from multivariable Cox proportional hazards models. During 24 years of follow-up, 1975 premature deaths were documented, including 894 from cancer and 172 from cardiovascular disease. Women who reported always having irregular menstrual cycles experienced higher mortality rates during follow-up than women who reported very regular cycles in the same age ranges. The crude mortality rate per 1000 person years of follow-up for women reporting very regular cycles and women reporting always irregular cycles were 1.05 and 1.23 for cycle characteristics at ages 14-17 years, 1.00 and 1.37 for cycle characteristics at ages 18-22 years, and 1.00 and 1.68 for cycle characteristics at ages 29-46 years. The corresponding multivariable adjusted hazard ratios for premature death during follow-up were 1.18 (95% confidence interval 1.02 to 1.37), 1.37 (1.09 to 1.73), and 1.39 (1.14 to 1.70), respectively. Similarly, women who reported that their usual cycle length was 40 days or more at ages 18-22 years and 29-46 years were more likely to die prematurely than women who reported a usual cycle length of 26-31 days in the same age ranges (1.34, 1.06 to 1.69; and 1.40, 1.17 to 1.68, respectively). These relations were strongest for deaths related to cardiovascular disease. The higher mortality associated with long and irregular menstrual cycles was slightly stronger among current smokers. Irregular and long menstrual cycles in adolescence and adulthood are associated with a greater risk of premature mortality (age <70 years). This relation is slightly stronger among women who smoke.
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.
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.
Women living with HIV (WLWH) have higher rates of prolonged secondary amenorrhea (no flow for ≥1 year) than HIV-negative women. Both having amenorrhea and being HIV positive are associated with lower areal bone mineral density (BMD). However, their combined BMD effects remain unclear. Therefore, we investigated prolonged amenorrhea and BMD in WLWH and controls. This cross-sectional study enrolled WLWH and HIV-negative control women aged 19-68 years of similar backgrounds. We assessed BMD (Hologic; as ageand ethnicity-matched Z-scores) in the Children and women: AntiRetrovirals and Markers of Aging cohort. Participants were stratified by amenorrhea history defined as past/present lack of menses for ≥1 year at age 45 and younger and not because of surgery, breastfeeding, pregnancy, or hormonal contraception. Hip and spine Z-scores by amenorrhea/no amenorrhea used linear models with multivariable analysis for relationships within WLWH. WLWH (N = 129) were similar to controls (N = 129) in age, body mass index, ethnicity, and substance use. Among WLWH, 21% experienced prolonged amenorrhea vs. 9% in controls. WLWH had significantly lower total 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 than controls. Amenorrhea was independently associated with hip (P = 0.01) but not spine (P = 0.94) BMD by multivariable linear regression. WLWH with amenorrhea had lower hip Z-scores (-0.8 ± 0.9) than those without (-0.3 ± 0.8; P = 0.01). They also had higher rates of substance use, smoking, opioid therapy, hepatitis C coinfection, and lower CD4 nadir. WLWH had higher rates of prolonged amenorrhea and lower BMD than controls. WLWH with amenorrhea experienced lower hip BMD Z-scores than those without. Prolonged amenorrhea is an added osteoporosis risk in WLWH.
Simmons RG et al., 2020·Best Pract Res Clin Obstet Gynaecol·
Fertility awareness-based methods (FABMs) of family planning involve monitoring various signs and symptoms of fertility during the menstrual cycle to identify the "fertile window," or the days of the cycle when unprotected intercourse is most likely to result in pregnancy. Signs and symptoms include menstrual cycle length, basal body temperature, urinary hormone measurements, and/or cervical fluid and may be used alone or in combination. Fertility signs reflect both physiological changes during the menstrual cycle and the life cycle of the ovum and sperm. Women learn to observe or measure and interpret these signs according to the instructions of their chosen FABM and avoid unprotected intercourse on fertile days. FABMs are appropriate for those who choose to use them, are able and willing to observe one or more fertility signs, and are in relationships that support the use of a coitus-related method such as a condom or abstaining from intercourse on fertile days.
Previous research has demonstrated that women instructed in fertility awareness methods can identify the Peak Day of cervical mucus discharge for each menstrual cycle, and the Peak Day has high agreement with other indicators of the day of ovulation. However, previous studies enrolled experienced users of fertility awareness methods or were not fully blinded. To assess the agreement between cervical mucus Peak Day identified by fertile women without prior experience on assessing cervical mucus discharge with the estimated day of ovulation (1 day after urine luteinising hormone surge). This study is a secondary analysis of data from a randomised trial of the Creighton Model FertilityCare(TM) System (CrM), conducted 2003-2006, for women trying to conceive. Women who had no prior experience tracking cervical mucus recorded vulvar observations daily using a standardised assessment of mucus characteristics for up to seven menstrual cycles. Four approaches were used to identify the Peak Day. The referent day was defined as one day after the first identified day of luteinising hormone (LH) surge in the urine, assessed blindly. The percentage of agreement between the Peak Day and the referent day of ovulation was calculated. Fifty-seven women with 187 complete cycles were included. A Peak Day was identified in 117 (63%) cycles by women, 185 (99%) cycles by experts, and 187 (100%) by computer algorithm. The woman-picked Peak Day was the same as the referent day in 25% of 117 cycles, within ±1 day in 58% of cycles, ±2 days in 84%, ±3 days in 87%, and ±4 days in 92%. The ±1 day and ± 4 days' agreement was 50% and 90% for the expert-picked and 47% and 87% for the computer-picked Peak Day, respectively. Women's daily tracking of cervical mucus is a low-cost alternative for identifying the estimated day of ovulation.
Bordewijk EM et al., 2020·The Cochrane database of systematic reviews
Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions. To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance. We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies. We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD. Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes. This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I2 = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I2 = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I2 = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I2 = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I2 = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I2 = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I2 = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I2 = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose. AUTHORS' Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
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.
Elboim-Gabyzon M et al., 2020·International journal of women's health
Primary dysmenorrhea is a chronic health condition that affects primarily young women. Transcutaneous electrical nerve stimulation (TENS) has been suggested as an effective pain reduction modality in primary dysmenorrhea. TENS is a noninvasive, inexpensive, portable method with minimal risks and a few contraindications. When necessary, it can be self-administered on a daily basis during everyday activities. Several studies have investigated the effectiveness of TENS in reducing pain, decreasing the use of analgesics, and improving the quality of life in primary dysmenorrhea patients. These studies have some limitations in methodological quality and therapeutic validation. However, the overall positive effects of TENS in primary dysmenorrhea encountered in all prior studies indicated its potential value. This review presents the clinical recommendations for TENS parameters for treating primary dysmenorrhea symptoms based on previously published studies.
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.
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.
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.
Kitazawa J et al., 2020·The Tohoku journal of experimental medicine·
Open Access
The uterus is an organ for raising the fetus, and its lumen is lined by the endometrium. The endometrium is an important site for the implantation and maturation of fertilized eggs. The endometrium undergoes repetitive proliferation, maturation (decidualization), and exfoliation changes every menstrual cycle. At the same time, the number and type of endometrial immunocompetent cells vary during the menstrual cycle. At the implantation stage, the immunocompetent cells occupy approximately half of the endometrial cells. Immunocompetent cells normally eliminate pathogenic microorganisms to protect the body; however, they also promote immune tolerance to accept the fetus during pregnancy. The immunocompetent cells in the uterus can perform both these functions. With the establishment of pregnancy, stimuli from the trophoblast (placenta) and fetus can also change the immune environment of the uterus, and pregnancy can be maintained only when the immune system is well adapted to the stimuli of some hormones and the fetus. Immunity for the establishment of pregnancy is not simple because multiple immunocompetent cells are involved in establishing and maintaining pregnancy. To understand the immune mechanisms associated with the establishment of pregnancy, we have to learn about each immune cell. This review, therefore, discusses the roles and distribution of the immunocompetent cells inside the uterus during menstruation and early pregnancy.
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.
Maijala A et al., 2019·BMC Womens Health·
Open Access
Body temperature is a common method in menstrual cycle phase tracking because of its biphasic form. In ambulatory studies, different skin temperatures have proven to follow a similar pattern. The aim of this pilot study was to assess the applicability of nocturnal finger skin temperature based on a wearable Oura ring to monitor menstrual cycle and predict menstruations and ovulations in real life. Volunteer women (n = 22) wore the Oura ring, measured ovulation through urine tests, and kept diaries on menstruations at an average of 114.7 days (SD 20.6), of which oral temperature was measured immediately after wake-up at an average of 1.9 cycles (SD 1.2). Skin and oral temperatures were compared by assessing daily values using repeated measures correlation and phase mean values and differences between phases using dependent t-test. Developed algorithms using skin temperature were tested to predict the start of menstruation and ovulation. The performance of algorithms was assessed with sensitivity and positive predictive values (true positive defined with different windows around the reported day). Nocturnal skin temperatures and oral temperatures differed between follicular and luteal phases with higher temperatures in the luteal phase, with a difference of 0.30 °C (SD 0.12) for skin and 0.23 °C (SD 0.09) for oral temperature (p < 0.001). Correlation between skin and oral temperatures was found using daily temperatures (r = 0.563, p < 0.001) and differences between phases (r = 0.589, p = 0.004). Menstruations were detected with a sensitivity of 71.9-86.5% in window lengths of ±2 to ±4 days. Ovulations were detected with the best-performing algorithm with a sensitivity of 83.3% in fertile window from - 3 to + 2 days around the verified ovulation. Positive predictive values had similar percentages to those of sensitivities. The mean offset for estimations were 0.4 days (SD 1.8) for menstruations and 0.6 days (SD 1.5) for ovulations with the best-performing algorithm. Nocturnal skin temperature based on wearable ring showed potential for menstrual cycle monitoring in real life conditions.
To quantify the frequency of use of selected fertility awareness indicators and to assess their influence on fecundability. Web-based prospective cohort study. Not applicable. PATIENT(S): Female pregnancy planners, aged 21-45 years, attempting conception for ≤6 cycles at study entry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We ascertained time to pregnancy, in menstrual cycles, with bimonthly questionnaires. We estimated adjusted fecundability ratios (FRs) and confidence intervals (CIs) using proportional probabilities models, controlling for age, income, education, smoking, intercourse frequency, and other lifestyle and reproductive factors. RESULT(S): A total of 5,688 women were analyzed, with a mean age of 29.9 years and mean time trying of 2.1 cycles at baseline; 30% had ever been pregnant. At baseline, 75% were using one or more fertility indicators (counting days or charting menstrual cycles [71%], measuring basal body temperature [BBT, 21%], monitoring cervical fluid [39%], using urine LH tests [32%], or feeling for changes in position of the cervix [12%]). Women using any fertility indicator at baseline had higher subsequent fecundability (adjusted FR 1.25, 95% CI 1.16-1.35) than those not using any fertility indicators. For each individual indicator, adjusted FRs ranged from 1.28-1.36, where 1.00 would indicate no relation with fecundability. The adjusted FR for women using a combination of charting days, cervical fluid, and urine LH was 1.48 (95% CI 1.31-1.67) relative to women using no fertility indicators. CONCLUSION(S): In a North American preconception cohort study, use of fertility indicators indicating the fertile window was common, and was associated with greater fecundability.
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.
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.
Women wishing to conceive are largely unaware of fertility symptoms at the time of ovulation. This study investigated the effectiveness of fertility-awareness in achieving pregnancy, particularly fertile mucus pattern, in the context of infertility. The 384 eligible participants were taken from consecutive women desiring pregnancy who attended 17 Australian Billings Ovulation Method(®) clinics from 1999-2003. This cohort included couples with infertility ≥12 months (51%) and female age >35 years (28%). Under fertility-awareness instruction, pregnancy was achieved by 240 couples (62.5%) after maximum follow-up of two years. Mucus symptom observations effectively stratified 'low pregnancy-potential' (35.2%) and 'high pregnancy-potential' groups. Pregnancy rates were ∼30% higher in the latter group (44.4% versus 72.3%) in addition to consistent effects observed on pregnancy achievements within subgroups defined by prognostic factors such as duration of infertility (p = 0.001) and increasing female age (p = 0.04). Fertile symptoms were also associated with significantly shorter time to conception (4.2 versus 6.4 months) in a survival analysis (p = 0.003). Billings Ovulation Method(®) observations strongly predicted successful conception. This has the capacity to provide a rapid, reliable and cost-effective approach to stratifying fertility potential, including directing timely and targeted investigations/management, and is accessible for women who may be remote from primary or specialist care.
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.
Women trying to conceive are increasingly using fertility-tracking software applications to time intercourse. This study evaluated the difference in conception rates between women trying to conceive using an application-connected ovulation test system, which measures urinary luteinizing hormone and an estrogen metabolite, versus those trying without using ovulation testing. This home-based study involved 844 volunteers aged 18-40 years seeking to conceive. Volunteers randomized to the test arm were required to use the test system for the duration of the study while those randomized to the control arm were instructed not to use ovulation testing. Pregnancy rate differences across one and two cycles between the two groups were examined. Volunteers in the test (n = 382) and control arms (n = 403) had similar baseline demographics. The proportion of women pregnant after one cycle was significantly greater in the test arm (25.4%) compared with the control arm (14.7%; p < 0.001). After two cycles, there continued to be a greater proportion of women pregnant in the test arm compared with the control arm (36.2% vs. 28.6%; p = 0.026). In the test arm, volunteers had intercourse less frequently per cycle compared with those not using ovulation testing (9 [range: 1-60] vs. 10 [range: 1-50]; p = 0.027), but were more likely to target intercourse to a particular part of their cycle compared with those not using ovulation testing (88.5% vs. 57.8%; p < 0.001). Using the test system to time intercourse within the fertile window increases the likelihood of conceiving within two menstrual cycles.
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.
For most women of reproductive age, assessing menstrual health and fertility typically involves regular visits to a gynecologist or another clinician. While these evaluations provide critical information on an individual's reproductive health status, they typically rely on memory-based self-reports, and the results are rarely, if ever, assessed at the population level. In recent years, mobile apps for menstrual tracking have become very popular, allowing us to evaluate the reliability and tracking frequency of millions of self-observations, thereby providing an unparalleled view, both in detail and scale, on menstrual health and its evolution for large populations. In particular, the primary aim of this study was to describe the tracking behavior of the app users and their overall observation patterns in an effort to understand if they were consistent with previous small-scale medical studies. The secondary aim was to investigate whether their precision allowed the detection and estimation of ovulation timing, which is critical for reproductive and menstrual health. Retrospective self-observation data were acquired from two mobile apps dedicated to the application of the sympto-thermal fertility awareness method, resulting in a dataset of more than 30 million days of observations from over 2.7 million cycles for two hundred thousand users. The analysis of the data showed that up to 40% of the cycles in which users were seeking pregnancy had recordings every single day. With a modeling approach using Hidden Markov Models to describe the collected data and estimate ovulation timing, it was found that follicular phases average duration and range were larger than previously reported, with only 24% of ovulations occurring at cycle days 14 to 15, while the luteal phase duration and range were in line with previous reports, although short luteal phases (10 days or less) were more frequently observed (in up to 20% of cycles). The digital epidemiology approach presented here can help to lead to a better understanding of menstrual health and its connection to women's health overall, which has historically been severely understudied.
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.
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 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.
The ability to accurately predict ovulation at-home using low-cost point-of-care diagnostics can be of significant help for couples who prefer natural family planning. Detecting ovulation-specific hormones in urine samples and monitoring basal body temperature are the current commonly home-based methods used for ovulation detection; however, these methods, relatively, are expensive for prolonged use and the results are difficult to comprehend. Here, we report a smartphone-based point-of-care device for automated ovulation testing using artificial intelligence (AI) by detecting fern patterns in a small volume (<100 μL) of saliva that is air-dried on a microfluidic device. We evaluated the performance of the device using artificial saliva and human saliva samples and observed that the device showed >99% accuracy in effectively predicting ovulation.
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.
A one-day meeting of physicians, professional nurses, and scientists actively involved in Natural Family Planning (NFP) research was held to review the state of the science of NFP and consider future priorities. The meeting had four (i) determine the gaps in research evidence for secure methods of NFP among women of all reproductive categories, (ii) determine the gaps in the research and development of new technology for providing NFP services, (iii) determine the gaps in the research that determine the benefits and challenges with use of NFP among married couples, and (iv) provide prioritized ideas for future research needs from the analysis of evidence gaps from objectives above. This article summarizes the discussion and conclusions drawn from topics reviewed. While much has been accomplished in the fifty years since Humane vitae, there are still many gaps to address. Five areas for future research in NFP were identified as high priority: (1) well-designed method effectiveness studies among various reproductive categories including important subpopulations (postpartum, perimenopause, posthormonal contraceptive), normally cycling women (especially US women), and comparative studies between NFP methods; (2) validation studies to establish the benefit of charting fertility signs (both currently known and potential new indicators) as a screening tool for women's health issues; (3) ongoing independent evaluation of fertility monitoring apps to provide users perspective on the relative merits of each and to identify those most worthy of further effectiveness testing; (4) studies evaluating the impact of new technologies on NFP adoption, use, and persistence; and (5) creation of a shared database across various NFP methods to collaborate on shared research interests, longitudinal studies, and so on. This summarizes a meeting to review the scientific and medical progress related to natural family planning made in the 50 years since Humane Vitae and to define priorities for future work. Areas reviewed included the evidence for avoiding pregnancy in normally cycling, postpartum, and perimenopausal women, the impact of new technology, including fertility charting apps, on NFP, and the impact on relationships and personal well-being from use of NFP. Five priority focus areas for future research were also identified.
Diagnostic Criteria and Classification · Staging and Classification Systems
Munro MG et al., 2018·Int J Gynaecol Obstet·
Open Access
The International Federation of Gynecology and Obstetrics (FIGO) systems for nomenclature of symptoms of normal and abnormal uterine bleeding (AUB) in the reproductive years (FIGO AUB System 1) and for classification of causes of AUB (FIGO AUB System 2; PALM-COEIN) were first published together in 2011. The purpose was to harmonize the definitions of normal and abnormal bleeding symptoms and to classify and subclassify underlying potential causes of AUB in the reproductive years to facilitate research, education, and clinical care. The systems were designed to be flexible and to be periodically reviewed and modified as appropriate. To review, clarify, and, where appropriate, revise the previously published systems. To a large extent, the process has been an iterative one involving the FIGO Menstrual Disorders Committee, as well as a number of invited contributions from epidemiologists, gynecologists, and other experts in the field from around the world between 2012 and 2017. Face-to-face meetings have been held in Rome, Vancouver, and Singapore, and have been augmented by a number of teleconferences and other communications designed to evaluate various aspects of the systems. Where substantial change was considered, anonymous voting, in some instances using a modified RAND Delphi technique, was utilized.
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.
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.
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.
Murcia Lora JM et al., 2018·Journal of Labor and Childbirth
Observational Study. The objective of the study was to contrast the evolution and progression of the viscoelasticity of the cervical secretion in the fertile window of ovulatory menstrual cycles compared with a software tool. 12 records obtained by vaginal discharge of the cervical secretion (VDRS) analyzed by means of the key filament of the Creighton Model Fertility (CrMS), and a computer software tool applied to the recognition of viscoelasticity. Peak day of cervical discharge “P” established as the estimated day of ovulation (EDO). The clinical window in this article was established as (mucus-mucus: CrMS/filancia) by retrospective evaluation of the aforementioned scale taking into account the previous 6 days at peak day: P (-6). The calculated fertile window was defined as (Soft-CrMS/filancia), which was obtained from an applied computer tool, (Soft-CrMS/filancia) was calculated without contributing EDO to the integration of the computer calculation. The verification and justification of the calculation of the fertile window was based on the analysis of the progression of the elasticity of the cervical secretion. The methodology used consisted of comparing the two fertile windows with EDO. To check the evolution in the characterization of the viscoelasticity parameter of cervical secretion, the last day of maximum fertility was established, with the letter “P” of peak day, according to the rules of recognition of the Peak day of CrMS. The fertile window was detected in 100% of the cases with both methods. A correlation coefficient of 0.71 was obtained, between the clinical fertile window detected by means of the parameter of viscoelasticity of the cervical secretion, and the prediction of viscoelasticity by means of a software computer tool. Analysis of the interval using SFW (Soft-CrMS / filance) showed a normal distribution with a mean of 5.08 (SD of + - 2.87). In this context, it is evident that as soon as the cervical mucus stretches more, and the elasticity increases, both the days before the peak day and the days after the vescoelasticity parameter it was possible to record it. Within another of the biophysical parameters, the characteristics of the last days of maximum fertility were taken into account through the concept of: Last Max Spinbarkheit (LMS) & Transparency by “K” of CrMS LMS The assessment of viscoelasticity using Spinbarkheit/ streching algoritm allowed in this pilot study to detect the fertile window, and to describe the evolutionary pattern of cervical discharge throughout the fertile window. The determination of the filancia and combination of transparency parameters may in conjunction detect by a clinical method to identify and describe the fertile window. The assessment of viscoelasticity using Spinbarkheit allowed in this pilot series to detect the fertile window in 100% of the cases, and it was possible to describe the evolutionary pattern of cervical secretion throughout the menstrual cycle. The fertile window interval can be observed with a 75% accuracy rate by viscoelasticity. The prediction in the progression of the elasticity pattern of the cervical secretion allows detecting the typical evolution of the cervical secretion in 70% around the peak day of ovulation. The determination of the filancia is a parameter that in conjunction with a clinical method can help to identify and characterize the fertile window.
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.
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.
The accuracy of prediction of ovulation by cycle apps and published calendar methods was determined by comparing to true probability of ovulation. A total of 949 volunteers collected urine samples for one entire menstrual cycle. Luteinizing hormone was measured to assign surge day, enabling probability of ovulation to be determined across different cycle lengths. Cycle-tracking apps were downloaded. As none provided their methodology, four published calendar-based methods were also examined: standard days, rhythm, alternative rhythm and simple calendar method. The volunteer ovulation data was applied to the app/calendar methods to determine their accuracy. Mean cycle length was 28 days (range: 23-35); 34% of women believed they had a 28-day cycle, but only 15% did. No LH surge was seen for 99 women. Most likely day of ovulation for a 28-day cycle was day 16 (21%). Accuracy of ovulation prediction was no better than 21% by the apps. The standard days and rhythm methods were most likely to predict ovulation (70% and 89%, respectively) but had very low accuracy. Ovulation day varies considerably for any given menstrual cycle length, thus it is not possible for calendar/app methods that use cycle-length information alone to accurately predict the day of ovulation. National Clinical Trial Code: NCT01577147. Registry website: www.clinicaltrials.gov .
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.
Bouchard TP et al., 2018·Front Med (Lausanne)·
Open Access
To determine the effectiveness of achieving pregnancy with focused intercourse in the fertile window identified using natural fertility indicators. 24-cycle prospective effectiveness study.
A North American web-based fertility monitoring service. 256 North American women aged 20-43 (mean age 29.2 years) seeking to achieve pregnancy. Participants identified their fertile window with either electronic hormonal fertility monitoring or cervical mucus monitoring, or both, and recorded their observations on an online fertility tracking system. Pregnancies were validated by nurses with an online self-assessed pregnancy evaluation form. Survival analysis was used to determine pregnancy rates. There were 150 pregnancies among the 256 participants with an overall pregnancy rate of 78 per 100 women over 12 menstrual cycles. There were 54 pregnancies (68%) among the 80 women using the fertility monitor, 11 pregnancies (46%) among the 24 women using mucus monitoring, and 90 (63%) among the 143 women using both mucus and monitor. The 12-cycle pregnancy rates per 100 women were 83 (monitor group), 72 (mucus group), and 75 (mucus and monitor group). Pregnancy rates reached 100% at 24 cycles of use for those women using the hormonal fertility monitor. Use of the hormonal fertility monitor alone seems to offer the best natural estimate of the fertile phase of the menstrual cycle for women wishing to achieve a pregnancy. Focusing intercourse through 24 menstrual cycles can be beneficial for achieving pregnancy.
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.
Metabolic and Endocrine Agents · GLP-1 Receptor Agonists
Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment. To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS. This is a 24-week open-label prospective, randomized, clinical study. This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 μg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks. After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05). Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.
Cerqueira RO et al., 2017·Archives of women's mental health
The objective of this study was to evaluate whether Vitex agnus castus is a safe and effective treatment for PMS and premenstrual dysphoric disorder (PMDD) and to discuss the implications of these findings for clinical practice. A systematic review of literature was conducted using PubMed and Scielo databases. The inclusion criteria were randomized controlled trials (RCT) using V. agnus castus in individuals with PMS or PMDD that compared this intervention with placebo or an active comparator and included a description of blinding and dropouts/withdrawals. The search was conducted by two independent investigators who reached consensus on the included trials. A total of eight RCTs were included in this study. Most studies focused on PMS, and the diagnostic criteria of PMS and PMDD changed over the years. Three different preparations of V. agnus castus (VAC) were tested, and there was significant variability in the measurement of treatment outcomes between the studies. Nevertheless, all eight studies were positive for VAC in the treatment of PMS or PMDD and VAC was overall well tolerated. Main limitations were differences in definition of diagnostic criteria, the instruments used as main outcome measures, and different preparations of VAC extracts limit the comparison of results between studies. In conclusion, the RCTs using VAC for treatment of PMS/PMDD suggested that the VAC extract is a safe and efficacious alternative to be considered for the treatment of PMS/PMDD symptoms.
Core and peripheral body temperatures are affected by changes in reproductive hormones during the menstrual cycle. Women worldwide use the basal body temperature (BBT) method to aid and prevent conception. However, prior research suggests that taking one's daily temperature can prove inconvenient and subject to environmental factors. We investigate whether a more automatic, non-invasive temperature measurement system can detect changes in temperature across the menstrual cycle. We examined how wrist skin temperature (WST), measured with wearable sensors, correlates with urinary tests of ovulation and may serve as a new method of fertility tracking. One hundred and thirty-six eumenorrheic, non-pregnant women participated in an observational study. Participants wore WST biosensors during sleep and reported their daily activities. An at-home luteinizing hormone (LH) test was used to confirm ovulation. WST was recorded across 437 cycles (mean cycles/participant = 3.21, S.D. = 2.25). We tested the relationship between the fertile window and WST temperature shifts, using the BBT three-over-six rule. A sustained 3-day temperature shift was observed in 357/437 cycles (82%), with the lowest cycle temperature occurring in the fertile window 41% of the time. Most temporal shifts (307/357, 86%) occurred on ovulation day (OV) or later. The average early-luteal phase temperature was 0.33°C higher than in the fertile window. Menstrual cycle changes in WST were impervious to lifestyle factors, like having sex, alcohol, or eating prior to bed, that, in prior work, have been shown to obfuscate BBT readings. Although currently costlier than BBT, the present study suggests that WST could be a promising, convenient parameter for future multiparameter fertility awareness methods.
Su HW et al., 2017·Bioengineering & translational medicine
The ability to identify the precise time of ovulation is important for women who want to plan conception or practice contraception. Here, we review the current literature on various methods for detecting ovulation including a review of point-of-care device technology. We incorporate an examination of methods to detect ovulation that have been developed and practiced for decades and analyze the indications and limitations of each-transvaginal ultrasonography, urinary luteinizing hormone detection, serum progesterone and urinary pregnanediol 3-glucuronide detection, urinary follicular stimulating hormone detection, basal body temperature monitoring, and cervical mucus and salivary ferning analysis. Some point-of-care ovulation detection devices have been developed and commercialized based on these methods, however previous research was limited by small sample size and an inconsistent standard reference to true ovulation.
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).
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.
NaProTECHNOLOGY is a new field of medicine specializing in the promotion of human procreation. Its foundation is a teaching system called the Creighton Model Fertility Care System. It is based on the ability to observe and record biological biomarkers, enabling spouses to recognize and understand the naturally occurring cycle of fertility and infertility. The spouses can use their acquired knowledge both for achiving pregnancy and avoiding pregnancy. The system also enables them to broaden their knowledge to better understand sexuality and deepen their mutual love. It also plays an important role in diagnosing and treating reproductive health according to the natural cycle of women. NaProTECHNOLOGY is involved in building a "new culture of life" through integral concern for human fertility by restoring natural procreation and respecting the principles of responsible parenthood.
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.
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.
Background/aims: To estimate the prevalence of diagnosed endometriosis (DE) in women in the United States and assess the associated symptomatic burden. An online, cross-sectional survey of women aged 18-49 years was conducted from August 6, 2012, through November 14, 2012. Survey data (weighted by age, race, education, income, geographical distribution, and propensity score) were used to estimate the prevalence and symptomatic burden of DE in women in the United States. Weighted logistic regressions were used to assess differences in symptom burden between women with and without endometriosis. The prevalence of DE was estimated at 6.1% (2,922 of 48,020 women surveyed); 52.7% of women were 18-29 years of age when they were diagnosed with endometriosis. Most (86.2%) women experienced symptoms before diagnosis. More women with (vs. without) DE had menstrual pelvic pain/cramping (52.7 vs. 45.2%), non-menstrual pelvic pain/cramping (36.7 vs. 14.3%), infertility (11.6 vs. 3.4%), and dyspareunia (29.5 vs. 13.4%). Women with endometriosis were also more likely to report severe symptoms (OR (95% CI) 2.7 (2.3-3.1) for menstrual pelvic pain/cramping, 2.2 (1.7-2.9) for non-menstrual pelvic pain/cramping, and 2.4 (1.8-3.2) for dyspareunia). The prevalence of DE among US women is notable, and affected women experience a substantial symptom burden.
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.
Various fertility indicators are used by natural family planning methods to identify the fertile and infertile phases of a woman's menstrual cycle: mucus observations, cycle-day probabilities, basal body temperature readings, and hormonal measures of LH and estrogen. Simplified NFP methods generally make use of a single fertility indicator such as cycle-day probabilities (Standard Days Method) or mucus observations (Billings Ovulation Method). The Couple Bead Method integrates the two simplest fertility indicators, cycle-day probabilities and mucus observations, expanding its applicability to all women, regardless of cycle regularity and length. In determining cycle-day probabilities, the Couple Bead Method relies on a new data set from ultrasound-derived determinants of gestational age that more directly define the day of conception and the fertile window. By using a visual-based system of inexpensive colored beads, the Couple Bead Method can be used by couples of all educational and income levels. Lay Natural family planning methods provide education in regard to the signs of a woman's body which indicate if she is possibly fertile or not. Two important signs are the day of her menstrual cycle and her observations of bleeding and cervical mucus or dryness. The Couple Bead Method teaches a couple how to observe these signs and chart them with a system of colored beads. The Couple Bead Method can be used by women with regular or irregular cycles. The bead sets are inexpensive and consist of a length of plastic cord, colored "pony beads" and safety pins.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Insulin resistance (IR) plays a pivotal role in PCOS. Insulin-sensitizer agents such as metformin and inositols have been shown to improve the endocrine and metabolic aspects of PCOS. The purpose of this study is to compare their effects on the clinical and metabolic features of the women with PCOS. Fifty PCOS women with IR and/or hyperinsulinemia were randomized to treatment with metformin (1500 mg/day) or myo-inositol (4 g/day). IR was defined as HOMA-IR >2.5, while hyperinsulinemia was defined as a value of AUC for insulin after a glucose load over the cutoff of our laboratory obtained in normal women. The Matsusa Index has been calculated. The women have been evaluated for insulin secretion, BMI, menstrual cycle length, acne and hirsutism, at baseline and after 6 months of therapy. The results obtained in both groups were similar. The insulin sensitivity improved in both treatment groups. The BMI significantly decreased and the menstrual cycle was normalized in about 50% of the women. No significant changes in acne and hirsutism were observed. The two insulin-sensitizers, metformin and myo-inositol, show to be useful in PCOS women in lowering BMI and ameliorating insulin sensitivity, and improving menstrual cycle without significant differences between the two treatments.
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.
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.
Purdue-Smithe AC et al., 2016·The American journal of clinical nutrition·
Open Access
Clinically significant premenstrual syndrome (PMS) affects 15-20% of premenopausal women, substantially reducing quality of life. Women with PMS often are counseled to minimize caffeine intake, although only limited evidence supports this recommendation. We evaluated the association between total caffeine, coffee, and tea intake and the development of PMS in a case-control study nested within the prospective Nurses' Health Study II. All participants were free from PMS at baseline (1991). PMS cases reported a new clinician-made diagnosis of PMS on biennial questionnaires between 1993 and 2005, and then confirmed symptom timing and moderate-to-severe impact and severity of symptoms with the use of a retrospective questionnaire (n = 1234). Controls did not report PMS and confirmed experiencing no symptoms or few mild symptoms with limited personal impact (n = 2426). Caffeine, coffee, and tea intake was measured by food-frequency questionnaires every 4 y, and data on smoking, body weight, and other factors were updated every 2-4 y. Logistic regression was used to evaluate the associations of total caffeine intake and frequency of coffee and tea consumption with PMS. After adjustment for age, smoking, and other factors, total caffeine intake was not associated with PMS. The OR comparing women with the highest (quintile median = 543 mg/d) to the lowest (quintile median = 18 mg/d) caffeine intake was 0.79 (95% CI: 0.61, 1.04; P-trend = 0.31). High caffeinated coffee intake also was not associated with risk of PMS or specific symptoms, including breast tenderness (OR for ≥4 cups/d compared with <1/mo: 0.73; 95% CI: 0.48, 1.12; P-trend = 0.44). Our findings suggest that caffeine intake is not associated with PMS, and that current recommendations for women to reduce caffeine intake may not help prevent the development of PMS.
Polycystic ovary syndrome is the most common endocrinopathy among reproductive-aged women in the United States, affecting approximately 7% of female patients. Although the pathophysiology of the syndrome is complex and there is no single defect from which it is known to result, it is hypothesized that insulin resistance is a key factor. Metabolic syndrome is twice as common in patients with polycystic ovary syndrome compared with the general population, and patients with polycystic ovary syndrome are four times more likely than the general population to develop type 2 diabetes mellitus. Patient presentation is variable, ranging from asymptomatic to having multiple gynecologic, dermatologic, or metabolic manifestations. Guidelines from the Endocrine Society recommend using the Rotterdam criteria for diagnosis, which mandate the presence of two of the following three findingshyperandrogenism, ovulatory dysfunction, and polycystic ovaries-plus the exclusion of other diagnoses that could result in hyperandrogenism or ovulatory dysfunction. It is reasonable to delay evaluation for polycystic ovary syndrome in adolescent patients until two years after menarche. For this age group, it is also recommended that all three Rotterdam criteria be met before the diagnosis is made. Patients who have marked virilization or rapid onset of symptoms require immediate evaluation for a potential androgen-secreting tumor. Treatment of polycystic ovary syndrome is individualized based on the patient's presentation and desire for pregnancy. For patients who are overweight, weight loss is recommended. Clomiphene and letrozole are first-line medications for infertility. Metformin is the first-line medication for metabolic manifestations, such as hyperglycemia. Hormonal contraceptives are first-line therapy for irregular menses and dermatologic manifestations.
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.
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.
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.
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.
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.
Daily JW et al., 2015·Pain medicine (Malden, Mass.)
There has been no attempt to date to synthesize the available evidence for the efficacy of ginger for treating primary dysmenorrhea. This systematic review evaluates the current evidence for the effectiveness of ginger for treating primary dysmenorrhea. Literature searches were conducted using 12 electronic databases including PubMed, EMBASE, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were: "ginger" or "Zingiber officinale" and "dysmenorrhea" and "pain." Studies using ginger as a treatment of primary dysmenorrhea were considered for inclusion. The major outcome of primary dysmenorrhea was assessed using a pain visual analogue score (PVAS). Initial searches yielded 29 articles. Of these original results, seven met specific selection criteria. Four of the RCTs compared the therapeutic efficacy of ginger with a placebo during the first 3-4 days of the menstrual cycle and were included in the meta analysis. The meta-analysis of these data showed a significant effect of ginger in reducing PVAS in subjects having primary dysmenorrhea (risk ratio, -1.85; 95% CI of -2.87, -0.84, P = 0.0003). Six RCTs out of 7 exhibited low to moderate of risk of bias. Collectively these RCTs provide suggestive evidence for the effectiveness of 750-2000 mg ginger powder during the first 3-4 days of menstrual cycle for primary dysmenorrhea.
Guidelines by Clinical Area · Gynecologic Guidelines
Despite variations worldwide and within the U.S. population, median age at menarche has remained relatively stable-between 12 years and 13 years-across well-nourished populations in developed countries. Environmental factors, including socioeconomic conditions, nutrition, and access to preventive health care, may influence the timing and progression of puberty. A number of medical conditions can cause abnormal uterine bleeding, characterized by unpredictable timing and variable amount of flow. Clinicians should educate girls and their caretakers (eg, parents or guardians) about what to expect of a first menstrual period and the range for normal cycle length of subsequent menses. Identification of abnormal menstrual patterns in adolescence may improve early identification of potential health concerns for adulthood. It is important for clinicians to have an understanding of the menstrual patterns of adolescent girls, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate the adolescent girl patient. By including an evaluation of the menstrual cycle as an additional vital sign, clinicians reinforce its importance in assessing overall health status for patients and caretakers.
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.
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.
Fehring RJ et al., 2015·J Midwifery Womens Health·
The length of periodic abstinence, due to overestimation of the fertile phase of the menstrual cycle, is often a cause for dissatisfaction, discontinuation, and user error with natural family planning (NFP) methods. The objective of this research was to compare the length of required abstinence (ie, estimated fertility) and coital frequency between 2 NFP methods. This was an analysis of data from a 12-month prospective comparison study in which participants were randomized into either an electronic hormonal fertility monitor (EHFM) group or a cervical mucus monitoring (CMM) group-both of which included a fertility algorithm as a double check for the beginning and end of the estimated fertile window. The number of days of estimated fertility and coitus was extracted from each menstrual cycle of data, and t tests were used to compare the means of these 2 variables between the 2 NFP methods. The study involved 197 women (mean [SD] age 29.7 [5.4]) who used the EHFM to estimate the fertile window and 160 women (mean [SD] age 30.4 [5.3]) who used CMM to estimate the fertile window. They produced 1,669 menstrual cycles of data. After 12 months of use, the EHFM group had statistically fewer days of estimated fertility than the CMM group (mean [SD] days, 13.25 [2.79] vs 13.68 [2.99], respectively; t = 2.07; P = .039) and significantly more coitus (mean [SD] coital acts, 4.22 [3.16] vs 4.05 [2.88], respectively; t = 1.17; P = .026). The use of the EHFM seems to provide more objectivity and confidence in self-estimating the fertile window and using nonfertile days for intercourse when avoiding pregnancy.
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.
Nikkhah S et al., 2015·Complementary therapies in clinical practice
Primary dysmenorrhea refers to painful menstrual cramps without pelvic pathology. The condition is highly prevalent among women and exerts negative effects on their quality of life. Considering the evidence for anti-inflammatory properties of Boron, the present study aimed to determine the effects of Boron supplementation on the severity and duration of menstrual pain in female university students. This triple-blind randomized clinical trial study recruited 113 university students. The participants were matched for the severity and duration of dysmenorrhea and randomly allocated into the case and control groups (n = 58 and 55, respectively). The case group consumed 10 mg/day Boron from two days before the menstrual flow until its third day. The control group received placebo capsules (similar to those distributed among the cases). All subjects were asked to take the capsules for two consecutive menstrual cycles. Pain severity (measured on a visual analog scale) and duration (in hours) were measured at baseline and during the two cycles. The two groups had no significant differences in the severity and duration of pain at baseline. After the intervention, however, the severity and duration of pain were significantly lower in the case group than in the control group (P < 0.05). Based on our findings, Boron supplementation can reduce the severity and duration of menstrual pain through exerting anti-inflammatory effects. In order to clarify the effects of Boron on dysmenorrhea, future studies are required to measure the levels of hormones and inflammatory biomarkers.
Ovulation occurs on 1 day during each menstrual cycle (even if multiple follicles are involved), and the several days preceding ovulation are when intercourse is most likely to result in pregnancy. Collectively, the potentially fertile days up to and including the day of ovulation are called the “fertile window” (1). Since the 1930s, several biomarkers of the fertile window have been investigated for the purposes of empowering women and couples seeking to use fertility-awareness based methods or natural family planning to avoid pregnancy, as well as to expand understanding of human reproductive physiology.
To assess the sensitivity and specificity of the self-identified fertile window. Observational study. Not applicable. PATIENT(S): A total of 107 women. INTERVENTION(S): Women recorded cervical mucus observation and basal body temperature daily while undergoing daily ovarian ultrasound. MAIN OUTCOME MEASURE(S): The biological fertile window, defined as the 6 days up to and including the day of ovulation; and the 2-day ovulation window, defined as the day before and the day of ovulation. RESULT(S): The self-identification of the biological fertile window by the observation of any type of cervical mucus provides 100% sensitivity but poor specificity, yielding a clinical fertile window of 11 days. However, the identification of the biological fertile window by peak mucus (defined as clear, slippery, or stretchy mucus related to estrogen) yielded 96% sensitivity and improved specificity. The appearance of the peak mucus preceded the biological fertile window in less than 10% of the cycles. Likewise, this type of mucus identified the ovulation window with 88% sensitivity. CONCLUSION(S): These results suggest that, when perceived accurately, more accurate clinical self-detection of the fertile window can be obtained by identification of peak mucus. This may improve efforts to focus intercourse in the fertile phase for couples with fertility concerns.
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?
Iacovides S et al., 2015·Human reproduction update
Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea. Comprehensive literature searches on primary dysmenorrhea were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts published between the years 1944 and 2015 were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. In combination with the word 'dysmenorrhea' one or more of the following search terms were used to obtain articles published in peer-reviewed journals only: pain, risk factors, etiology, experimental pain, clinical pain, adenomyosis, chronic pain, women, menstrual cycle, hyperalgesia, pain threshold, pain tolerance, pain sensitivity, pain reactivity, pain perception, central sensitization, quality of life, sleep, treatment, non-steroidal anti-inflammatory drugs. Women with dysmenorrhea, compared with women without dysmenorrhea, have greater sensitivity to experimental pain both within and outside areas of referred menstrual pain. Importantly, the enhanced pain sensitivity is evident even in phases of the menstrual cycle when women are not experiencing menstrual pain, illustrating that long-term differences in pain perception extend outside of the painful menstruation phase. This enhanced pain sensitivity may increase susceptibility to other chronic pain conditions in later life; dysmenorrhea is a risk factor for fibromyalgia. Further, dysmenorrheic pain has an immediate negative impact on quality of life, for up to a few days every month. Women with primary dysmenorrhea have a significantly reduced quality of life, poorer mood and poorer sleep quality during menstruation compared with their pain-free follicular phase, and compared with the menstruation phase of pain-free control women. The prescribed first-line therapy for menstrual pain remains non-steroidal anti-inflammatory drugs, which are effective in relieving daytime and night-time pain. Further study is needed to determine whether effectively blocking dysmenorrheic pain ameliorates risk for the development of chronic pain disorders and to explore whether it is possible to prevent the development-and not just treat-severe dysmenorrheic pain in adolescent girls. In conclusion, we demonstrate the extensive multi-factorial impact of dysmenorrhea and we encourage and direct researchers to necessary future studies.
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.
Balık G et al., 2014·Journal of Pediatric and Adolescent Gynecology
Menstrual problems are common among adolescent females. Mood changes are related to menstrual problems (menorrhagia, dysmenorrhea, and abnormal menstrual cycle length). The aim of this study was to determine the relationship between depressive symptoms, anxiety, and premenstrual syndrome (PMS) with dysmenorrhea in adolescent girls. A total of 159 adolescent girls (aged 13-19 y) with regular menstrual cycles presenting to the gynecology clinic with any complaints were included in the study during April-May 2013. All of the participants filled up the sociodemographic data collection form, FACES Pain Rating Scale, Beck anxiety inventory (BAI), Beck depression inventory (BDI), and a questionnaire form on criteria for PMS. Mann-Whitney U and chi-square tests were used to analyze the data. The prevalence of dysmenorrhea was 67.9%. The mean BAI and BDI scores of the patients were 13.64 ± 12.81 and 11.88 ± 10.83, respectively. Statistically significant differences were observed between patients and control groups on the BAI and BDI scoring (P < .05). At least 1 of the symptoms of the PMS was detected in all of the participants and 29 (18.2%) of them were diagnosed as premenstrual dysphoric disorder (PMDD). The mean BAI score of the patients with PMS and PMDD were 9.65 ± 9.28 and 21.31 ± 15.75, respectively. The mean BDI score of the patients with PMS and PMDD were 8.39 ± 8.62 and 19.1 ± 11.85, respectively. Statistically significant differences were observed between PMS/PMDD and BAI/BDI scoring (P = .00). Adolescent girls with dysmenorrhea have an increased risk of depression and anxiety. These results of our study are significant in emphasizing the importance of a multidisciplinary approach to primary dysmenorrhea follow-up and treatment.
Fertility awareness based methods (FABMs) can be used to ameliorate the likelihood to conceive. A literature search was performed to evaluate the relationship of cervical mucus monitoring (CMM) and the day-specific -pregnancy rate, in case of subfertility. A MEDLINE search revealed a total of 3331 articles. After excluding articles based on their relevance, 10 studies and were selected. The observed studies demonstrated that the cervical mucus monitoring (CMM) can identify the days with the highest pregnancy rate. According to the literature, the quality of the vaginal discharge correlates well with the cycle-specific probability of pregnancy in normally fertile couples but less in subfertile couples. The results indicate an urgent need for more prospective randomised trials and -prospective cohort studies on CMM in a subfertile population to evaluate the effectiveness of CMM in the subfertile couple.
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.
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.
The purpose of this study was to assess the prevalence of endometriosis in women with premenstrual spotting and to determine the predictive value of this symptom in the diagnosis of endometriosis. We conducted a retrospective cohort study of 80 consecutive women who presented to the infertility clinic for evaluation and who subsequently underwent laparoscopic assessment for infertility with or without pelvic pain. Our main outcome measure was the presence or absence of histologically confirmed endometriosis in women with and without premenstrual spotting. Endometriosis was significantly more prevalent in subfertile women who reported premenstrual spotting for ≥2 days relative to women without this symptom (89% [34/38 women] vs 26% [11/42 women]; P < .0001). Multinomial logistic regression analysis demonstrated the presence of premenstrual spotting for ≥2 days to be associated significantly with the presence of endometriosis (odds ratio, 16; 95% confidence interval, 3.9-65.4; P < .01) and red vesicular lesion type (odds ratio, 52.6; 95% confidence interval, 8.6-323.1; P < .001). In this cohort of women with infertility, premenstrual spotting of ≥2 days was associated strongly with histologically confirmed endometriosis and a better predictor than dysmenorrhea or dyspareunia of finding endometriosis at laparoscopy. Premenstrual spotting of at least 2 days was also associated strongly with both higher stage disease and the red vesicular peritoneal endometriosis phenotype.
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.
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.
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.
Porucznik CA et al., 2014·BMC Womens Health·
Open Access
Transient exposures may influence fertility and early embryonic development. To assess the time of conception in vivo and conduct concurrent biomonitoring, ovulation must be identified prospectively. We report on the development and validation of a simple, prospective method, the Peak Day method, to determine likely day of ovulation based upon daily observations of cervical fluid. We recruited 98 women to learn the Peak Day method from a brochure, 26 of whom concurrently used the method with blinded daily urine hormone monitoring (estrone glucuronide and luteinizing hormone). All women were instructed to complete an exposure questionnaire immediately upon identifying ovulation. Briefly, the exposure questionnaire captured time-varying and transient exposures such as medication use, water consumption, and amount of sleep. We assessed timely completion of the exposure questionnaire, agreement of women's estimated day of ovulation (EDO) and the EDO by expert review, and agreement between the EDO by expert review and by blinded urine monitoring. Of 147 cycles evaluated, women selected an EDO in 130 (88%) and subsequently completed the periovulatory exposure questionnaire in 122 (94%) cycles. Of the 26 cycles evaluated with blinded hormonal monitoring, the Peak Day "best quality" algorithm, based upon cervical fluid, identified ovulation ± 3 days of the urine monitor in 24 cycles (92%). With simple written instructions, women can identify an estimated day of ovulation and perform periovulatory exposure assessment. The Peak Day method is highly cost-effective and could be applied by researchers to target periconceptional or very early developmental stage exposure assessment.
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.
To compare pregnancy rates when women have intercourse on self-estimated high and peak fertile days and when they only have intercourse on low fertile days during the fertile window (FW). We used a prospective observational cohort study design. Our convenience sample included 124 women who utilized our online charting Web sites to achieve pregnancy from January 2010 to November 2012. Participants used an electronic hormonal fertility monitor (EHFM) or self-observed cervical mucus or both to determine fertility during the estimated FW. Pregnancy rates were determined with Kaplan-Meier survival analysis. Chi square analysis was used to evaluate the efficacy of achieving pregnancy between two different intercourse patterns. The pregnancy rate was 87 per 100 women at 12 months when intercourse happened on high or peak days and 5 per 100 when intercourse occurred only on low days of the FW. Chi square analysis showed a greater proportion of pregnancies with intercourse on high and peak fertile days of the menstrual cycle (x2 = 40.2, p < .001, df = 1). NURSING Focusing intercourse on high or peak fertile days during the estimated FW enhances the probability of achieving a desired pregnancy. Fertility awareness-based online charting system is effective in helping women to determine their FW and target intercourse accordingly to achieve pregnancy.
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.
L’auto-osservazione e il follow-up grafico del ciclo mestruale in caso di presunta sterilita, aiutano a diagnosticare e trattare certe alterazioni ginecologiche, al fine di attuare il rapporto sessuale finalizzato ad ottimizzare concepimento. Attraverso queste procedure naturali (naprotecnologia), prive di aspetti negativi da un punto di vista etico, possiamo ottenere tassi di natalita che sono paragonabili, o addirittura superiori, a quelle ottenute con trattamenti invasivi. ---------- Self-observation and the graphic follow-up of the menstrual cycle in cases of supposed infertility, help to diagnose and treat certain gynaecological alterations in order to carry out the sexual intercourse focused on optimising conception. Through these natural procedures (Naprotechnology), with no ethical drawbacks, we can obtain birth rates that are comparable, or even higher, to those obtained with invasive treatments.
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.
To assess the use of cervical mucus monitoring (CMM) in women trying to conceive and determine whether monitoring is associated with increased cycle-specific probability of conception (fecundability). Time-to-pregnancy cohort study. Population-based cohort. PATIENT(S): Three hundred thirty-one women trying to conceive, ages 30 to 44 years, without known infertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CMM prevalence and fecundability. RESULT(S): During the first cycle of the study, CMM was performed consistently (checked on >66% of pertinent cycle days) by 20 women (6%), inconsistently (34% to 66% of days) by 60 women (18%), infrequently (≤33% of days) by 73 women (22%), and not performed by 178 women (54%). Cycles in which CMM was consistently performed were statistically significantly more likely to result in conception after adjusting for age, race, previous pregnancy, body mass index, intercourse frequency, and urinary luteinizing hormone (LH) monitoring. Fecundability also increased with increasing consistency of CMM. CONCLUSION(S): Among women trying to conceive, CMM is uncommon, but our study suggests that CMM-a free, self-directed method to determine the fertile window-is associated with increased fecundability independent of intercourse frequency or use of urinary LH monitoring.
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.
Hansen SO et al., 2013·Eur J Obstet Gynecol Reprod Biol·
To review the literature on the effects of diet on endometriosis and dysmenorrhoea. A systematic search for trials investigating a relationship between diet and endometriosis/dysmenorrhoea was undertaken, and 23 studies were included in this review. Data on the relationship between diet and endometriosis were limited to 12 trials, three of which were animal studies, resulting in a total of 74,708 women. One large study (n=70,709) found a relatively strong association between endometriosis and trans-fatty acid consumption, and a lower risk of endometriosis with increased consumption of long-chain omega-3 fatty acids. The latter finding was also supported by smaller studies. No further dietary recommendations for reducing the risk of endometriosis were possible, and results for intake of vegetable, fibre and fruit were equivocal. The relationship between diet and dysmenorrhoea was investigated in 11 trials with different designs, including a total of 1433 women. Intake of fish oil seemed to reduce dysmenorrhoea. The literature on endometriosis and dysmenorrhoea in relation to diet is sparse, yielding equivocal results on specific elements. Overall, however, the literature suggests that specific types of dietary fats are associated with endometriosis and/or dysmenorrhoea, thereby indicating that there may be modifiable risk factors. Further research is recommended on both subjects.
Guidelines by Clinical Area · Gynecologic Guidelines
Initial evaluation of the patient with acute abnormal uterine bleeding should include a prompt assessment for signs of hypovolemia and potential hemodynamic instability. After initial assessment and stabilization, the etiologies of acute abnormal uterine bleeding should be classified using the PALM-COEIN system. Medical management should be the initial treatment for most patients, if clinically appropriate. Options include intravenous conjugated equine estrogen, multi-dose regimens of combined oral contraceptives or oral progestins, and tranexamic acid. Decisions should be based on the patient's medical history and contraindications to therapies. Surgical management should be considered for patients who are not clinically stable, are not suitable for medical management, or have failed to respond appropriately to medical management. The choice of surgical management should be based on the patient's underlying medical conditions, underlying pathology, and desire for future fertility. Once the acute bleeding episode has been controlled, transitioning the patient to long-term maintenance therapy is recommended.
In the last 50 years, a surge of reproductive technology has revolutionized the practice of obstetrics and gynecology. First, effective hormonal contraceptives were made available to the public in the 1960s and, since their debut, have been used to treat almost every gynecologic abnormality [1]. Second, in the past 30 years, infertility has largely been managed using assisted reproductive technologies (ART), primarily intrauterine insemination (IUI) with recourse to in vitro fertilization (IVF) when insemination fails [2]. As a result, the modus operandi in mainstream gynecology has been to suppress, or to bypass, the woman’s fertility cycle.
Physicians and patients who (1) conscientiously object to the therapeutic use of hormonal contraceptives on the grounds that it subjects patients to ineffective treatment of symptoms rather than treating their underlying disease and (2) morally oppose the ART approach to infertility on the grounds that it jettisons a loving act of marital intercourse, the one context worthy of the conception of a new human being, are now able to pursue an alternative approach that accords with their consciences. NaProTECHNOLOGY (an acronym for natural procreative technology) is a woman’s health science that encompasses a unique medical and surgical application of gynecology. The foundation of NPT is the Creighton Model FertilityCare System (CrMS), see Figure 1, the only prospective and standardized means of monitoring the various patterns of a woman’s menstrual and fertility cycle for the natural regulation of fertility.
For example, because it views infertility as a symptom rather than a disease, NPT seeks to diagnose and treat the underlying causes of infertility so that the couple can more successfully conceive within their own acts of intercourse, especially during peak-day-focused intercourse. NPT infertility protocols depend on patient-specific charting data. Some observations during the fertility cycle—dry, limited, or continuous mucus; short or variable post-peak phase; premenstrual spotting or tail-end brown bleeding—are external signs of possible underlying disease processes.
A medical interpretation of these abnormal CrMS observations leads to a targeted biochemical and hormonal evaluation, which in turn identifies target organ dysfunctions: decreased production of estrogenic cervical mucus, intermenstrual bleeding or spotting, short or variable luteal phases, and suboptimal levels of the ovarian hormones (estrogen or progesterone). Common treatments for these pathologies include induction or stimulation of ovulation, medications to enhance cervical mucus, and hormonal support in the luteal phase. When these NPT medical approaches to infertility were used in a study of 1,239 infertile couples, they resulted in a live birth rate similar to that of cohort ART treatments [3].
In many cases, medical applications of NPT are sufficient to treat infertility successfully; in other cases, surgical intervention is also required. Surgical NPT is a specialized form of gynecologic surgery the primary aim of which is to reconstruct the uterus, fallopian tubes, and ovaries. The ovarian wedge resection (surgical removal of a portion of an enlarged ovary to restore its normal size), for example, is effective in healing polycystic ovaries (contributing to the long-term treatment of some of the endocrine and menstrual cycle abnormalities associated with polycystic ovaries). It also brings the patient a 70 percent chance of pregnancy i.e., it is twice as effective as clomiphene [4].
A significant benefit of surgical NaProTECHNOLOGY is “near adhesion-free” surgery. One of the biggest pitfalls of surgery, of course, is the formation of postoperative adhesions, which can decrease tubal motility (adversely affecting fertility) and cause small bowel obstructions (that frequently require emergency reoperation) [5]. To prevent these complications, NPT surgical techniques pay meticulous attention to detail, take a systematic approach, and use Gore-Tex adhesion barriers [6]. Published Gore-Tex protocols reveal a statistically significant decrease in subsequent adhesion scores on second-look laparoscopy [7]. For some reason, the use of Gore-Tex has been overlooked in even the most recent adhesion prevention reviews [8]. One even laments that adhesion prevention is a “surprisingly neglected aspect of the treatment of endometriosis,” but the reviewers make no mention of the use of Gore-Tex as an adhesion barrier.
Other techniques of surgical NPT include laser vaporization and pelvic excision and repair surgery (PEARS) of peritoneal or ovarian endometriosis. PEARS is a form of plastic reconstructive surgery of the pelvis with the primary intent of removing diseased tissue within the pelvic organs and repairing organs in a way that does not form pelvic adhesions. PEARS can entail robot-assisted laparoscopy or laparotomy, minimizing postoperative adhesions and optimizing the patient’s chances for pregnancy.
The effectiveness of treating infertility with medical and surgical NPT is comparable to that of ART interventions. The cumulative live birth rate in patients receiving IVF is between 45-55% [10]. In a study population of 1,045 patients treated with NPT infertility protocols, more than 60 percent became pregnant within 24 months and nearly 70 percent within 36 months [11]. The overall �per-woman� NPT pregnancy rate is higher than that of ART due, in part, to the high rate of dropout or discontinuation in patients who undergo IVF treatment [12]. In addition, a meta-analysis comparing conventional surgery and IVF for treatment of endometriosis-related infertility found that the per-woman pregnancy rates with surgery were 55.3 percent while those with IVF were 9.9 percent [13]. However, while it is true patients treated with NPT have significantly lower overall fecundability (a 3.13 percent chance of conceiving within a given period) than those treated with IVF (13.3 percent), it is also true that the number of women who ultimately achieve a pregnancy with NPT is higher than the number who get pregnant using ART [14]. Thus, although achieving a live birth with NPT may take longer, it has a greater chance of occurring than with IVF.
For those interested in training in NPT, the Pope Paul VI Institute and Creighton University School of Medicine offer educational programs for those in primary care or ob/gyn (including fourth-year medical students) to train in the medical applications of NaProTECHNOLOGY [15]. They also offer a 1-year fellowship in the surgical applications of NPT for ob/gyns who have completed their residencies [16].
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.
The postpartum period is a challenging time for family planning, especially for women who breastfeed. Breastfeeding delays the return of menses (lactational amenorrhea), but ovulation often occurs before first menses. For this reason, a protocol was developed to assist women in identifying their return of fertility postpartum to avoid pregnancy. In this prospective, 12-month, longitudinal cohort study, 198 postpartum women aged 20 to 45 years (mean age, 30.2 years) were taught a protocol for avoiding pregnancy with either online or in-person instruction. A hand-held fertility monitor was used to identify the fertile period by testing for urinary changes in estrogen and luteinizing hormone, and the results were tracked on a web site. During lactational amenorrhea, urine testing was done in 20-day intervals. When menses returned, the monitor was reset at the onset of each new menstrual cycle. Participants were instructed to avoid intercourse during the identified fertile period. Kaplan-Meier survival analysis was used to calculate unintentional pregnancy rates through the first 12 months postpartum. There were 8 unintended pregnancies per 100 women at 12 months postpartum. With correct use, there were 2 unintended pregnancies per 100 women at 12 months. The online postpartum protocol may effectively assist a select group of women in avoiding pregnancy during the transition to regular menstrual cycles.
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.
Natural family planning methods provide a unique option for committed couples. Advantages include the lack of medical adverse effects and the opportunity for participants to learn about reproduction. Modern methods of natural family planning involve observation of biologic markers to identify fertile days in a woman's reproductive cycle. The timing of intercourse can be planned to achieve or avoid pregnancy based on the identified fertile period. The current evidence for effectiveness of natural family planning methods is limited to lower-quality clinical trials without control groups. Nevertheless, perfect use of these methods is reported to be at least 95 percent effective in preventing pregnancy. The effectiveness of typical use is 76 percent, which demonstrates that motivation and commitment to the method are essential for success. Depending on the method, couples can learn about natural family planning methods in a single office visit, through online instruction, or from certified instructors.
The Standard Days Method (SDM) is a method of family planning that assumes ovulation to be close to the midpoint of the menstrual cycle; fertility falls between days 8 and 19; and is most effective for cycle lengths between twenty-six and thirty-two days. The purpose of this study was to evaluate the assumptions of the SDM with a new data set of 714 menstrual cycles produced by 131 women (mean age twenty-nine) who tracked their fertility with an electronic fertility monitor that measured urinary estrogen and luteinizing hormone (LH). The LH peak was used to estimate the day of ovulation (EDO) and the six-day fertile window. Results indicated the majority (80 percent) of menstrual cycles had EDOs within three days of the midpoint of the cycle (86 percent with cycle lengths between twenty-six and thirty-two days). Approximately 22.5 percent (172) of the cycles had fertile window days outside of days 8 to 19, 10.2 percent (78) before, and 12.1 percent (92) after. However, there is a low probability of pregnancy when women experience short cycles and the early days of the fertile window are outside of days 8 through 19. We concluded assumptions of the SDM outside of the fertile window with long cycles could be problematic. However, the SDM is valid for women who have most cycles within the twenty-six to thirty-two day range.
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.
The UNDP/WHO/World Bank/Special Programme of Research, Development and Research Training in Human Reproduction (Geneva) set up a study to determine whether it is feasible for women to monitor their ovarian activity reliably by home testing. Daily self-monitoring of urinary hormone metabolites for menstrual cycle assessment was evaluated by comparison of results obtained with the Home Ovarian Monitor by untrained users both at home and in study centres. Women collected daily data for urinary estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) for two cycles, then the procedure was repeated in the women's local centre (in Chile, Australia or New Zealand) giving a total of 113 duplicate cycles. The tests were performed without the benefit of replicates or quality controls. The home and centre cycles were normalized and compared to identify assay errors, and the resulting home and centre menstrual cycle profiles were averaged. Reliable mean cycle profiles were obtained with the home and centre excretion rates agreeing to within 36 ± 21 nmol/24 h for E1G and 0.77 ± 0.28 µmol/24 h for baseline PdG values (1-5 µmol/24 h). The cycles had a mean length of 28.1 ± 3.1 days (n = 112; 5th and 95th percentiles: 24 and 35 days, respectively), a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th percentiles: 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n = 106; 5th and 95th percentiles: 11 and 17 days), calculated from the day of the LH peak. The study confirmed that the Ovarian Monitor pre-coated assay tubes worked well even in the hands of lay users, without standard curves, quality controls or replicates. Point-of-care monitoring to give reliable fertility data is feasible.
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.
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.
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.
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.
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.
Diagnostic Criteria and Classification · Staging and Classification Systems
Munro MG et al., 2011·International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
There is general inconsistency in the nomenclature used to describe abnormal uterine bleeding (AUB), in addition to a plethora of potential causes-several of which may coexist in a given individual. It seems clear that the development of consistent and universally accepted nomenclature is a step toward rectifying this unsatisfactory circumstance. Another requirement is the development of a classification system, on several levels, for the causes of AUB, which can be used by clinicians, investigators, and even patients to facilitate communication, clinical care, and research. This manuscript describes an ongoing process designed to achieve these goals, and presents for consideration the PALM-COEIN (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified) classification system for AUB, which has been approved by the International Federation of Gynecology and Obstetrics (FIGO) Executive Board as a FIGO classification system.
To estimate, from the literature, when nonlactating postpartum women regain fertility. We searched PubMed and Cochrane Library databases for all articles (in all languages) published in peer-reviewed journals from database inception through May 2010 for evidence related to the return of ovulation and menses in nonlactating postpartum women. Search terms included "Fertility" (Mesh) OR "Ovulation" (Mesh) OR "Ovulation Detection" (Mesh) OR "Ovulation Prediction" (Mesh) OR fertility OR ovulat* AND "Postpartum Period" (Mesh) OR postpartum OR puerperium AND Human AND Female. We included articles assessing nonlactating women's first ovulation postpartum. Studies in which women breastfed for any period of time or in whom lactation was suppressed with medications were excluded. TABULATION, We identified 1,623 articles; six articles reported four studies met our inclusion criteria. In three studies utilizing urinary pregnanediol levels to measure ovulation, mean day of first ovulation ranged from 45 to 94 days postpartum; 20%-71% of first menses were preceded by ovulation and 0%-60% of these ovulations were potentially fertile. In one study that used basal body temperature to measure ovulation, mean first ovulation occurred on day 74 postpartum; 33% of first menses were preceded by ovulation and 70% of these were potentially fertile. Most nonlactating women will not ovulate until 6 weeks postpartum. A small number of women will ovulate earlier, potentially putting them at risk for pregnancy sooner, although the fertility of these early ovulations is not well-established. The potential risk of pregnancy soon after delivery underscores the importance of initiating postpartum contraception in a timely fashion.
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.
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.
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.
Bremer AA, 2010·Metab Syndr Relat Disord·
Open Access
Polycystic ovary syndrome (PCOS) is a common disorder characterized by hyperandrogenism and disordered gonadotropin secretion, often associated with insulin resistance. The syndrome, which modulates both hormonal and metabolic processes, is the most common endocrinopathy in reproductive-age women and increases a woman's risk of infertility, endometrial pathology, and cardiometabolic disease. As it is currently defined, PCOS most likely encompasses several distinct diseases with similar clinical phenotypes but different underlying pathophysiological processes. However, hyperandrogenism remains the syndrome's clinical hallmark. The clinical manifestations of PCOS often emerge during childhood or in the peripubertal years, suggesting that the syndrome is influenced by fetal programming and/or early postnatal events. However, given that the full clinical spectrum of PCOS does not typically appear until puberty, a "two-hit" hypothesis has been proposed: (1) a girl develops hyperandrogenism via one or more of many different potential mechanisms; (2) the preexisting hyperandrogenism subsequently disturbs the hypothalamic–pituitary–ovarian axis, resulting in ovulatory dysfunction and sustained hyperandrogenism. No consensus guidelines exist regarding the diagnosis and management of PCOS in the pediatric population; however, because the syndrome is a diagnosis of exclusion, the clinical evaluation of girls suspected of having PCOS is aimed at excluding other causes of androgen excess and menstrual dysfunction. For the syndrome's management, emphasis is placed on lifestyle and symptom-directed treatment.
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.
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.
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
Reproductive Immunology · Autoimmune Conditions and Fertility
Celiac disease is an intestinal inflammatory disease that is triggered by gluten in the diet. Patients present with a wide array of symptoms due to malabsorption that include diarrhea, abdominal pain, bloating and weight loss. In women, this disease may have implications on menstrual and reproductive health. The symptom complex includes delayed menarche, early menopause, secondary amenorrhea, infertility, recurrent miscarriages and intrauterine growth restriction. These women benefit from early diagnosis and treatment. Therefore, celiac disease should be considered and screening tests performed on women presenting with menstrual and reproductive problems and treated accordingly. The objective of this article is to review the current literature on celiac disease and its association with the above-mentioned disorders.
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.
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.
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.
Wong CL et al., 2009·Cochrane Database of Systematic Reviews·
Open Access
Dysmenorrhoea (painful menstrual cramps) is common. Combined OCPs are recommended in the management of primary dysmenorrhoea. To determine the effectiveness and safety of combined oral contraceptive pills for the management of primary dysmenorrhoea. We conducted electronic searches for randomised controlled trials (RCTs) in the Cochrane Menstrual Disorders and Subfertility Group Register of controlled trials CENTRAL, CCTR, MEDLINE, EMBASE, and CINAHL (first conducted in 2001, updated on 5 November 2008). RCTs comparing all combined OCPs with other combined OCPs, placebo, no management, or management with nonsteroidal anti-inflammatories (NSAIDs) were considered. One study of low dose oestrogen and four studies of medium dose oestrogen combined OCPs compared with placebo, for a combined total of 497 women, reported pain improvement. For the outcome of pain relief across the different OCPs the pooled OR suggested benefit with OCPs compared to placebo (7 RCTs: Peto OR 2.01 [95% CI 1.32, 3.08]). The Chi-squared test for heterogeneity showed there is significant heterogeneity. A sensitivity analysis removing the studies with inadequate allocation concealment suggested significant benefit of treatment with the pooled OR of 2.99 (95% CI 1.76, 5.07). AUTHORS' There is limited evidence for pain improvement with the use of the OCP (both low and medium dose oestrogen) in women with dysmenorrhoea. There is no evidence of a difference between different OCP preparations.
Dynamic latent class models provide a flexible framework for studying biologic processes that evolve over time. Motivated by studies of markers of the fertile days of the menstrual cycle, we propose a discrete-time dynamic latent class framework, allowing change points to depend on time, fixed predictors, and random effects. Observed data consist of multivariate categorical indicators, which change dynamically in a flexible manner according to latent class status. Given the flexibility of the framework, which incorporates semi-parametric components using mixtures of betas, identifiability constraints are needed to define the latent classes. Such constraints are most appropriately based on the known biology of the process. The Bayesian method is developed particularly for analyzing mucus symptom data from a study of women using natural family planning.
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.
Bedford JL et al., 2009·Eur J Obstet Gynecol Reprod Biol·
To assess computerised least-squares analysis of quantitative basal temperature (LS-BT) against urinary pregnanediol glucuronide (PdG) as an indirect measure of ovulation, and to evaluate the stability of LS-QBT to wake-time variation. Cross-sectional study of 40 healthy, normal-weight, regularly menstruating women aged 19-34. Participants recorded basal temperature and collected first void urine daily for one complete menstrual cycle. Evidence of luteal activity (ELA), an indirect ovulation indicator, was assessed using Kassam's PdG algorithm, which identifies a sustained 3-day PdG rise, and the LS-QBT algorithm, by determining whether the temperature curve is significantly biphasic. Cycles were classified as ELA(+) or ELA(-). We explored the need to pre-screen for wake-time variations by repeating the analysis using: (A) all recorded temperatures, (B) wake-time adjusted temperatures, (C) temperatures within 2h of average wake-time, and (D) expert reviewed temperatures. Relative to PdG, classification of cycles as ELA(+) was 35 of 36 for LS-QBT methods A and B, 33 of 34 (method C) and 30 of 31 (method D). Classification of cycles as ELA(-) was 1 of 4 (methods A and B) and 0 of 3 (methods C and D). Positive predictive value was 92% for methods A-C and 91% for method D. Negative predictive value was 50% for methods A and B and 0% for methods C and D. Overall accuracy was 90% for methods A and B, 89% for method C and 88% for method D. The day of a significant temperature increase by LS-QBT and the first day of a sustained PdG rise were correlated (r=0.803, 0.741, 0.651, 0.747 for methods A-D, respectively, all p<0.001). LS-QBT showed excellent detection of ELA(+) cycles (sensitivity, positive predictive value) but poor detection of ELA(-) cycles (specificity, negative predictive value) relative to urinary PdG. Correlations between the methods and overall accuracy were good and similar for all analyses. Findings suggest that LS-QBT is robust to wake-time variability and that expert interpretation is unnecessary. This method shows promise for use as an epidemiological tool to document cyclic progesterone increase. Further validation relative to daily transvaginal ultrasound is required.
Bromer JG et al., 2009·Fertility and sterility·
Open Access
To evaluate proliferative phase endometrial development in a heterogeneous infertility population. Retrospective study. University-based infertility practice. PATIENT(S): Two hundred forty-six treatment cycles. INTERVENTION(S): Clomiphene citrate or FSH ovarian stimulation, followed by IUI or IVF. MAIN OUTCOME MEASURE(S): Endometrial thickness according to transvaginal ultrasonography; clinical pregnancy rate. RESULT(S): Endometrial growth began from a nadir of approximately 4.5 mm on cycle day 4 and increased linearly to a plateau of approximately 10 mm on cycle day 9. This same pattern was observed in all cycles, regardless of pregnancy, drug, or underlying diagnosis. Follicle-stimulating hormone-stimulated cycles showed a significantly increased endometrial thickness compared with clomiphene citrate cycles (10.1 vs. 8.3 mm). Maximum endometrial thickness achieved showed a correlation with age, body mass index, and maximum E(2) level. Subjects who carried a primary diagnosis of polycystic ovary syndrome, endometriosis, or recurrent pregnancy loss all achieved a significantly lower peak endometrial thickness than control subjects. There was a trend toward increased endometrial thickness in cycles resulting in pregnancy compared with those not (10.1 vs. 9.6 mm, respectively). CONCLUSION(S): Endometrial development follows a predictable pattern, with a plateau in growth at cycle day 9. Diseases associated with infertility manifest a proliferative phase defect that can be recognized clinically.
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.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
Ozgoli G et al., 2009·Journal of alternative and complementary medicine (New York, N.Y.)
To compare the effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea. This was a double-blind comparative clinical trial conducted from September 2006 to February 2007. Participants were 150 students (18 years old and over) with primary dysmenorrhea from the dormitories of two medical universities who were alternately divided into three equal groups. Students in the ginger group took 250 mg capsules of ginger rhizome powder four times a day for three days from the start of their menstrual period. Members of the other groups received 250 mg mefenamic acid or 400 mg ibuprofen capsules, respectively, on the same protocol. A verbal multidimensional scoring system was used for assessing the severity of primary dysmenorrhea. Severity of disease, pain relief, and satisfaction with the treatment were compared between the groups after one menstruation. There were not significant differences between groups in baseline characteristics, p > 0.05. At the end of treatment, severity of dysmenorrhea decreased in all groups and no differences were found between the groups in severity of dysmenorrhea, pain relief, or satisfaction with the treatment, p > 0.05. No severe side effects occurred. Ginger was as effective as mefenamic acid and ibuprofen in relieving pain in women with primary dysmenorrhea. Further studies regarding the effects of ginger on other symptoms associated with dysmenorrhea and efficacy and safety of various doses and treatment durations of ginger are warranted.
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.
Valeggia C et al., 2009·American journal of human biology : the official journal of the Human Biology Council
Lactation has long been recognized as a major determinant of interbirth intervals. The temporal pattern of nursing has been proposed as the mechanism behind lactational amenorrhea. We present a new model of the dynamic regulation of lactational amenorrhea that identifies maternal energy availability as the main determinant of ovarian resumption. Variation in the intensity of lactation remains a component of the model as a determinant of the absolute energetic cost of milk production. However, maternal energy supply determines net energy availability; a larger energy supply leaves a greater net energy surplus than a smaller energy supply (lactation costs being equal). We characterize the hormonal postpartum profile of 70 lactating Toba women of Argentina. We use C-peptide, which reflects maternal insulin production, as a measure of energy availability. Initially low, insulin production rises as the postpartum period progresses, reflecting the declining metabolic load of lactation. A short period of supernormal insulin production precedes menstrual resumption. The high levels of insulin may play a role in stimulating the resumption of ovarian activity, which in turn may help to resolve the transient period of insulin resistance. The dynamics of insulin sensitivity during lactation would aid in synchronizing the resumption of ovarian function with a reduction in the energy demands of milk production. This hypothesis is supported by the sustained weight gain experienced by lactating women during the months preceding the first postpartum menses. The link between fecundity and energy balance could serve as a mechanism for adjusting the duration of lactational amenorrhea to the relative metabolic load of lactation.
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.
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.
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.
Chavarro JE et al., 2007·Obstetrics and gynecology
To evaluate the relation of a dietary pattern and other lifestyle practices to risk of ovulatory disorder infertility. We followed a cohort of 17,544 women without a history of infertility for 8 years as they tried to become pregnant or became pregnant. A dietary score based on factors previously related to lower ovulatory disorder infertility (higher consumption of monounsaturated rather than trans fats, vegetable rather than animal protein sources, low glycemic carbohydrates, high fat dairy, multivitamins, and iron from plants and supplements) and other lifestyle information was prospectively related to the incidence of infertility. Increasing adherence to a "fertility diet" pattern was associated with a lower risk of ovulatory disorder infertility. The multivariable-adjusted relative risk of ovulatory disorder infertility comparing women in the highest with women in the lowest quintile of the "fertility diet" pattern score was 0.34 (95% confidence interval 0.23-0.48; P for trend<.001). This inverse relation was similar in subgroups defined by women's age, parity, and body weight. A combination of five or more low-risk lifestyle factors, including diet, weight control, and physical activity was associated with a 69% lower risk of ovulatory disorder infertility and an estimated population attributable risk of 66% (95% confidence interval 29-86%). Following a "fertility diet" pattern may favorably influence fertility in otherwise healthy women. Further, the majority of infertility cases due to ovulation disorders may be preventable through modifications of diet and lifestyle. II.
The period in each menstrual cycle during which sexual intercourse can result in conception is called the "fertile window". Although the fertile window closes on the day of ovulation, little is known about the moment it opens. We defined the first day of normal sperm-mucus interaction as the opening of the fertile window. We hypothesized that length of the fertile window varies between couples and that the number of days the fertile window is "open" is related to the time to spontaneous conception. METHODS Serial post-coital tests and sperm-mucus penetration tests were performed to detect the first normal sperm-mucus interaction day. Ovulation was confirmed by serial ultrasound. Using Cox' regression analysis, we determined whether the fertile window length was associated with time to ongoing pregnancy. This association was expressed in fecundability ratios (FR). RESULTS The fertile window length was determined in 410 subfertile couples. The fertile window length varied among couples from <1 to >5 days. The FR increased with increasing fertile window length and varied between 0.11 (95% CI: 0.03-0.45) for a fertile window of 1 day, to 2.4 (95% CI: 1.1-5.2) for a fertile window of 5 days or more. CONCLUSIONS The longer the fertile window in subfertile couples, the higher is the probability of spontaneously conceiving an ongoing pregnancy.
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.
Diagnostic Criteria and Classification · Terminology and Definitions
There is considerable worldwide confusion in the use of terminologies and definitions around the symptom of abnormal uterine bleeding (AUB), and these are leading increasingly to difficulties in setting up multinational clinical trials and in interpreting the results of studies undertaken in single centres. An international initiative was established to develop an agreement process to recommend clear, simple terminologies and definitions with the potential for wide acceptance. After widespread consultation with relevant international and national organizations, journal editors and individuals, a modified Delphi process was developed to assess the current use of terminologies followed by a structured face-to-face meeting of 35 clinicians (mostly gynaecologists) and scientists in Washington. Focused small group discussions led to plenary assessment of concepts and recommendations using an electronic keypad voting system. There was almost universal agreement that poorly defined terms of classical origin used in differing ways in the English medical language should be discarded and that these should be replaced by simple, descriptive terms with clear definitions which have the potential to be understood by health professional and patient alike and which can be translated into most languages. The major recommendations were to replace terms such as menorrhagia, metrorrhagia, hypermenorrhoea and dysfunctional uterine bleeding. Suggestions for potentially suitable replacement terms and definitions are made. A simple terminology has been recommended for the description and definition of symptoms and signs of AUB. This manuscript should be a living document and should be part of an ongoing process with international medical and community debate. Classification of causes, investigations and cultural and quality of life issues should be part of the ongoing process.
Chavarro JE et al., 2007·The American Journal of Clinical Nutrition
Pharmacologic activation of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) improves ovulatory function in women with polycystic ovary syndrome, and specific dietary fatty acids can affect PPAR-gamma activity. The objective of the study was to assess whether the intakes of total fat, cholesterol, and major types of fatty acids affect the risk of ovulatory infertility. We conducted a prospective cohort study of 18 555 married, premenopausal women without a history of infertility who attempted a pregnancy or became pregnant between 1991 and 1999. Diet was assessed twice during follow-up by using a food-frequency questionnaire. During follow-up, 438 incidents of ovulatory infertility were reported. In logistic regression analyses, intakes of total fat, cholesterol, and most types of fatty acids were not related to ovulatory infertility. Each 2% increase in the intake of energy from trans unsaturated fats, as opposed to that from carbohydrates, was associated with a 73% greater risk of ovulatory infertility after adjustment for known and suspected risk factors for this condition [relative risk (RR) = 1.73; 95% CI: 1.09, 2.73]. Obtaining 2% of energy intake from trans fats rather than from n-6 polyunsaturated fats was associated with a similar increase in the risk of ovulatory infertility (RR = 1.79; 95% CI: 1.11, 2.89). In addition, obtaining 2% of energy from trans fats rather than from monounsaturated fats was associated with a more than doubled risk of ovulatory infertility (RR = 2.31; 95% CI: 1.09, 4.87).Conclusiontrans Unsaturated fats may increase the risk of ovulatory infertility when consumed instead of carbohydrates or unsaturated fats commonly found in nonhydrogenated vegetable oils.
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 . . .
The concept of the ovarian cycle as a continuum considers that all types of ovarian activity encountered during the reproductive life are responses to different environmental conditions in order to ensure the health of the woman. During the normal ovulatory cycle, a series of sequential events have to occur in a highly synchronized manner. Fertility awareness is useful in helping women to identify the different stages of their reproductive life cycle. Fertility awareness is also a valuable tool in helping women to identify gynecological disorders. Persistence of irregularities within the mucus patterns and the menstrual cycle should be of concern to women presenting with these problems. These irregularities may be due to obstetrical, endocrine, gynecological or iatrogenic disorders. Insight into early pregnancy complications, ovulatory dysfunction and pelvic inflammatory disease can be ascertained from abnormalities within the menstrual cycle and mucus pattern. Thus, fertility awareness will also enable the recognition and early treatment of several metabolic, endocrine and infectious diseases.
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.
With the collaboration of Italian centres providing services on natural family planning, a prospective study collected data on 2755 menstrual cycles of 193 women. A database was constructed using information on the daily characteristics of cervical mucus and episodes of intercourse. Taking the day of peak mucus as a conventional marker of ovulation, the database identified the length (12 days) and location of a 'window' of potential fertility, the highest level of conception probability being confined to the central five to six days. Univariate analysis provided evidence of the impact on fecundability of the woman's age and the basic infertile pattern of a cycle. Several analytical approaches highlighted the relationship between daily mucus characteristics and levels of fecundability
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.
Barron ML et al., 2005·MCN Am J Matern Child Nurs·
Advanced practice nurses in primary care settings are often asked to give appropriate advice to couples seeking pregnancy. This article examines the issue of basal body temperature (BBT), a time-honored way to establish the presence of ovulatory cycles, and asks if BBT is an outdated recommendation. The article also reviews the benefits and limitations of recommending BBT to couples seeking pregnancy in light of recent fecundity research.
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.
The objective of the present paper is to review the main results of recent European cycle databases on ovulation detection and determination of the fertile window performed by the women themselves. The ongoing German Long-term Cycle Database currently comprises 32788 prospectively collected cycle charts of 1551 women, the I European Cycle Database (10 countries) 1328 women/19048 cycles, the II European Cycle Database (six countries) 782 women/6724 cycles, and the World Health Organization Database (one European country) 234 women/2808 cycles. The women record cycle parameters (cervical mucus changes, temperature rise, etc.), family planning intention and sexual behavior. With the symptothermal method of natural family planning it has become possible to determine the fertile window in order to avoid pregnancy with a method effectiveness of 0.3%. According to a small sub-study, the ovulation time observed by the women themselves correlates closely with ovulation detected by ultrasound and measurement of luteinizing hormone (correlation within 1 day in 89% of the 62 cycles). Fertility awareness methods can be integrated into the management of sub-fertility. They seem to shorten the time to pregnancy. Self-observation of the fertile window puts women into a position to develop a high level of reproductive competence that could be used much more in different areas than is currently the case.
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.
Calendar-based methods are not usually considered effective or useful methods of family planning among health professionals. However, new "high-" and "low"-tech calendar methods have been developed, which are easy to teach, to use, and may be useful in helping couples avoid pregnancy. The low-tech models are based on a fixed-day calendar system. The high-tech models are based on monitoring urinary metabolites of female reproductive hormones. Both systems have high levels of satisfaction. This article describes these new models of family planning and the research on their effectiveness. The author proposes a new algorithm for determining the fertile phase of the menstrual cycle for either achieving or avoiding pregnancy.
For many years, individual women and doctors have experimented with extending the duration of active oral contraceptive (OC) pills between pill-free intervals (long OC) to control menstruation. The U.S. approval of an OC with 84 active days and 7 pill-free days in 2003 has attracted considerable media attention. In this review we consider the published evidence on the effectiveness, side effects, and risks of menstrual suppression with long OC. We performed a systematic review of published literature on long OC, up to April 2003. Ten papers were located; two were randomized trials comparing long OC to standard OC; the remaining studies were single-group observational studies. Women on long OC schedules had fewer days of scheduled bleeding during days without pills but more days of unscheduled bleeding and spotting than those on standard OC. These problems were worse for women new to OC and diminished over time. Women on long OC were more likely to discontinue due to poor control of bleeding; women on standard OC were more likely to stop because of problems with headaches. Women on long OC and standard OC both showed increases in physiological factors related to clotting, with a nonsignificant tendency for those on long OC to be more affected. No studies considered the effects of long OC on breast tissue, breast density, endometrial safety, or adolescent maturation and reproductive development. No systematic data were available on the return to reproductive function and fertility after taking long OC. There were no placebo-controlled trials and no information on how long OC compares to normal, unmedicated menstrual cycles. Therefore we believe scientific evidence for safety of long OC use is presently lacking.
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.
The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.
Intercourse results in a pregnancy essentially only if it occurs during the 6-day fertile interval ending on the day of ovulation. The strong association between timing of intercourse within this interval and the probability of conception typically is attributed to limited sperm and egg life times. A total of 782 women recruited from natural family planning centres in Europe contributed prospective data on 7288 menstrual cycles. Daily records of intercourse, basal body temperature and vaginal discharge of cervical mucus were collected. Probabilities of conception were estimated according to the timing of intercourse relative to ovulation and a 1-4 score of mucus quality. There was a strong increasing trend in the day-specific probabilities of pregnancy with increases in the mucus score. Adjusting for the mucus score, the day-specific probabilities had limited variability across the fertile interval. Changes in mucus quality across the fertile interval predict the observed pattern in the day-specific probabilities of conception. To maximize the likelihood of conception, intercourse should occur on days with optimal mucus quality, as observed in vaginal discharge, regardless of the exact timing relative to ovulation.
Fehring RJ et al., 2004·Contraception·
Open Access
The purpose of this study was to compare the fertile phase of the menstrual cycle as determined by the Clearplan Easy Fertility Monitor (CPEFM) with self-monitoring of cervical mucus. One-hundred women (mean age = 29.4 years) observed their cervical mucus and monitored their urine for estrogen and luteinizing hormone metabolites with the CPEFM on a daily basis for 2-6 cycles and generated 378 cycles of data; of these, 347 (92%) had a CPEFM peak. The beginning of the fertile window was, on average, day 11.8 (SD = 3.4) by the monitor and day 9.9 (SD = 3.0) by cervical mucus (r = 0.43, p < 0.001). The average first day of peak fertility by the monitor was 16.5 (SD = 3.6) and by cervical mucus 16.3 (SD = 3.7) (r = 0.85, p < 0.001). The mean length of the fertile phase by the monitor was 7.7 days (SD = 3.1) and by cervical mucus 10.9 days (SD = 3.7) (t = 12.7, p < 0.001). The peak in fertility as determined by the monitor and by self-assessment of cervical mucus is similar but the monitor tends to underestimate and self-assessment of cervical mucus tends to overestimate the actual fertile phase.
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·
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·
This 2004 textbook chapter by Thomas W. Hilgers outlines the structure and content of the formal introductory session used to enroll couples in the Creighton Model FertilityCare System (CrMS). It covers the biological foundation of fertility charting, the role of cervical mucus as a biomarker of the reproductive cycle, and the educational framework designed to train couples in systematic, real-time cycle observation.
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·
NaProTECHNOLOGY uses the Peak Day of the Creighton Model chart — the last day of the most fertile-type cervical mucus — as the reference point for dating conception, providing a biologically grounded alternative to last menstrual period dating that remains accurate across irregular cycles. Precise cycle-based dating improves the clinical interpretation of early pregnancy hormone levels, ultrasound findings, and obstetric gestational age assignments, reducing unnecessary interventions triggered by apparent growth discordance.
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·
NaProTECHNOLOGY (Natural Procreative Technology) is defined as a women's health science that monitors and cooperates with the menstrual and fertility cycles to identify, evaluate, and treat gynecologic and reproductive disorders at their root cause. Unlike suppressive approaches such as hormonal contraception or ART, NaProTECHNOLOGY maintains procreative potential and treats underlying pathology while preserving the human ecology of reproduction.
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.
Stanford JB, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
The Mucus Cycle Score, derived from the standardized CrMS daily observations, quantifies cervical mucus quality and quantity across a cycle and correlates with measured estrogen levels and fecundity rates, providing a non-invasive index of reproductive potential. Declining mucus scores are clinically actionable, directing investigation into hypoestrogenism, cervical pathology, or medication effects that reduce cycle fecundity and can be corrected before ART is considered.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Serial transvaginal ultrasound monitoring of follicular dynamics -- growth, rupture, corpus luteum formation, and free fluid -- forms the basis of a systematic classification of human ovulation disorders, including anovulation, luteinized unruptured follicle (LUF), follicular arrest, premature luteinization, and PCOS-type patterns. Anchoring sonographic findings to the CrMS Peak day allows precise correlation between ultrasound events and cervical mucus biomarkers, creating a reproducible diagnostic taxonomy that drives targeted medical and surgical treatment within the NaProTECHNOLOGY framework.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Adaptations of CrMS instruction for physiologically distinct reproductive states — including breastfeeding, post-hormonal contraceptive use, long or irregular cycles, and premenopause — are described with specific observational guidance for each context. These special protocols extend the clinical reach of the CrMS to all phases of a woman's reproductive life and ensure that charting remains interpretable even when cycle dynamics are atypical.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
The Creighton Model's standardized daily vulvar observation system -- recording discharge color, consistency, quantity, and sensation -- allows chronic pathological discharges (persistent yellow or cloudy mucus, continuous post-Peak discharge, premenstrual brown bleeding, or refractory vulvovaginitis) to be distinguished from normal cyclical mucus patterns and tracked longitudinally as a diagnostic tool. NaProTECHNOLOGY uses chronic discharge patterns as biomarkers that prompt organism-specific cultures, targeted hormonal evaluation, ultrasound, and etiology-directed treatment -- including antimicrobials, cooperative hormone replacement, or fertility-sparing surgery -- rather than empirical cycle suppression.
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.
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·
The Creighton Model FertilityCare System (CrMS) is introduced as a standardized, scientifically grounded method for observing and recording cervical mucus biomarkers and bleeding patterns across the menstrual cycle. Its development from earlier natural family planning methods into a fully systematized fertility monitoring tool is traced, establishing the CrMS as the observational substrate for all subsequent NaProTECHNOLOGY medical applications.
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·
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·
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 et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Family physicians are optimally positioned to introduce NaProTECHNOLOGY to patients presenting with infertility, irregular cycles, or recurrent pregnancy loss during routine primary care, enabling early evaluation and restorative treatment before referral to subspecialists. Familiarity with CrMS charting interpretation, basic hormone panels timed to identified cycle phases, and the range of treatable NaPro diagnoses allows the family physician to substantially expand reproductive care at the primary care level.
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.
Hilgers TW et al., 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Pregnancy achievement rates among couples using the CrMS to target fertile days are analyzed by cycle type, reproductive history, and duration of use, demonstrating the system's capacity to accommodate irregular and abnormal cycles without reducing its fertility-targeting utility. These data are foundational to NaProTECHNOLOGY's application in infertility management, establishing that the CrMS identifies fertile windows even in subfertile populations with disrupted cycle parameters.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Ovarian cysts in NaProTECHNOLOGY are classified as functional (follicular cysts, luteinized unruptured follicle, corpus luteum cysts) or pathological (endometriomas, neoplasms) through serial cycle-timed transvaginal ultrasound correlated with CrMS Peak day observations and post-Peak progesterone and estradiol profiles. Management of functional cysts uses cooperative progesterone replacement and targeted HCG injections to normalize corpus luteum function and reduce cyst recurrence without contraceptive suppression, while pathological or persistent cysts are addressed through fertility-sparing laparoscopic surgery with anti-adhesion technique.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
A quantitative taxonomy for classifying the cervical mucus cycle is established, using standardized descriptors for mucus type, quantity, consistency, and Peak Day timing to produce objectively comparable cycle profiles across patients and study populations. This classification system is indispensable to NaProTECHNOLOGY research and clinical correlation, as it enables the linkage of specific mucus pattern anomalies to underlying endocrine pathology.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
The CrMS charting system is explained in full, including the stamp-based notation for recording mucus characteristics, bleeding, and dry days on the standardized chart, and the conventions for identifying the Peak Day. Accurate chart reading is the foundational clinical skill for NaProTECHNOLOGY practitioners, as the chart provides the biomarker timeline against which hormone profiles and pathology are interpreted.
Hilgers TW, 2004·The Medical and Surgical Practice of NaProTECHNOLOGY·
Women with persistent or continuous vaginal discharges — including those from chronic cervicitis, hormonal imbalance, or other gynecologic sources — present a distinct charting challenge, and this chapter provides CrMS-specific protocols for distinguishing pathologic discharge from fertile-quality cervical mucus. Correct identification is clinically critical because misclassification distorts cycle interpretation, effectiveness calculations, and the hormone-assessment timeline.
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.
Polycystic ovary syndrome (PCOS) affects about 4 to 6% of women of reproductive age and accounts for at least 75% of hyperandrogenic patients. PCOS is diagnosed by the presence of oligo-ovulation and hyperandrogenism after the exclusion of related disorders, such as 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH). In turn, NCAH is a homozygous recessive disorder, diagnosed by a corticotropin-stimulated 17-hydroxyprogesterone (17-HP) level greater than10 ng/mL (30.3 nmol/L) and confirmed by genotyping of the CYP21 gene. The prevalence of NCAH is approximately 50 times less than that of PCOS, affecting between 1 and 10% of hyperandrogenic women, depending on ethnicity. However, it is generally difficult to distinguish NCAH from PCOS solely on clinical grounds, as both demonstrate varying degrees of hyperandrogenism and ovulatory dysfunction. Most PCOS patients have insulin resistance, in contrast to those with NCAH. Likewise, polycystic ovaries are observed in up to 40% of NCAH patients. Both disorders have a strong familial component. The only method that allows the separation of NCAH from PCOS patients is the measurement of 17-HP levels. In conclusion, PCOS and NCAH have differences in prevalence and pathophysiology. However, because the disorders have significant clinical and hormonal similarities, the measurement of 17-HP, preferably basally as a screening method, should be incorporated into the evaluation of all hyperandrogenic patients.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. Systematic review and meta-analysis. Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.
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.
Measurement and Statistics · Instrument Development and Validation
A study was conducted to determine the accuracy and reliability of the Home Ovarian Monitor for measuring estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) during ovulatory cycles as a means of monitoring ovarian activity. Approximately 60 ovulating women in three centres collected timed specimens of urine (3h or more) for a total of six cycles each. The women measured the E1G and PdG excretion per 24h in their urine specimens using the Monitor. A local laboratory using the Monitor also measured the excretion. Urine specimens from 18 to 19 cycles were sent frozen to the WHO Reference Laboratory in London where they were analysed for E1G and PdG by the Monitor and by radioimmunoassay (RIA). The correlation coefficients between the Monitor and radioimmunoassay results obtained in London were better than 0.84 in 80% of the cycles. A urine bias caused the Monitor E1G results to be higher than those obtained by radioimmunoassay but the daily patterns were the same. In 50% of the cycles, this bias caused a delay of up to 3 days in identifying the beginning of the E1G rise compared with radioimmunoassay. Timing of the preovulatory E1G peak and the postovulatory PdG rise agreed within the experimental errors of the two systems. The study confirmed that women using the Monitor at home obtained results that were as accurate as those obtained by laboratory procedures. Careful supervision was required to maintain laboratory levels of quality control and interpretation of results.
To assess the day-specific and cycle-specific probabilities of conception leading to clinical pregnancy, in relation to the timing of intercourse and vulvar mucus observations. This was a retrospective cohort study of women beginning use of the Creighton Model Fertility Care System in Missouri, Nebraska, Kansas, and California. Data were abstracted from Creighton Model Fertility Care System records, including women's daily standardized vulvar observations of cervical mucus discharge, days of intercourse, and clinically evident pregnancy (conception). Established statistical models were used to estimate day-specific probabilities of conception. Data were analyzed from 1681 cycles with 81 conceptions from 309 normally fertile couples (initially seeking to avoid pregnancy) and from 373 cycles with 30 conceptions from 117 subfertile couples (who were initially trying to achieve pregnancy). The highest probability of pregnancy occurred on the peak day of vulvar mucus observation (.38 for normally fertile couples and.14 for subfertile couples). The probability of pregnancy was greater than.05 for normally fertile couples from 3 days before to 2 days after the peak, and for subfertile couples from 1 day before to 1 day after the peak. The cycle-specific probability of conception correlated with the quality of mucus discharge in normally fertile couples but not in subfertile couples. Standardized vulvar observations of vaginal mucus discharge identify the days with the greatest likelihood of conception from intercourse in normal fertility and subfertility and provide an indicator of the overall potential for conception in a given menstrual cycle in normal fertility.
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.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
To review the effectiveness of metformin in restoring regular menstrual cycles and ovulation and achieving pregnancy in women with polycystic ovary syndrome (PCOS). Systematic review of pertinent studies identified using the bibliographic databases MEDLINE and EMBASE. References of selected articles identified were hand-searched for additional relevant citations. PATIENT(S): Women with PCOS undergoing treatment with metformin alone, metformin combined with other methods of ovulation induction such as clomiphene citrate (CC) or gonadotropin injections, or metformin combined with in vitro fertilization (IVF). RESULT(S): Thirty published studies were included in the overall review. Studies consisted of 12 randomized controlled trials, two cohort studies, and 16 uncontrolled descriptive studies. Due to a strong variability in the use of metformin according to study population, exposure, and outcome of interest, it was not possible to combine the data of the 12 randomized controlled trials to perform a meta-analysis. Limited data on predominately obese PCOS patients demonstrate that metformin alone improves both restoration of regular menses and spontaneous ovulation, but there are no data supporting an improvement in pregnancy rate. The addition of metformin to CC results in an improved ovulation and pregnancy rate in both unselected and CC-resistant PCOS women. There are insufficient data to make any conclusions on the effect of metformin on FSH ovulation induction or IVF. CONCLUSION(S): The effectiveness and role of metformin in the treatment of PCOS anovulatory infertility in clinical practice is difficult to assess from currently available research. Further well-designed prospective, perhaps multicenter, randomized controlled trials with the primary end point of pregnancy or live-birth rate are required.
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.
Physicians who counsel women for preconception concerns are in an excellent position to give advice to couples regarding the optimal timing of intercourse to achieve pregnancy. The currently available evidence suggests that methods that prospectively identify the window of fertility are likely to be more effective for optimally timing intercourse than calendar calculations or basal body temperature. There are several promising methods with good scientific bases to identify the fertile window prospectively. These include fertility charting of vaginal discharge and a commercially available fertility monitor. These methods identify the occurrence of ovulation clinically and also identify a longer window of fertility than urinary luteinizing hormone kits. Prospectively identifying the full window of fertility may lead to higher rates of conception. Proper information given early in the course of trying to achieve pregnancy is likely to reduce time to conception for many couples, and also to reduce unnecessary intervention and cost.
The (PD) peak day of cervical mucus is an important biologic marker for the self-determination of the optimal time of fertility in a woman's menstrual cycle. The purpose of this article is to provide evidence (literature and empiric) for the accuracy of the PD of cervical mucus as a biologic marker of peak fertility and the estimated day of ovulation. An analysis of data from four published studies that compared the self-determination of the PD of cervical mucus with the urinary luteinizing hormone (LH) surge was conducted. The four studies yielded 108 menstrual cycle charts from 53 women participants. The 108 cycles ranged in length from 22 to 75 days (mean 29.4 SD 6.0). Ninety-three of the 108 cycles had both an identified PD and LH surge. Data charts showed that 97.8% of the PD fell within +/-4 days of the estimated day of ovulation. Use of a standardized mucus cycle scoring system indicated that the peak in cervical mucus ratings was highest on the day of the LH surge. Self-determination of the PD of cervical mucus is a very accurate means of determining peak fertility and a fairly accurate means of determining the day of ovulation and the beginning of the end of the fertile time.
This multicenter study has produced a database of 7017 menstrual cycles contributed by 881 women. It provides improved knowledge on length and location of the "fertile window" (identified as of up to 12 days duration) and the patterns and level of daily conception probability. The day of ovulation was identified in each cycle from records of basal body temperature and mucus symptoms. By referencing days of intercourse to the surrogate ovulation markers, estimates of daily fecundability were computed either directly or by the Scwartz model, both for single and multiple acts of intercourse in the fertile window. The relationship between coital pattern and fecundability has been explored. Univariate analysis underlines the significant link with fecundability only of the woman's reproductive history.
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.
Measurement and Statistics · Instrument Development and Validation
To assess the reliability and factor structure of the Calendar of Premenstrual Experiences (COPE) in premenstrual syndrome (PMS) patients. Healthy women diagnosed with PMS (N = 215) completed daily diaries assessing 22 PMS behavioral and physical symptoms over two consecutive months. Internal consistency (alpha) was high (.93-.94) for the COPE total score and behavioral subscale score and moderately high (.79) for the physical subscale score. Test-retest correlations produced lower estimates of reliability (.55-.59). Four factors, accounting for 64% of the total variance, were extracted: mood symptoms, somatic/cognitive symptoms, appetitive symptoms and fluid retention symptoms. Symptom reports increased in consecutive luteal phases for three of the four factors; however, the factor structure remained consistent in consecutive months. The COPE diary is a reliable instrument for identifying fluctuations in behavioral and physical symptoms during the luteal phase, and PMS symptoms can be reliably conceptualized within four factors. Symptom expression may increase in response to daily self-monitoring.
Most analyses of age-related changes in fertility cannot separate effects due to reduced frequency of sexual intercourse from effects directly related to ageing. Information on intercourse collected daily through each menstrual cycle provides the data for estimating day-specific probabilities of pregnancy for specific days relative to ovulation, and these estimates allow unconfounded analysis of ageing effects. A total of 782 healthy couples using natural family planning methods contributed prospective data on 5860 menstrual cycles. Day of ovulation was based on basal body temperature measurements. Estimates of day-specific probabilities of pregnancy and the length of the fertile window were compared across age groups. Nearly all pregnancies occurred within a 6 day fertile window. There was no evidence for a shorter fertile window in older men or women. On average, the day-specific probabilities of pregnancy declined with age for women from the late 20s onward, with probabilities of pregnancy twice as high for women aged 19-26 years compared with women aged 35-39 years. Controlling for age of the woman, fertility was significantly reduced for men aged >35 years. Women's fertility begins to decline in the late 20s with substantial decreases by the late 30s. Fertility for men is less affected by age, but shows significant decline by the late 30s.
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.
To determine whether a new monophasic oral contraceptive containing drospirenone/ethinyl estradiol reduces premenstrual symptoms. In an open-label study measuring intrasubject changes in premenstrual symptoms and comparing effects between women who were new users of oral contraceptives and those who switched from previous contraceptives, ethinyl estradiol (30 micrograms) and drospirenone (3 mg) were administered for 13 menstrual cycles to 326 healthy women aged 18-35 years. Subjects completed the 23-item Women's Health Assessment Questionnaire at baseline and at the end of the sixth cycle. At the end of cycle 6, premenstrual and menstrual symptom scores on the negative affect and water retention scales were reduced significantly relative to baseline, as was increased appetite during the premenstrual and menstrual phases. Similar improvements were seen among new users of hormonal contraceptives and those who switched from previous contraceptives. Impaired concentration scale scores were not significantly reduced from baseline, and assessments of undesired hair changes and feelings of well-being did not change appreciably. An oral contraceptive containing drospirenone/ethinyl estradiol may reduce the premenstrual symptoms of negative affect, water retention and increased appetite.
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.
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 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.
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.
To compare clinical accuracy and ease of use for several of the new rapid one-step home urinary LH detection kits compared with the preexisting OvuQuick brand LH detection kit (designated as the standard).
Prospective cohort study.
University-based infertility clinic. PATIENT(S): All women undergoing intrauterine inseminations at the clinic, regardless of infertility diagnosis, were offered enrollment during a 28-month study period. INTERVENTION(S): Each participant was supplied three one-step test kits (OvuQuick One-Step, ClearPlan Easy, and SureStep) in addition to a multistep OvuQuick test kit and instructed to run the tests in parallel on the same urine sample and to record the results. Urine testing was performed every 12 hours, beginning 3 days before the anticipated onset of an LH surge, and continued with the one-step kits every 12 hours for 48 hours after the surge was first detected by OvuQuick. Subjects also completed questionnaires evaluating the use of each test kit. MAIN OUTCOME MEASURE(S): Correlation of LH surge detection by one-step kits in comparison to surge detection by OvuQuick. Satisfaction and ease of use questionnaires. RESULT(S): Sixty-three volunteers returned useable data, from which 81 evaluable cycles were analyzed. The majority of patients found the newer one-step kits to be easier to use and less time consuming than OvuQuick. The three one-step kits detected the LH surge within +/- one testing period (+/-12 hours) of detection by OvuQuick 68%-84% of the time. OvuQuick One-Step, with modified instructions allowing for an equal color intensity in the test and reference areas, had the highest correlation with OvuQuick (84%). However, with a study power (alpha = 0.05, beta = 0.10) sufficient to detect a 10% difference between Ovuquick and each one-step kit, all one-step kits were statistically equivalent to each other. There was no cycle in which a one-step kit detected a positive LH surge but OvuQuick did not. CONCLUSION(S): One-step urinary LH kits are easier for patients to use than a multistep home urinary LH kit and have reasonable correlation with the multistep kit when used clinically for timing artificial inseminations.
To evaluate whether some ultrasound parameters of ovarian morphology can discriminate between control women and patients with polycystic ovary syndrome (PCOS). Retrospective data analysis. Volunteers women in an academic research environment. PATIENT(S): Eighty amenorrheic or oligomenorrheic women and 30 normal ovulatory control participants. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We evaluated ovarian volume, area, stroma, and the stroma/total area (S/A) ratio by use of transvaginal pelvic ultrasound; and we assayed serum levels of gonadotropin, androgen, and estradiol during the early follicular phase (days 2 to 5) of the menstrual cycle in regularly cycling controls and on a random day in amenorrheic patients. RESULT(S): Patients with PCOS showed significantly higher ovarian volume, area, stroma, and mean S/A ratio when compared to multifollicular and control groups. Cut-off values have been defined for ovarian volume (13.21 mL), area (7.00 cm2), stroma (1.95 cm2), and S/A ratio (0.34). The sensitivity for PCOS diagnosis was 21%, 4%, 62%, and 100%, respectively. The S/A ratio showed the most significant correlation with the androgen levels. CONCLUSION(S): The evaluation of the S/A ratio can differentiate between PCOS and control or multifollicular women with both a sensitivity and a specificity of 100%. Furthermore, this ultrasound parameter is strictly related to hormonal milieu and to anthropometric characteristics.
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.
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 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.
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 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.
Measurement and Statistics · Instrument Development and Validation
To assess the reliability of the most widely used clinical methods for predicting or confirming ovulation. We monitored spontaneous cycles in 101 infertile women using basal body temperature (BBT), transvaginal ultrasound, a urinary stick system for LH surge, and three serum progesterone measurements in the midluteal phase. Transvaginal ultrasound monitoring was standard for ovulation detection and sensitivity. We calculated specificity and accuracy of each method compared with that standard. Follicular development and ultrasound evidence of ovulation were confirmed in 97 of 101 cycles (96%). Urinary LH surge preceded follicular rupture assessed by ultrasonography in all cycles and showed concordance with ultrasound-evidenced ovulation in 98 of 101 cases. The timing of BBT nadir had wide variability, and BBT and ultrasonography agreed in a similar percentage of cases (74%). Midluteal serum progesterone assessments showed ovulatory values in 93 subjects, and ovulation was concordant with ultrasonography in 90 subjects. Urinary LH was accurate in predicting ovulation with ultrasonography as the standard for detection, but time varied widely. The nadir of BBT predicted ovulation poorly. The BBT chart was less accurate for confirming ovulation, whereas a single serum progesterone assessment in midluteal phase seemed as effective as repeated serum progesterone measures.
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.
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.
Selective serotonin-reuptake inhibitors (SSRIs) are increasingly being used as first-line therapy for severe premenstrual syndrome (PMS). We undertook a meta-analysis on the efficacy of SSRIs in this disorder. We searched medical and scientific databases, approached pharmaceutical companies, and reviewed citations of relevant articles to identify 29 studies of the use of SSRIs in PMS. 14 were excluded (no placebo group, preliminary report of included trial, or low quality). 15 randomised placebo-controlled trials were included. Information on study design, participants, drugs used and dosing regimens, outcome measures, side-effects, and sources of funding was extracted. Standardised mean differences between treatment and placebo groups were calculated to obtain an overall estimate of efficacy. The primary outcome measure was a reduction in overall PMS symptoms. The primary analysis included data on 904 women (570 assigned active treatment and 435 assigned placebo, including 101 in crossover trials). The overall standardised mean difference was -1.066 (95% CI -1.381 to -0.750), which corresponds to an odds ratio of 6.91 (3.90 to 12.2) in favour of SSRIs. SSRIs were effective in treating physical and behavioural symptoms. There was no significant difference in symptom reduction between continuous and intermittent dosing or between trials funded by pharmaceutical companies and those independently funded. Withdrawal due to side-effects was 2.5 times more likely in the active-treatment group than in the placebo group. SSRIs are an effective first-line therapy for severe PMS. The safety of these drugs has been demonstrated in trials of affective disorder, and the side-effects at low doses are generally acceptable.
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.
A significant number of women worldwide use periodic abstinence as their method of family planning. Many of them use some type of calendar-based approach to determine when they should abstain from unprotected intercourse to avoid pregnancy; yet they often lack correct knowledge of when during their menstrual cycle they are most likely to become pregnant. A simple method of natural family planning (NFP) based on a fixed formula to define the fertile window could be useful to these women. This article reports the results of an analysis of the application of a fixed formula to define the fertile window. A large existing data set from a World Health Organization study of the Ovulation Method was used to estimate the theoretical probability of pregnancy using this formula. Information about the variable probability of pregnancy on different cycle days relative to ovulation also was considered in the analysis. Results suggest that a fixed formula in which days 8-19 of the menstrual cycle are considered to be the fertile window would provide the appropriate basis of a simple, effective, family planning method.
The Polycystic Ovary Disease (PCOD) is one of the most common endocrine disorders in women with a prevalence of 5%. Affected women often consult a gynecologist because of menstrual irregularities, fertility problems or problems of androgen excess. However, PCOD is a metabolic disorder affecting multiple organs. Studies suggest that those women are at risk for developing several complications such as type II diabetes mellitus, hypertension, dyslipidemia and myocardial infarction. The risk to develop endometrial carcinoma is also elevated. To give adequate treatment to women with PCOD, an interdisciplinary approach of gynecologists together with endocrinologists specialized in metabolic and nutritional disorders at the University of Basel is presented. The work-up for diagnosis and assessment of risk factors is outlined. Goal of this interdisciplinary approach is an adequate evaluation of affected patients and their long-term follow-up to test if proposed interventions as weight loss, treatment of hyperinsulinemia, regulation of menstrual cycle and others can avoid long-term sequelae.
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.
A previously undescribed cause of abnormal uterine bleeding is presented. Nine of 310 women evaluated by sonohysterography for abnormal bleeding demonstrated an 8 to 17 mm gap in the anterior lower uterine segment myometrium at the site of prior cesarean deliveries. All women were premenopausal and had a history of 2 to 12 days of postmenstrual spotting. Presumably a lack of coordinated muscular contractions occurs around the cesarean scar, allowing the defect to collect menstrual debris. Subsequently, the debris leaches out through the cervix for several days after the majority of menstrual flow has ceased.
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.
Small hand-held microscopes have been developed for self-observation of salivary ferning patterns to detect the fertile time of a woman's menstrual cycle. The purpose of this study was to evaluate one such microscope, the Lady Free Biotester, by comparing it with the self-observation of cervical-vaginal mucus and with the self-detection of luteinizing hormone (LH) in the urine. Twelve natural family planning teachers (average age 34.6 years) observed their cervical-vaginal mucus, tested their urine for LH, and observed salivary and cervical-vaginal mucus ferning patterns (with the Lady Free Biotester) for two menstrual cycles. Data indicated that there was a strong correlation between the LH in the urine and the peak in self-observed cervical-vaginal mucus ferning (r = 0.99, p < or = 0.001) and salivary ferning (r = 0.98, p < or = 0.001). However, it was difficult to assess the beginning and end of the fertile time based on the salivary ferning patterns. Further testing of salivary ferning patterns is recommended before widespread use of these devices for family planning.
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.
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.
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.
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.
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.
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 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.
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.
Cancer and Fertility · Fertility Preservation Before Treatment
The purpose of this study was to compare the CUE Ovulation Predictor with the ovulation method in determining the fertile period. Eleven regularly ovulating women measured their salivary and vaginal electrical resistance (ER) with the CUE, observed their cervical-vaginal mucus, and measured their urine for a luteinizing hormone (LH) surge on a daily basis. Data from 21 menstrual cycles showed no statistical difference (T = 0.33, p = 0.63) between the CUE fertile period, which ranged from 5 to 10 days (mean = 6.7 days, SD = 1.6), and the fertile period of the ovulation method, which ranged from 4 to 9 days (mean = 6.5 days, SD = 2.0). The CUE has potential as an adjunctive device in the learning and use of natural family planning methods.
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.
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.
To investigate whether luteal and endometrial abnormalities occur more frequently in an infertile population and thus contribute to infertility. Prospective controlled clinical study. Outpatient clinic in an academic research institution. Thirty-three fertile controls and 31 infertile women without ovulatory disorders, tubal disease, or male factors. All women underwent an endometrial biopsy 9 days after the LH surge followed by an IM injection of 5,000 IU hCG. Blood samples were drawn immediately before hCG administration for serum P and placental protein 14 (PP14) measurements, at 6 hours after hCG stimulation for serum P concentrations, and on day 5 after hCG administration for serum PP14 levels. Histologic dating of the endometrium and serum P and PP14 measurements. Abnormal endometrial biopsies occurred more frequently in infertile (43%) than in fertile women (9%). Except for one case, these specimens were not associated with low hCG-stimulated P levels. Serum PP14 measurements varied widely and did not discriminate subjects with abnormal endometrial development. Disruption of endometrial maturation without a concomitant defect of the corpus luteum occurs more frequently in an infertile population and thus may contribute to infertility.
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.
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.
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.
The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception, although the actual number of fertile days in a woman's menstrual cycle is uncertain. The timing of intercourse may also be associated with the sex of the baby. We recruited 221 healthy women who were planning to become pregnant. At the same time the women stopped using birth-control methods, they began collecting daily urine specimens and keeping daily records of whether they had sexual intercourse. We measured estrogen and progesterone metabolites in urine to estimate the day of ovulation. In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated, as indicated by increases in the urinary concentration of human chorionic gonadotropin around the expected time of implantation. Two thirds (n = 129) ended in live births. Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. There was no evident relation between the age of sperm and the viability of the conceptus, although only 6 percent of the pregnancies could be firmly attributed to sperm that were three or more days old. Cycles producing male and female babies had similar patterns of intercourse in relation to ovulation. Among healthy women trying to conceive, nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation. For practical purposes, the timing of sexual intercourse in relation to ovulation has no influence on the sex of the baby.
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.
The scientific foundations and most notable features of modern natural family planning (NFP) methods are described. NFP techniques require observation of the signs and symptoms occurring during the fertile and infertile phases of the menstrual cycle. Abstinence during the fertile period is implied when NFP is used to avoid pregnancy. Modern NFP methods are associated with success rates similar to those of oral contraceptives, the IUD, and condoms. NFP methods are based on such phenomena as the limited survival time of the ovum and sperm, the occurrence of ovulation only once per cycle, the ability to diagnose ovulation using simple means, and the ability of human beings to delay sexual satisfaction. Among the advantages of NFP methods are low cost, brevity of the required training time, increased knowledge of the body and capacity for self control, shared responsibility by both partners, and moral and religious acceptability. The Billings and symptothermal methods have shown average use-effectiveness rates ranging from 71.5 to 89.5% and from 83.4 to 97.8%, respectively. All studies of symptothermal methods conducted since 1985 have shown Pearl indexes under 5. The symptothermal method is based on observation of the duration of previous cycles, cervical mucus, basal body temperature, and optionally on palpation of the cervix and other symptoms such as breast swelling, acne, intermenstrual bleeding, and mood changes. Use of the symptothermal method requires special graph paper for recording the temperature and other symptoms. The beginning of the fertile phase is recognized by subtracting 19 from the shortest cycle in the past year, or by the appearance of cervical changes or changes in the mucus.
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.
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 whether successive cycles of clomiphene citrate affect endometrial thickness. Thirty-four women presenting for treatment of anovulation, oligoovulation, or follicle maturation defects were given the smallest dose of clomiphene citrate necessary to attain a mature follicle. If no pregnancy ensued, the same dose was continued if a follicle 18-24 mm in diameter and a serum estradiol (E2) level greater than 200 pg/mL were achieved. Ethinyl E2 was supplemented for poor cervical mucus only. Endometrial thickness and echo patterns were measured each cycle at peak follicular maturation. There was no difference in mean endometrial thickness during the first six cycles of therapy, nor was there a trend for thickness to increase or decrease with successive cycles with or without the addition of ethinyl E2. There was no change in the distribution of echo patterns with successive cycles of clomiphene citrate. Post-treatment measures of thickness and echo pattern did not differ from baseline pre-treatment values. The homogeneous hyperechogenic pattern was the rarest. Mean serum E2 and progesterone levels at mid-cycle did not change with successive cycles. One proposed mechanism for the dichotomy between ovulation and pregnancy rates after clomiphene citrate therapy is that the drug adversely affects the endometrium. If clomiphene citrate does affect implantation adversely, the mechanism does not seem to be related to thinning the endometrium or causing an echo pattern that indicates a poor prognosis. The data also suggest that estrogen supplementation does not influence endometrial thickness and would best be used exclusively for hostile cervical mucus.
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.
Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria. The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle. Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P < 0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P < 0.001). Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.
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.
To assess uterine receptivity in women with unexplained infertility using integrin cell adhesion molecules as markers. Prospective, controlled study design. Eighty-seven nulliparous women with unexplained infertility and 32 fertile and infertile parous controls. Immunohistochemical staining for alpha 1, alpha 4, and beta 3 integrin subunits in endometrial biopsies obtained during the window of implantation (days 20 to 24), using the semiquantitative HSCORE by two observers in a blinded fashion. All endometrial biopsies from parous controls contained positive immunostaining for the alpha 1, and beta 3 integrin subunits in glandular epithelium. Some samples from parous controls were missing the alpha 4 subunit. In contrast, compared with parous controls, biopsies from women with unexplained infertility had reduced significantly beta 3 expression, with similar expression of alpha 1 and alpha 4. Two distinct defects in integrin expression were identified: "out-of-phase" samples that lacked beta 3 because of histologic lag (type I defects) and "in-phase" endometrium that still failed to express this integrin (type II defects). These subclassifications accounted for 26% and 39% of the total unexplained infertility group, respectively. Abnormal endometrial integrin expression was a frequent finding in women with unexplained infertility. These data suggest that defective uterine receptivity may be an unrecognized cause of infertility in this population of women.
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 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 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).
Natural family planning (NFP) methods can be effective if taught well and practised by well-motivated couples. Midwives should be able to give couples an understanding of the basic principles of the methods. The observable signs of the fertile cycle are changes in basal body temperature, in the consistency of cervical mucus and in the texture and position of the cervix. Practised properly the ovulation method can have a failure rate of as little as 2.2 pregnancies per 100 woman-years. The ovulation method is a suitable method for mothers who have breastfed to detect the onset of ovulation.
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.
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.
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 determine the magnitude of intraobserver variation in dating endometrial biopsies and its impact on clinical management. Blinded histopathologic interpretation of endometrial biopsy specimens 1 year apart by five pathologists. Large military tertiary care center. Endometrial biopsy specimens from 51 patients undergoing evaluation for potential luteal phase defects. None. Calculation of the magnitude of the individual and overall intraobserver variation in endometrial dating for the five pathologists and estimation of its potential impact on clinical management. The intraobserver variation was 0.69 +/- 0.05 days (means +/- SE). There was no significant difference in the magnitude of the variation for 1-day or 2-day dating ranges. The theoretical probability of altering clinical management by having the same pathologist redate a given specimen ranged from 15% to 28%. Histologic dating of endometrial biopsies is subject to a small but highly clinically significant intraobserver variability that may have a major impact on clinical management.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
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.
Delangue AF, 1993·Soins Gynecol Obstet Pueric Pediatr·
The Billings method, or cervical mucus method, is a natural family planning method developed during the 1970s by the Australian physicians John and Evelyn Billings. The method requires periodic abstinence during the periods recognized as fertile according to the characteristics of the mucus. The method can be used to avoid pregnancy or to favor it through identification of the day of maximum fecundity. The method does not alter the natural rhythms of the body or entail unpleasant side effects. At the beginning of the menstrual cycle, the cervix is closed by a mucus plug and the sperm survive less than two hours in the acidic environment of the vagina. Several days before ovulation, the cervix begins to secrete mucus that will protect the sperm from the acidity of the vagina and permit their passage to the uterus. Thus protected, the sperm can survive up to four days. Mucus at this stage has an elastic quality. After ovulation, the mucus thickens and becomes increasingly impenetrable to sperm. It feels sticky and gelatinous. The Billings method requires observation of the sensation of wetness or dryness and the characteristics of the mucus. Each evening the woman should note that day's observations on a chart. The "peak day" is the last day of elastic mucus that gives a sensation of wetness. The peak day is the most visible sign of ovulation and can be recognized only on the next day. The three days following the peak day are considered fertile, because ovulation can occur up to 48 hours after the peak and the ovum can survive up to 24 hours. If the Billings method is used to avoid pregnancy, intercourse should be avoided during menstruation as the appearance of mucus may be masked in a short cycle. Intercourse is permissible in the evening of every second day until the appearance of the mucus.
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.
Although its etiology is unknown, it has been hypothesized that premenstrual syndrome (PMS) is linked to a deficiency of central serotoninergic activity. In the present study, we evaluated the effect of fluoxetine, a specific serotonin uptake inhibitor, on PMS symptoms. Following extensive screening, including several psychological inventories, eight women with severe persistent PMS participated in a 6-month double-blind, placebo-controlled, crossover study which included three months each of daily fluoxetine 20 mg or placebo, administered in a randomized order. Symptoms were evaluated using the Calendar of Premenstrual Experiences and other psychometric measures. Compared with placebo, treatment with fluoxetine was associated with an improvement in PMS symptoms as judged by highly significant decreases in behavioral (P less than .005), physical (P less than .05), and total (P less than .005) Calendar of Premenstrual Experiences scores; Beck Depression Inventory scores (P less than .005); Profile of Mood States subscales scores including depression (P less than .005), tension (P less than .005), and anger (P less than .01); and State-Trait Anxiety Inventory scores. The use of fluoxetine was associated with a greater mean reduction in behavioral (75%) than in physical scores (40%), with a mean decrease in total Calendar of Premenstrual Experiences scores of 62%, which rendered these scores similar to follicular phase values. Thus, the luteal phase symptomatology of PMS was effectively abolished. At this dose, no significant side effects or complications were noted during treatment. Fluoxetine appears to be a highly effective, well-tolerated treatment for the psychological and physical symptoms accompanying severe PMS.
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.
The empty follicle syndrome was assessed using transvaginal ultrasonography in a group of 152 consecutive women with unmedicated menstrual cycles being studied because of primary or secondary infertility or repetitive miscarriage. The overall frequency of the empty follicle syndrome was found to be 43.4%. The frequency increased with age but was independent of gravidity. The empty follicle syndrome may be a significant etiologic factor in infertility or other reproductive abnormalities, and transvaginal ultrasound represents a good, non-invasive means of evaluating it.
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.
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.
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.
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).
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.
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.
Measurement and Statistics · Research Tooling and Reproducibility
To characterize the extent and sources of imprecision in histologic dating of the endometrial biopsy. Duplicate endometrial biopsies from 25 women were dated by five evaluators on two separate occasions to evaluate the overall precision of the measure. Using variance component analysis, estimates of intrauterine, intraevaluator, and interevaluator variability were determined. Samples were obtained during outpatient fertility testing. Evaluators were colleagues at the same institution. PATIENTS, Women presenting with infertility undergoing routine evaluation. None. Variability in histologic dating of the endometrium. Inconsistencies between evaluators accounted for 65% of the observed variability, whereas 27% was because of inconsistencies in duplicate readings by the same evaluator. Regional differences in the uterus accounted for only 8% of the total variability. The overall error from these sources have the potential to result in a substantial false-positive rate for diagnosis of luteal phase defect.
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)
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.
In this study we have evaluated the score, sperm migration and ultrastructural characteristics of cervical mucus present in amenorrhoeic women under exclusive breastfeeding at 30, 60, 90, 120, 150 and 180 days post-partum. Periovulatory mucus samples from seven normally cycling women were used as a control. The average scores of post-partum and periovulatory mucus were 4.6 +/- 0.4 and 14.1 +/- 0.5 respectively. Twenty-one (39%) of the 54 post-partum cervical mucus samples and all (100%) periovulatory mucus samples allowed sperm migration. Positive sperm migration into post-partum mucus was observed at all time intervals studied. The only parameter that correlated with sperm migration into post-partum mucus was ferning formation. Sperm migration was obtained in all post-partum mucus samples with a score greater than 8, but samples with scores between 2 and 7 also showed sperm penetration. Scanning electron microscopic studies showed the characteristic spongy appearance of periovulatory mucus. Post-partum mucus was formed by a dense mesh (rocky appearance), when samples were generally unable to sustain sperm migration, but samples where sperm migration occurred showed small areas of spongy mucus mixed with areas in which a dense mesh and high cellularity was observed.
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)
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.
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.
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.
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.
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.
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.
Measurement and Statistics · Instrument Development and Validation
Basal temperature data are known to provide unreliable assessments of luteal phase length when they are evaluated by qualitative, visual-pattern methods. This study of 24 cycles in 24 women compared the serum LH peak day with the luteal phase onset day determined by three quantitative basal temperature a) a new computerized least mean square method developed by the authors; b) the mean temperature method reported by Vollman; and c) a computerized version of the World Health Organization cumulative sum method of Royston. The luteal phase onset day determined by the three quantitative basal temperature methods, (a, b, and c) correlated well with the midcycle LH peak (r = 0.879, 0.891, and 0.791, respectively, all p less than 0.001). The cumulative sum method, however, was only able to analyze 19/24 cycles. The mean delay between the LH peak day and the luteal phase onset day determined by thermal shift was 2.4 +/- 1.5, 2.7 +/- 1.4, and 4.1 +/- 2.0 d (mean +/- SD), respectively. The mean temperature method, but not the other two methods, showed an increasing delay between the LH peak day and the thermal shift day with longer follicular phase lengths. Rectal and oral temperature data from the same cycle give identical luteal onset days when analyzed by the least mean square and mean temperature methods, but discrepant days by the cumulative sum analysis. The least mean square technique is a reliable and precise method for population documentation of luteal phase lengths.
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."
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.
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.
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.
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.
The sonographic definition of the empty follicle syndrome is presented in a group of 89 consecutive, unmedicated menstrual cycles in women with primary or secondary infertility. The incidence of the empty follicle syndrome was found to be 50%. The incidence increased with age and was independent of gravidity or the type of follicular rupture (or lack of rupture). These data suggest that the empty follicle syndrome may represent a significant etiologic factor in infertility or other reproductive abnormalities.
Few subjects have provoked such controversy in the field of reproductive endocrinology as polycystic ovary syndrome (PCOS). It is characterized by heterogeneous clinical and endocrine features and this has led to considerable debate about its definition. The controversy has been fuelled by uncertainty about the aetiology of the syndrome. It seems probable that there are several causes of the typical ovarian appearance although, as will be discussed later, a familial basis for the disorder appears to be the most common of these. Traditionally, since the classic description of the syndrome by Stein and Leventhal in 1935, the diagnosis has rested primarily on the typical appearance of bilateral sclerocystic ovaries in women presenting with anovulation or hirsutism (or both). But the results from subsequent publications indicated that there could be a wide variety of clinical presentations in women who had evidence of polycystic ovaries (PCO) at ovarian biopsy (Goldzieher & Axelrod, 1963; Goldzicher & Green, 1962; Jeffcoate, 1963; Smith et al.. 1965; Givens, 1977, 1984; Yen, 1980). Although most of the women had menstrual disorders or hirsutism, there were also those who had evidence of ovulatory cycles and others who were non-hirsute. McArthur, Ingersoll and Worcester (1958) made the important observation that women with bilateral PCO characteristically had elevated urinary excretion of luteinizing hormone (LH). When radioimmunoassay became widely available in the early 1970s the emphasis changed from diagnosis by histology to use of biochemical markers of the syndrome. The typical endocrine abnormalities in PCS were raised serum concentrations of LH and testosterone (and/or androstenedione) to which could be added, in later studies, evidence of hypersecretion of adrenal androgens and abnormalities of estrogen secretion, particularly estrone (Yen et al., 1970; Gambrell et al., 1973; Rebar et al., 1976; Baird et al.. 1977; Kandeel et al.. 1978; Yen, 1980). So great was the reliance on biochemical diagnosis that, in some studies, the appearance of the ovaries was considered to be of secondary importance. One problem has been that there has seldom been total agreement as to the biochemical definition of PCOS. Some groups, for example, have taken a raised serum LH to be important for the diagnosis (Lobo, 1985; Waldstreicher et al.. 1988). However, it was clear from early biochemical studies that some women with all the other clinical and biochemical features of PCOS had normal serum LH concentra-
tions (Givens et al., 1976; Rebar er al., 1976).
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.
Sixty-three endometrial biopsies were dated histologically by using the standard criteria on two separate occasions by the same observer. Overall, it was found that exact agreement occurred in 15 (24%), but disagreement of more than 2 days occurred in 6 (10%). The proportion of exact agreement in the first half of the luteal phase (32%) was found to be significantly higher (P less than 0.05) than that in the second half of the luteal phase (9%). In a separate part of the study, 27 women had two endometrial biopsies, each performed in a separate cycle. The within-subject between-cycle variation of the results of endometrial dating (exact agreement: 4%, disagreement of more than 2 days: 41%) was found to be significantly different from intraobserver variation (P less than 0.01 for both). The amount of intraobserver variation suggests that the traditional dating criteria are not precise enough to quantify corpus luteum function in the second half of the luteal phase, whereas the amount of within-subject between-cycle variation implies that the result of endometrial dating in one cycle cannot be used reliably to predict that of another cycle.
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.
Ultrasound (US) has been demonstrated to be the method of choice for diagnosing luteinized unruptured follicle syndrome and to be a valuable adjuvant in the assessment of luteal phase defect. In this prospective study, the use of US with postcoital testing (PCT) is evaluated. Fifty control infertility patients were examined with serial US for follicle dynamics in conjunction with PCT. Standard curves for follicle dynamics versus cervical mucus quality (Insler score) were calculated. Eighteen patients referred for abnormal mucus underwent similar evaluation. Their follicle dynamics versus mucus quality were compared with those of the controls. The findings were: (1) there is a predictable relationship between follicle size and mucus quality, (2) the majority of patients with abnormal mucus have normal follicular dynamics, and (3) a minority of patients with abnormal mucus have either a narrow mucus window or abnormal follicular dynamics. In addition, US was found to be cost-effective in the overall fertility evaluation.
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.
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.
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)
Sonographic visualization of the cumulus oophorus or of morphologic alterations in the wall of the dominant follicle have been reported to be reliable signs of imminent ovulation when conventional transabdominal sonography is used. To determine if transvaginal sonography could allow a more frequent and confident prediction of imminent ovulation, we prospectively monitored 22 ovulatory menstrual cycles in four women undergoing artificial insemination and in 13 normally menstruating volunteers. Scanning was done on alternate days in the periovulatory period; a 7.5-MHz transvaginal transducer was used. Despite the improved resolution obtained with transvaginal sonography, confident identification of the cumulus oophorus or of mural changes in the follicle was not possible in any of the cycles followed. No other consistent follicular characteristic predicted imminent ovulation. We conclude that confident prediction of imminent ovulation is not possible with sonographic analysis.
Endometrial biopsy specimens (n = 62) were evaluated by five pathologists to assess the effect of interobserver variation on histologic dating of the endometrium. The potential effect of this variation on the diagnosis of luteal phase defects (LPDs) and resulting clinical management was also determined. Mean (+/- standard error) interobserver variation was 0.96 +/- 0.08 days, comparable to results reported by other investigators. The magnitude of the variation was not affected by whether the biopsy specimen was obtained in the mid or late luteal phase, the degree of lag between the dating and subsequent menses, or the presence of an LPD. Redating of a specimen by another pathologist would have resulted in a change in the determination of "in" or "out" of phase in 22% of cases. The subsequent probability of changing patient management altered ranged from 22% to 39% depending on the clinical setting.
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 …
Women can accurately predict the day of ovulation by examining vaginal mucus using the Billings Ovulation Method (BOM). they then can choose to either have sexual intercourse if they wish to conceive or to refrain if they do not want to become pregnant by being able to identify the peak day of fertility and the 3 following days of diminishing fertility. A preovulatory phase of the ovulatory cycle follows menstruation which generally includes a sensation of dryness around the genital area but sometimes no dry days occur. At this point progesterone activates the secretion of a thick sticky mucus into the cervical canal which sperms cannot penetrate. This mucus also serves to guard against infection in the reproductive tract and abdominal cavity. When circulating estrogen increases due to follicular development a fluid clear and stringy mucus replaces the thick mucus. this mucus is like a raw egg white. Under the microscope it has a distinctive fern pattern. Sexual intercourse during this time period may result in pregnancy because this mucus sustains sperm cells in cervical crypts for 48-72 hours. Not all women notice the changes in the mucus however but they can sense the vulva as soft swollen and moist. The final day of this sensation identifies the peak day (day 1) in which ovulation customarily occurs. Even though fertility decreases in the next 3 days conception may occur in days 1-3. Infertility sets in on day 4 and last on average 2 weeks. any mucus now seems sticky and opaque. WHO field trials in El Salvador and 4 other countries confirmed that BOM is >99% effective when couples adhere to the guidelines. Research demonstrated that illiterate couples from low socioeconomic status understand it and apply it successfully.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Twenty women with the diagnosis of premenstrual syndrome (PMS) participated in a double-blind, placebo-controlled, crossover study to evaluate the efficacy of naltrexone, an oral opiate antagonist. This study was designed to test the hypothesis that inhibition of opiate withdrawal would aid in the treatment of PMS. The subjects received either placebo or naltrexone from days 9-18 of the cycle for three consecutive cycles. The mean scores of the three day-25 Menstrual Distress Questionnaires of 16 patients on naltrexone were compared with the mean scores of the same patients on placebo. Scores were at least ten points lower on naltrexone in 11 patients and at least ten points higher on naltrexone in two patients. Score changes of less than ten points were noted in the other three patients. The mean scores dropped 28 points on naltrexone (P = .016). The general acceptability of naltrexone was good, with side effects including nausea, decreased appetite, and dizziness. These results suggest that naltrexone alleviates many PMS symptoms and may be an effective treatment for this syndrome.
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.
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.
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.
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.
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.
A double-blind controlled study of the effects of vitamin B6 supplementation on premenstrual symptoms was conducted. Fifty-five women who reported moderate to severe premenstrual mood changes participated in the study. Symptoms were monitored prospectively through daily home record-keeping over a one-month baseline period followed by two months of treatment. Subjects were randomly assigned to receive daily supplements of 150 mg of vitamin B6 or placebo over the entire two-month treatment period. Analysis of covariance suggested that even though vitamin B6 may improve premenstrual symptoms related to autonomic reactions (eg, dizziness and vomiting) and behavioral changes (eg, poor performance and decreased social activities), a significant amount of physical and affective symptomatology remained during the premenstrual phase. In light of recently reported, potentially toxic effects of low doses of vitamin B6, our results call for caution in using this therapy for premenstrual symptoms.
A double-blind, placebo-controlled, randomized multiple crossover study was designed to determine the effectiveness of alprazolam in the treatment of premenstrual syndrome. Patients maintained daily diaries of 22 premenstrual symptoms for one pretreatment control cycle and four treatment cycles. Alprazolam 0.25 mg or placebo was administered three times daily from cycle day 20 until the second day of menstruation, at which time the dosage was tapered by one tablet per day to minimize withdrawal effects. The results of the clinical trial indicate that alprazolam is significantly more effective than placebo in relieving the severity of premenstrual nervous tension, mood swings, irritability, anxiety, depression, fatigue, forgetfulness, crying, cravings for sweets, abdominal bloating, abdominal cramps, and headache. The low incidence of side effects makes alprazolam an acceptable treatment for premenstrual syndrome for those women unresponsive to other therapies.
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.
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.
Indirect evidence of the occurrence of ovulation, which is generally accepted, is an increase in plasma or serum progesterone. Pelvic ultrasonography can estimate the probable time of ovulation within 12 h. There is a close association between the rise in progesterone, luteinizing hormone (LH) and oestrogen peaks and ovulation. A WHO study reported that ovulation occurred at a median time of 8 h after the rise in plasma progesterone, 15 h after the LH peak and 24 h after the oestrogen peak. The basal body temperature (BBT) method is the most effective in determining the premenstrual infertile period, but it is unreliable for an accurate determination of ovulation and the postmenstrual infertile period. Nor is BBT an effective method of predicting ovulation during postpartum lactational amenorrhoea. Therefore, BBT is usually used as a secondary indicator of ovulation and is combined with more reliable indicators. Observed changes in cervical mucus patterns can be used to define the probable fertile period, although this method produces a wide range of days. The peak mucus symptom is closely correlated with ovulation. Mucus symptoms can be used as a guide for the timing of blood or urine samples for estimation of LH, oestrogen and progesterone or their metabolites. Symptothermal methods incorporate other symptoms such as cervical changes, intermenstrual pain, breast tenderness and backaches, but these are secondary signs of ovulation and are recommended to be used in conjunction with mucus and BBT.
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 nature and incidence of normal and abnormal spontaneous ovarian cycles, identified with ultrasound and endocrine tracking, were examined in 45 regularly cycling infertile women with no definitive cause and 15 women who were apparently normal and were receiving donor insemination because of clearly infertile partners. In 136 cycles, four apparently distinct abnormal patterns were detected. The total incidence in the infertile group was 58% compared with 23% in the donor insemination group (P less than 0.005). Twelve of 26 subjects who had at least three cycles tracked showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. These results suggest that abnormal cycles are a significant factor in unexplained infertility and that diagnosis and treatment cannot be based on the study of a single cycle.
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.
Six months of exercise training was associated with decreased premenstrual symptoms in two groups of women. There was no change in symptoms in nontraining women. Eight sedentary (ST) women increased running from 0 to 76 +/- 26 km/cycle (mean +/- standard deviation) over 6 months and seven runners (MT) trained for a marathon (42.2 km). Six normally active, nontraining (C-NT) women kept their activity constant. Each subject completed monthly intensity-graded questionnaires or kept daily symptoms diaries concerning premenstrual symptoms. All monitored basal body temperature, weight, and exercise. Gonadal steroids were measured in ST women. For ST subjects, breast (P = 0.005), fluid (P = 0.01), and personal stress (P = 0.025) decreased. MT women experienced decreased fluid (P = 0.034) and depression (P = 0.014). Anxiety tended to decrease (P = 0.087). ST and MT subjects experienced decreases in premenstrual symptoms without documented hormonal, menstrual cycle, or weight changes. These symptom changes appear to be the earliest evidence of the effects of conditioning exercise on the reproductive system.
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.
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.
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%).
Natural Family Planning (NFP) is defined by the World Health Organization (WHO) as "methods for planning or avoiding pregnancies by observation of the natural signs and symptoms of the fertile and infertile phase of the menstrual cycle. It is implicit in the definition of natural family planning, when used to avoid conception that drugs, devices and surgical procedures are not used, there is abstinence from sexual intercourse during the fertile phase of the menstrual cycle, and the act of intercourse, when it occurs, is complete."(1) The fertile period may be determined by using Rhythm, a calculation based on previous cycles, basal body temperature (BBT) charting alone, mucus secretion alone (Billings or Ovulation method), or symptothermal charting (Serena method), which includes observation of both mucus and BBT. The effectiveness of each method is discussed, and the social and psychological profile of couples who use NFP is reviewed. Nfp methods can be used not only to avoid pregnancy, but also to achieve pregnancy and thus are particularly useful in investigating and treating infertility. The function of the Family Life Clinic at St. Michael's Hospital in Toronto is described.
Anti-Infective and Anti-Inflammatory Agents · Nonsteroidal Anti-Inflammatory Drugs
The use of mefenamic acid in the treatment of premenstrual syndrome (PMS) was investigated in 15 women over six menstrual cycles. A randomized, double-blind, cross-over, placebo-controlled design was used to overcome the methodologic criticisms of other medication trials in this condition. Mefenamic acid significantly improved many of the physical, mood, and performance symptoms associated with PMS. The physical symptoms that showed marked improvement were fatigue, headache, and general aches and pains (P less than .001). Most mood symptoms were improved, the most significant being freedom from mood swings (P less than .005).
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.
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.
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.
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.
Prior JC et al., 1986·Eur J Appl Physiol Occup Physiol·
Conditioning exercise decreased premenstrual symptoms during 3 months of a prospective controlled training study. Eight women with normal ovulatory menstrual cycles began a running exercise training programme while completing intensity-graded questionnaires concerning molimina. Six sedentary control women followed the same protocol for 3 months but did not exercise. Oral basal temperatures evaluated by mean temperature analysis were obtained for all cycles. Exercise distance and time, average exercise heart rate, basal and maximal heart rate and body weights were recorded prospectively and evaluated during the control (0) and 3rd month of the study. Mid-luteal phase progesterone and estrogen levels were sampled during the analyzed cycles for the exercise group. Molimina did not change over 3 months time in the control group. The exercise group, after increasing distance run to 51.0 +/- 18.1 km/cycle at 3 months, showed decreases in overall molimina (scores on a 9-point scale) 6.5 +/- 1.8 to 3.5 +/- 0.9, p less than 0.01). Breast symptoms decreased from 8.3 +/- 0.7, p less than 0.005. Fluid symptoms also decreased from 7.3 +/- 1.8 to 5.5 +/- 0.9, p less than 0.025. Menstrual cycle intervals, luteal lengths, body weights and mid-luteal estrogen and progesterone levels were normal and unchanged. Moderate exercise training without major weight, hormonal or menstrual cycle alteration significantly decreased premenstrual symptoms.
We studied endometrial luteal phase in specimens from 660 biopsies done in 300 patients from our infertility clinic. A minimum of two (240 women) or three (60 women) endometrial biopsy specimens from separate cycles were taken regardless of the previous histologic findings in all patients. Statistical analysis of results by the McNemar and the Cochran Q tests for the significance of changes leads us to conclude that a minimum of two, and even three, endometrial biopsy specimens are needed for diagnosis of luteal phase deficiency.
Nutrition and Metabolic Health · Body Weight and Composition
The onset and progression through the various stages of puberty are influenced by a number of factors (Fig. 2). In both animals and humans, the age of puberty appears to be related more to body weight than to chronologic age. Undernutrition and low body fat, or an altered ratio of lean mass to body fat, seem to delay the adolescent spurt and to retard the onset of menarche. According to Frisch, a minimum level of fatness (17% of body weight) is associated with menarche; however, a heavier minimum weight for height, representing an increased amount of body fat (22%), appears necessary for the onset and maintenance of regular menstrual cycles in girls over 16 years of age. This critical amount of body fat implies that a particular body composition, in addition to other environmental and psychosocial factors, is important in triggering and maintaining the pubertal process.
A prospective six-year study (1975-1980) of 273 patients, monitored in the use of natural family planning (NFP), has shown that those with previously irregular menstrual cycles are disadvantaged in the subsequent use of the ovulation method after pregnancy in that they have fewer recognizable safe days and/or are more likely to have unplanned pregnancies than women who had regular cycles prior to pregnancy. Eight patients, seven nursing and one non-nursing mother, conceived during postpartum amenorrhoea. The reliability of memory in the recall of previous menstrual histories is discussed in relation to the results of an international study of menstrual cycles by the World Health Organization (WHO 1983). The relevance of prediction of menstrual events in natural family planning is also considered.
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.
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.
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.
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.
The current status of natural family planning (NFP) was reviewed. There is renewed interest in NFP, and many couples who find other methods unacceptable for medical, safety, or personal reasons are turning to NFP methods. The percent of contraceptive users who rely on behavioral methods in developing countries in 35% in Peru, 20%-25% in Haiti, Philippines, and Sri Lanka, and average 7.5% for the remaining 23 developing countries. IN the US about 4.7% of all contraceptive users rely on behavioral methods. Worldwide, rhythm is the most commonly used form of behavior fertility control, but this method is not promoted by most NFP programs. The 3 modern methods of NFP are 1) the basal body temperature method, 2) the cervical mucus, or Billings method, and 3) the sympto-thermal method. All these methods rely on physical signs and symptoms to detect ovulation and require sexual abstinence during the fertile phase of the menstrual cycle. The basal body temperature method requires women to detect the slight rise in temperature which occurs at the time of ovulation. The method is 94%-97% effective if intercourse is restricted to the postovulatory phase of the cycle. Disadvantages of the method are that intercourse must be restricted to only 7-13 days of the cycle, women must take their temperature daily, the method cannot be used during fever episodes, and the method is inappropriate for use during lactation or near menopause. The cervical mucus method is based on observing cervical mucus changes during the cycle. These changes signal the fertile and infertile phases of the cycle. According to a World Health Organization study, 93% of the women instructed in the method were able to detect mucus changes, and illiterate women were as adept at identifying these changes as university graduates. Findings also indicated that the method was 97% effective if abstinence was practiced during 15 days of the cycle, but use-effectiveness was only about 80%. This method has the advantage of not requiring ovulatory regularity. The sympto-thermal method uses a combination of symptoms including temperature shifts and mucus changes to detect ovulation. Some studies indicate that the combined method is more effective than those methods based on only 1 symptom, but many individuals find the combined method difficult and confusing. The advantages of NFP methods are that they require no medical supervision and that they have no side effects. Family planning providers often have negative attitudes toward NFP and many programs do not provide NFP services. Many providers maintain that the methods are ineffective and difficult to apply and that there is little demand for NFP. Research should be undertaken to determine if these opinions are valid. The major source of funding for NFP programs and projects is the US Agency for International Development (USAID). The agency is currently supporting 22 NFP projects under USAID grants and another 16 bilateral NFP programs. The research undertaken in connection with these projects should provide needed information on NFP advantages, disadvantages, effectiveness, and demand.
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.
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.
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.
Ninety-five menstrual cycles were studied in 20 women undergoing donor artificial insemination (AID). In 49 cycles basal body temperature (BBT) changes were charted daily and both daily cervical mucus scoring (modified Insler score) and daily realtime ultrasonography (USS) were performed from day 11 to ovulation. AID was performed only on the day of follicular rupture. A control group, not subjected to USS, were inseminated two to three times per cycle over 46 cycles in the periovulatory period. The Insler score was found to be a reliable indicator of follicular development and rupture. The BBT was found to be less reliable than the Insler score or USS. While USS may be used to confirm follicular development, the Insler score is reliable and less costly.
Sonographic criteria of endometrial tissue were obtained following serial observations in normally ovulating women, and a prospective identification of a specific phase was made in those with regular menstrual cycles. This may be the first report of endometrial tissue characterization. Clinical management of infertility and monitoring of follicular growth will thus be facilitated.
Reliable indicators to detect the fertile and infertile phases in the menstrual cycle are now available, largely due to the intensive scientific research into fertility over the past decade. This means that couples who follow the rules of the different NFP methodologies have a highly effective means of birth control, without the introduction of hormones, chemicals or devices into the body. New scientific techniques can be expected within the next couple of years which will simplify the detection of the fertile phase and hopefully help to elucidate the grey area of the early fertile days, where most of the unplanned pregnancies occur. Fertility awareness by both partners is an important positive contribution to the whole sexual relationship and emphasizes that NFP is an educational delivery system rather than a technological one. The modification of sexual behaviour and the motivation of both partners for the successful use of NFP may initially present a problem to some couples. On the other hand, many partners find the discipline enhances their sexual relationship and dialogue. Whatever the motivation, today more and more couples are happier to be in autonomous control of their bodies and their fertility.
The author reviews and makes further recommendations for 3 points of the discussion in G. Freundl's pilot study of "Natural Family Planning (Symptothermal Method) and Objective Ovulation Indicators" published by Georg Thieme Verlag in Vlume 6, "Geburtshilfe und Frauenheilkunde," in 1984. It is suggested that the scientific basis of changes in methodological rules, such as the BT3 modified for the double control method in paragraph 3 of the discussion, must be reported Natural Family Planning (NFP) instructors in Bonn, West Germany, along with failure statistics whenever possible, to enable instructors to participate responsibly. In response to errors by users cited in paragraph 4 of the discussion, the reviewer asserts that adequate instructional materials (photos and slides) are available to acquaint the users with changes in cervical mucus and that personal guidance of a couple or small group should be carried out until detection of fertility signals is performed without difficulty and the couple has proved itself capable of abstaining for the required periods, the latter being the more difficult. The author further cautions that before shortening of the abstinence period can be promoted, instructors must be scientifically assured of the accuracy of the basal temperature -6 indicator. She emphasizes that user errors can be reduced with a shorter abstinence period, but that the couple demands reliable rules first and foremost. The author concludes with a call for closer cooperation between gynecologists and NFP instructors.
The Billings/ovulation method is a periodic abstinence method of regulating births based on the client's interpretation of changing patterns in secretions of cervical mucus monitored by external self-examination. It was developed in Australia and is now widely promoted overseas. This paper outlines the method's recent history and goes on to discuss its physiological basis, its use-effectiveness as measured in a number of major trials, and some evidence concerning its general acceptability and applicability in family planning programs.
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.
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.
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.
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)
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.
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.
Despite skepticism on the part of the health care delivery system, increasing numbers of women and couples are relying on natural family planning methods to avoid or achieve pregnancy. Most clients require 2-4 cycles to become familiar with the delineation of the fertile phase. Both the ovulation and the sympto-thermal methods are considered to have a method effectiveness of at least 98%. Teaching-related unplanned pregnancies fall below 5%. Use of the Billings ovulation method requires the couple to abstain from intercourse from the beginning of mucus until the 4th day after peak. The sympto-thermal method is preferred by those desiring a multiple-index approach. 75-80% of users of this method can detect cervical softening and dilatation, and 50% are aware of the change of position of the cervix. Knowledge of mucus buildup patterns can be expecially important for adolescents, lactating women, and premenopausal women in helping them to determine whether cycles are ovulatory. Instruction in interpretation of the mucus cycle is further advised in cases of infertility. Unwillingness of the partners to practice it constitutes the only contraindication to natural family planning. However, couples are advised to wait for the postovulatory infertile phase of the cycle to have intercourse in cases where prgnancy would pose a serious threat to the life of the mother or fetus. Although some groups recommend the use of a barrier method rather than abstinence during fertile periods, this practice makes mucus recognition more difficult and impedes confidence in the method. Attainment of couple autonomy in natural family planning involves 2 phases: 1) correct recognition of the signs of fertility and 2) comfort with periodic asbsinence. Successful autonomy is reflected in the high continuation rates found in programs that offer adequate counseling support.
This is a survey of 14 placebo-controlled studies regarding the treatment of premenstrual symptoms with bromocriptine. There is no substantial support that bromocriptine is an effective drug in the premenstrual syndrome as an entity. Symptoms such as irritability, depression, and anxiety were not significantly improved during treatment with bromocriptine compared to placebo treatment. Bromocriptine appears to be the treatment of choice in premenstrual mastodynia if the dosage of bromocriptine is at least 5 mg daily. Bromocriptine may therefore have a place in selected cases of the premenstrual syndrome with associated mastodynia.
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.
Parenteau-carreau S, 1983·Contracept Fertil Sex (Paris)·
The symptothermal methods include all those that identify the woman's fertile period through the basal body temperature and the periovulatory signs. Research conducted following the discovery over a century ago of the hyperthermic plateau in the later part of the menstrual cycle has confirmed that under normal conditions, and when the daily temperature is taken under comparable conditions, infertility may be assumed when the high temperature plateau is confirmed. A reliable temperature curve requires certain conditions: it should be taken upon awakening with a basal thermometer over a sufficient time to obtain an accurate measure, at almost the same time every day, and the graph paper should be appropriately scaled for recording. Various guidelines of interpretation have been developed throughout the world. Serena considers infertility assured from the 3rd consecutive day of elevated temperature as long as other fertility symptoms have disappeared. Among symptoms of ovulation that are perceptible to the woman are cyclic changes in the quantity and consistency of the cervical mucus, which has the advantage of predating and thus forecasting ovulation and of being less sensitive than the basal temperature to nongenital infections, sleepless nights, or other stresses. Use of mucus changes alone as an indicator of fertility carries the risk that such changes may not be noticed or may be due to an estrogen surge not related to ovulation. Other symptoms that are useful for some women in confirming temperature or mucus changes include 4 different alterations in the cervix, abdominal pain or mittelschmerz, intramenstrual bleeding, feeling of heaviness in the breasts, and variations in mood and libido. Many groups that teach the temperature curve and clyclical symptoms also provide instructions or mathematical rules for determining the number of infertile days at the beginning of the cycle. Some programs state that 6-7 days are usually infertile provided that the menses were preceded by a hyperthermic plateau. Many groups recommend the calculation of Ogino or a variant. The symptothermal method of fertility control combines the basal temperature curve with the other signs of fertility to serve as a basis for modification of sexual behavior to enhance or suppress fertility. Different programs stress different elements or combinations. The efficacy of the symptothermal methods depends on precise recordkeeping and observation and on competent instruction and counseling, as well as the willingness of the couple to modify their sexual behavior. Statistical measures of the method's efficacy are complex and unsatisfactory as they attempt to apply rigid rules to actions and decisions that are in fact filled with nuance.
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.
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 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.
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.
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.
Hjortrup A et al., 1983·Acta Obstet Gynecol Scand·
Twenty-nine consecutive patients with polycystic ovary (PCO) syndrome (defined as hirsutism plus oligomenorrhea or secondary amenorrhea, and excluding Cushing's syndrome, an androgen-secreting adrenal or ovarian tumor or adrenocortical hyperplasia) were treated with ovarian wedge resection leaving normal-sized ovaries. Long-term follow-up from 2.3-9.5 years (mean 5.7 years) showed that 26 of 29 patients (90%) had established normal menstrual cycles. Fertility and normal pregnancies were achieved in all 10 patients (100%) with normal postoperative menstrual cycles who desired to conceive, but not in the 3 patients with remaining postoperative oligomenorrhea. Eight of 9 patients who were obese preoperatively and who had normal postoperative menstrual cycles showed a major weight loss after wedge resection. In contrast, none of the preoperatively obese patients, who remained oligomenorrheic after surgery, lost weight. Hirsutism was not cured by wedge resection. It is concluded that ovarian wedge resection should still be considered useful in patients with PCO.
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.
Frequently, when one mentions natural family planning methods, the response is doubt, bewilderment, ridicule, or scorn. Much of this is due to the fact that many people know only of the rhythm method, which depends on a calculation based on the menstrual pattern. What many people do not know, including physicians and nurses, is that in Australia Drs. John and Lyn Billings have been scientifically researching natural methods of family planning for 25 years, and they have pioneered this Ovulation Method of family planning. The Billings Ovulation Method depends only on the mucus sign. It is based on a scientific knowledge of the combined fertility of husband and wife, and an understanding of the physiology of the female body through simple observations. Important facts relating to the practice of the method include: ovulation takes place only once in the cycle; mucus is secreted by the cervical mucosa before ovulation; the ovum lives for only 3 days at the most; and the sperms live for 5 days at the most, and only in the presence of this fertile mucus. There a 2 types of mucus. The 1st type to appear is cloudy or white. It is nonslippery, sticky, and breaks when stretched between 2 fingers. The 2nd type is like the part of a hen's egg. It is very slippery, much clearer than the former, and stretches when pulled between 2 fingers. This is fertile mucus, and ovulation occurs on the last day that this is present. Of course, it cannot be recognized as the last day until its absence is observed on the following day. The mucus sign can be both seen and felt. After a few months a woman will readily recognize her fertile time, but daily charting is advocated. Simple signs, representing the various observations, are taught. Once a couple knows and understands their combined fertility through the observation of the mucus sign they can plan their family. Rules of the method are outlined. The self control required by this method can only serve to increase the selfless love and unselfish care and respect between partners.
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.
Pip: The concept of utilizing changes in cervical secretion offers a potentially simple method of natural family planning. A detailed international trial has been conducted to test the effectiveness of the method. 5 centers are involved: Auckland; Bangalore; Dublin; Manila; and San Miguel. The observations provide an indication of the value and success of the method. They also reveal interesting variations between the different centers and between various socioeconomic classes. The work was divided into a teaching phase and an effectiveness phase. The initial phase was designed to teach individual women how to recognize the symptoms in cervical mucus, and it usually covered the first 3 complete cycles. The subjects were ovulatory, of proven fertility, less than 39 years, nonlactating, and with a history of a menstrual cycle of between 23 and 35 days. Data were collected from the patient and returned to the organizers for analysis. Comparisons were then made between different centers on the 2 study phases. In the teaching phase 94% of the women could soon recognize and record their own cervical mucus symptoms. Many women could understand the principle of the method within the 1st teaching cycle. Almost 90% of the subjects completed the teaching phase, and 7% discontinued for various reasons, including 1.3% who failed to learn the method, and 5% who became pregnant. The average number of days of abstinence by the method was 17 in the 3rd teaching cycle, a high proportion of the length of the average menstrual cycle. After the teaching phase, 725 subjects were studied in an effectiveness phase which lasted for 13 cycles. More than 7500 cycles were analysed. High rates of method failures were found in the 2 most socially developed centers, Auckland and Dublin. Pearl rates for method failure ranged from 9.4/100 women years in Auckland to 1.1 in Manila and 0 in Bangalore and San Miguel. The accumulative probability of discontinuation after 13 cycles was 35.6%, more than half of this figure being due to pregnancy. Detailed pregnancy rates/100 woman years, using the modified Pearl Index, were found to be as follows: conscious departure from the rules of the method, 15.4; inaccurate application of instructions 3.5; method failure 2.8; inadequate teaching 0.4; and uncertain reasons 0.5. Subjects were not selected randomly.
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.
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.
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 review of natural family planning (NFP) focuses on the following: components of the fertile phase; sympto-thermal methods; the history and methodology of NFP (calendar rhythm, basal body temperature, cervical mucus--the Billings Ovulation method); special circumstances--periods of erratic ovulation (puberty, lactation, premenopause, discontinuation of ovulation suppression, cervicitis and vaginitis, ovulation suppression by stress and pharmaceuticals); effectiveness of natural family planning; achieving pregnancy; achieving couple autonomy (confidence in the method, periodic abstinence, dynamics of the learning process, and support systems); problem areas; and delivery systems. The number of users of NFP methods increased from 2.8% of currently married couples in 1973 to 3.4% in 1976. In 1979, 75,000 new clients received training in contemporary NFP, while the number increased to over 100,000 in 1980. NFP is planning for achieving or preventing a pregnancy by the timing of intercourse. A couple can, by observing and recording certain natural symptoms and bodily changes that occur in a woman's menstrual cycle and using the information as a guide, learn to identify fertile and infertile phases in the menstrual cycle. Precise prediction of ovulation forms one of the components of delineation of the fertile phase. Billings pioneered the use of cervical mucus as a single parameter for the prediction of ovulation and its application to NFP. Women are instructed to observe their mucus patterns at the vulva, relying primarily on the sensation of wetness and lubrication, the use of the Kegel exercise, palpation with the finger, a "wipe-through" with toilet paper, or a combination of these observations. In the absence of ovulation, the usual changing mucus pattern is also absent. NFP can be used either to achieve or to avoid pregnancy. When NFP is used to avoid pregnancy, one will encounter method-related pregnancies, teaching-related pregnancies due either to poor teaching or poor learning or both. The major use effectiveness studies are listed in table form, and the results are shown under new headings. To achieve pregnancy, it is the general practice of NFP instructors to teach women to recognize and record their fertility signs and to suggest some months of merely concentrating coitus at the time of maximum fertility. Mastery of NFP calls for both identification of the fertile phase and integration of that knowledge into the couple's sexual decision making and behaviors. Studies are reviewed in terms of the spectre of genetically damaged offspring. NFP instruction is available in nearly every country outside the Soviet bloc.
Messinis IE et al., 1982·Acta Obstet Gynecol Scand·
The effectiveness of tamoxifen and clomiphene in inducing ovulation was compared in 46 women with anovulatory infertility. All the women were given both the drugs in an alternate way. If one cycle was treated by tamoxifen the next was treated by clomiphene and vice versa. Forty-one out of the 46 women (89.1%) ovulated at least once during the study. Similar ovulation rates were achieved by tamoxifen (56.2%) and clomiphene (62.9%). The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation.
Meier-Vismara E et al., 1982·Geburtshilfe Frauenheilkd·
During the last decade, the World Health Organization has paid increasing attention to some reliable methods of birth control based on periodic abstinence. There are 2 main methods of natural family planning--the Sympto-Thermal method and the Billings Ovulation method. The latter is explained in this paper. Its scientific basis, use, effectiveness, and importance as a birth control method as well as for understanding certain types of infertility are discussed. (author's)
Past practices of Natural Family Planning (NFP) have included such techniques as: 1) calendar rhythm in which a constant mathematical relationship was calculated between the day of ovulation and the beginning of the succeeding menstrual period, 2) temperature rhythm in which sexual intercourse is permitted by observing that the basal body temperature rises at the time of ovulation, 3) a combination of calendar and temperature rhythm methods, 4) paper test strips which measure glucose and electrolytes in vaginal secretions, 5) electronic devices of various sorts which record changes in the potentials of the pelvic organs at the time of ovulation, and 6) recent developments in computer technology which measure a number of variables. All of these techniques depend upon the identification of the fertile and infertile periods of the menstrual cycle. More recent studies by the World Health Organization have analyzed the teaching phase of NFP and the effectiveness phase of NFP using the detection of ovulation by following changes in the quality of cervical mucus. These studies tested 869 women with varied backgrounds in 5 countries. The data support the fact that many motivated women can detect ovulation reasonably accurately by following changes in their cervical mucus (the Billings method), although teaching time and motivation are considerable. Long-term and detailed data are necessary to determine the value of these methods. The advantage of NFP is the avoidance of drugs and devices. Disadvantages are that demands are placed on the sex life of couples, and there are associations between failures and increased rates of congenital abnormalities.
The estimated time of ovulation (ETO) was correlated with the day of defined postovulatory infertility in 66 hormonally normal menstrual cycles from 24 subjects for each of 15 different natural family planning methodologies. Inherent weaknesses were identified in methods based upon calendar calculations or basal body temperature only. These weaknesses could be removed for the basal body temperature-only methods if symptoms, especially the peak mucus symptom, were added to the temperature records. However, the peak mucus symptom alone had the greatest precision of all methods studied. No advantage could be identified in combining the basal body temperature with the peak symptom.
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.
The percentage of 869 women in five countries capable of being taught to recognize the periovulatory cervical mucus symptom of the fertile period was determined in a prospective multicentre trial of the ovulation method of natural family planning. The women were ovulating, of proven fertility, represented a spectrum of cultures and socioeconomic levels, and ranged from illiteracy to having postgraduate education. In the first of three standard teaching cycles, 93% recorded on interpretable ovulatory mucus pattern. Eighty-eight per cent of subjects successfully completed the teaching phase; 7% discontinued for reasons other than pregnancy, including 1.3% who failed to learn the method. Forty-five subjects (5%) became pregnant during the average 3.1-cycle teaching phase. The average number of days of abstinence required by the rules of the method was 17 in the third teaching cycle (58.2% of the average cycle length). To what extent the findings of this study can be extended to other couples remains to be demonstrated.
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.
Several periovulatory symptoms sometimes used in natural family planning are correlated with the estimated time of ovulation in 23 subjects and 64 hormonally normal menstrual cycles. The data suggest that intermenstrual pain may not be due to 1 specific cause but rather to several related factors. As a symptom of ovulation, intermenstrual pain was more specific than lower backache, abdominal bloating, and intermenstrual bleeding nonetheless, intermenstrual pain has a broad periovulatory association. The most reproducible and predictable sign of this series appeared to be the postovulatory occurrence of breast tenderness.
Serial sonographic examinations were performed on 15 volunteers five days during the expected midcycle. The 75 sonographic studies were evaluated in a nonbiased manner, and the following features were assessed: 1) the presence or absence of a follicle within the ovary; 2) if present, the average dimension of the follicle; 3) the ability to delineate both ovaries; and 4) the presence of associated changes, such as involution of the follicle, echogenic texture within the follicle, or fluid in the cul-de-sac. The sonographic findings were correlated with serial leutinizing hormone (LH) assays as well as basal body temperature charts. As defined in the study, the correlation between the sonographic findings and hormonal determination were considered excellent in 70% of the cases, good in 20%, and poor in 10%. Both ovaries were delineated in 73% of the examinations performed, thus substantiating the ability of sonography to detect maturing ovarian follicles.
Marked improvement in the severe hypertension (250/150 mmHg) and hirsutism of a patient suffering from polycystic ovary syndrome was quickly achieved by the use of spironolactone 200 mg per day. Substitution of spironolactone with bromocriptine induced further amelioration of these symptoms and renewal of ovulatory cycles. These drugs may afford another mode of therapy in patients with polycystic ovary syndrome.
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.
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.
The ovulation method provides a woman with an awareness of her cervical mucus pattern. This enables her to mark the beginning and end of the fertile phase of the cycle as well as the time of maximum fertility. Not only is the time of ovulation located but also there is recognition of infertility in the absence of ovulation. The key to understanding is the concept of the basic infertile pattern which precedes the commencement of follicular development; the key to successful use is competent teaching. After preliminary considerations on the fertile phase the determination of ovulation and the aspect of periodic abstinence two basic studies comparing clinical and hormonal observations are reviewed showing how accurately the cervical mucus reflects ovarian activity. Understanding the basic infertile pattern and the two sets of rules (the early day rules and peak rule identifying respectively the beginning and end of the fertile period) is basic to the application of the ovulation method. Criteria for the ideal family planning method and the importance of quality teaching are presented. Two problems requiring attention in NFP are restrictive terminology in data collection and a lack of fully developed and positive approach to periodic abstinence.
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.
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.
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.
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.
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.
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.
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.
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.
NFP (natural family planning) has replaced the term of rhythm method in the last decade as a designation for those methods of fertility regulation based on periodic abstinence. A graph presents the symptoms observable during the menstrual cycle and the ways in which these symptoms coincide with the fertile and infertile periods within the cycle. NFP counseling aims at teaching couples how to recognize the beginning and end of the fertile period within the menstrual cycle. Each of the following types of NFP are discussed and explained in detail: 1) calendar or calculation method; 2) temperature method; 3) symptothermal methods; and 4) cervical mucus methods. All of these involve detection of the time of ovulation combined with abstinence during the fertile period of the cycle. The symptoms to recognize are taught with each method. Findings from 5 retrospective and 12 prospective studies on the effectiveness of NFP are tabulated. Current research and suggested areas for future research in the field of NFP are mentioned. In the last 20 years, NFP has been popularized through more popular-oriented educational programs. Governments have taken over funding of some NFP programs. Now that NFP effectiveness has been well established, motivation and counseling will be the most important elements in NFP education in the future.
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.
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.
There are currently signs that more women are considering the natural family planning methods as an alternative to medical contraception. In response to this revival of interest, the World Health Organization is now conducting field work on 'natural' family planning methods in New Zealand, the Philippines, India, California, and Columbia and is also preparing a teaching package to be pilot tested in several countries. The natural methods of family planning are all based on the woman correctly ascertaining the pattern of her natural menstrual cycle and abstaining from sexual intercourse during the fertile time. In most women this means that there are 2 "safe periods" - at the beginning of the 28-day cycle until a few days before ovulation and at the end of the cycle from 3 or 4 days after ovulation has occurred. Originally, the "safe period" was taught by the calendar method, which involved a woman carefully plotting her menstrual cycle over a period of six months to a year and making calculations as to the shortest possible and longest possible cycle length, and thus the likely time of ovulation. A more accurate measure is to actually find out the point of ovulation by measuring basal body temperature. With this method the woman must take her temperature every morning immediately upon waking, before rising, smoking, eating or drinking. The Billings' ovulation method is the method now becoming increasingly popular. The method involves noticing the natural changes in the body over the whole menstrual cycle, particularly the quantity and quality of the cervical mucous. 1 new aid for pinpointing the exact time of ovulation is the Ovutime Fertility Detection System developed at Harvard University Medical School and the Massachusetts Institute of Technology. In the long-term, the rhythm method is unlikely to prove the answer to the problem of fertility regulation for the modern woman.
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.
The new methods of natural family planning, i.e., the cervical mucus and symptothermal methods, provide couples with a form of birth control which is medically safe, totally and immediately reversible, and highly effective for stronly motivated couples. Furthermore, these methods cost nothing, have no side effects, and are completely drug and device-free. These methods are totally distinct from the traditional rhythm method which requires a woman to make daily quesses about her fertility status on the basis of her previously observed menstrual cycle patterns. In contrast, the new methods allow a woman to identify with certainty her current fertility status. These innovative methods are based on recent research which indicates that women are naturally safeguarded from pregnancy during 60-70% of their reproductive lives. Women can easily be taught to recognize physical symptoms which identify the naturally fertile and infertile perods of each cycle, i.e., 1) changes in the appearance and texture of cervical mucus, and 2) changes in basal body temperature. During the fertile periods, the cervical mucus is thin, slippery, stretchy, and clear. In this state the mucus helps the sperm cells travel up through the cervix and also provides an environment that keeps sperm cells viable for up to 5 days. During infertile periods, the cervical mucus is thick and gummy and acts as a barrier to prevent sperm from traveling through the cervix. During the fertile period the vaginal opening has a sensation of wetness and slipperiness, but during the infertile period, the vaginal opening has a sensation of dryness. Changes in basal body temperature can be used to identify the 2-week, naturally infertile, postovulatory phase of the menstrual cycle. Immediately after ovulation, a woman's temperature rises by .3-.4 of a degree. A temperature rise, sustained for 3 days, indicates that ovulation has occurred and that the egg is no longer viable. Women may use either or a combination of these symptoms to identify their fertile and infertile days. These methods require couples to abstain from intercourse during the fertile period which generally lasts for 7-12 days. The use of creams, jellies, and other chemicals during the fertile period to avoid the need to abstain is not recommended because these substances may mask changes in cervical mucus. According to a 2-year Canadian study couples who used these methods for spacing purposes only had a failure rate of 14.9 pregnancies/100 woman years; however, couples who definitely wanted no moe children, had a failure rate of only 1.1 pregnancies/100 woman years. Apparently, the strength of the motivation to prevent pregnancy accounted for the marked differences in the failure rates of these 2 groups.
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.
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.
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.
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.
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.
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.
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.
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.
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 use of clomiphene in gradually increasing doses, in cases of infertility due to anovulation, oligo-ovulation and inadequate luteal phase, led to a high pregnancy rate, particularly in the initial stages of treatment. Although clomiphene is a relatively safe and inexpensive drug, there is a possibility that high doses in repeated cycles may adversely affect fertility by its anti-oestrogenic effect. It is therefore suggested that therapy be commenced with a lower dosage than that generally recommended.
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.
The ovulation method of family planning relies on self-recognition of physiological changes occuring around time of ovulation rather than a calendar to enable a couple to avoid sexual intercourse during the fertile period. The most practical signs are elevated basal body temperature, changes in the amount and physicochemical properties of cervical mucus, and ovulation pain. The basal body temperature rises about .3 degrees C following ovulation. The problem with this method is that it is retrospective. The mucus symptoms, as described by Billings and associates in Melbourne, Australia, are: 1) a variable number of days with no vaginal discharge following menstrual bleeding; 2) onset of mucus symptoms characterized by increasing quantities of ''cloudy'' or ''sticky'' secretion; 3) a clear, slippery lubricative mucus having the characteristics of raw white of egg (spinnbarkeit), which is an immediate forwarning of ovulation; 4) a variable period of thick, opaque, diminished volume discharge followed by dry days. The clear ''peak symptom'' mucus lasts 1-2 days; in a study of 22 women followed for 27 cycles this symptom occurred .9 days +3 or -2 days before ovulation. The problem is that 2 of the 22 cycles reported in detail had ovulation 3 days after the peak symptom and 1 had ovulation 4 days after. Intercourse on the 4th day, therefore, would have had a significant risk of pregnancy. Weissman and associates collected data on 282 women on the Pacific island of Tonga who used the mucus symptoms alone to control conception. In the 2503 cycles there were 53 unplanned pregnancies, 25.4 per 100 woman-years using the Pearl formula. 50 resulted from the couples ''taking a chance,'' 2 misunderstood the method, 28 abandoned the method because they wanted more children, and 1 woman became pregnant even though she thought she understood the method. Field trials with groups who are more motivated than those in the Tongan trial are needed.
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.
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.
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.
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.
Clomiphene citrate, in selected patients, is an effective agent for the treatment of infertility due to anovulation. An adequate laboratory and physical evaluation of each individual patient is essential for proper use of the drug. The major adverse reactions encountered are ovarian enlargements and cysts; in most patients, these conditions regress spontaneously after withdrawal of the drug.
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
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.
Since classical times there has been discussion on the existence or non-existence of variations in libido in women during the menstrual cycle.*This discussion reached its peak in the nineteenth and early part of the present century.The main difference of opinion lay between those who believed that there was increased libido in association with menstruation itself-that is, just before, just after, or during, or various combinations thereof (for example, Campbell, 1891 ; Kossmann, 1903; Havelock Ellis, 1910)-and those who denied the existence of any monthly enhancement of sexual desire in women (for example, Ftirbringer, 1918).The more recent literature continues to show marked differences of opinion.Thus Corner (1952) maintained that libido is maximal just before or just after menstruation, whereas Stopes (1937) considered the monthly rhythm to have two peaks, one just before menstruation and the other at mid-cycle.On the other hand, Eckstein and Zuckerman (1956) stated that " sexual behaviour in women very rarely manifests any rhythmic pattern."However, according to Swyer (1954), " Psychic changes occur throughout the menstrual cycle.So great are the variations in different individuals that generalizations are difficult to draw.Thus, whereas some women lose all or most of their libido during the menstrual period,
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.
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.
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.
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
*We are offering you a comprehensive look into women's health. By understanding natural methods and the science behind the menstrual period, the fundamental elements of conception and infertility can be easily understood.*
Creighton Model charting & scientific/physiological foundations
Creighton model data, and how it relates to the NaProTechnology application
Treatment approaches of NaProTechnology & Restorative Reproductive Medicine in gynecology and infertility
Benefits of RRM vs standard Conditions and Treatments