Schliep KC et al., 2026·J Gynecol Obstet Hum Reprod
Endometriosis has been linked to cardiometabolic alterations, but whether these associations vary by disease severity or phenotype is unclear. We examined lipid profiles across endometriosis diagnosis, stage, and typology. Data came from 476 women in the NICHD ENDO cohort. Endometriosis was confirmed laparoscopically and staged using the rASRM criteria (I-IV). Typology was categorized as superficial endometriosis (SE), ovarian endometrioma (OE), deep infiltrating endometriosis (DE), and OE+DE. We compared endometriosis status, stage (I/II vs III/IV), and typology to no endometriosis using adverse lipid thresholds (total cholesterol ≥200 mg/dL, HDL <50 mg/dL, LDL ≥100 mg/dL, triglycerides ≥175 mg/dL, non-HDL ≥130 mg/dL, VLDL ≥30 mg/dL, ApoA1 <125 mg/dL, and ApoB ≥120 mg/dL). Adjusted prevalence ratios (aPR) and 95 % CIs were estimated via generalized linear models, controlling for age, race/ethnicity, BMI, income, marital status, and serum cotinine. Endometriosis diagnosis alone was not associated with adverse lipid profiles. In contrast, moderate/severe disease showed higher prevalence of elevated triglycerides (aPR= 2.27; 95 % CI: 1.18,4.35) and VLDL (aPR= 2.41; 95 % CI: 1.50, 3.85). Typology OE and OE+DE were associated with adverse profiles across multiple markers (aPRs 1.59-4.09), particularly ApoB and triglycerides. Minimal/mild disease and SE were not associated. The metabolic signal was phenotype-driven rather than diagnosis-driven, with severe stage and OE/OE+DE showing clear associations with adverse lipid profiles. These findings suggest lipid profiles may serve as markers of phenotype severity or shared biological milieu. Replication in larger cohorts is needed.
EndometriosisAMH and Ovarian ReserveSurgical Staging and TypologyAnti-Müllerian Hormone
Endometriosis is a chronic, gynecologic condition in which tissue similar to the lining of the uterus implants throughout the body. Women with endometriosis have a higher prevalence of infertility and a greater risk of early natural menopause compared to those without endometriosis. This study aimed to evaluate preoperative serum AMH levels among women with and without incident endometriosis and to assess whether levels differ by surgical staging and typology. The ENDO (Endometriosis: Natural History, Diagnosis, and Outcomes) study was conducted between 2007 and 2009. The ENDO study consisted of an operative and population cohort (n=600). Only those in the ENDO operative cohort from the Utah site were used for this analysis, and included women aged 18 to 44 years who were scheduled for gynecologic surgery, irrespective of clinical indication (n=476). AMH levels were measured from stored serum collected before surgery using a quantitative enzyme-linked immunosorbent assay. After excluding participants with missing outcome data (n=51), unilateral oophorectomy (n=8), or those within the population cohort (n=69), 348 participants remained for the analysis. Surgically confirmed endometriosis diagnosis, staging (American Society for Reproductive Medicine I-IV), and typology (superficial, deep, ovarian) were ascertained by the operative report. Outliers for AMH (>14.0 ng/mL) were excluded from the analyses and AMH values were log-transformed. Multivariable linear regression models adjusted for age (squared and continuous), body mass index, serum cotinine levels, and exogenous hormonal contraceptive use were conducted. Percentage differences in AMH were calculated as (exp[β]-1)×100, and 95% confidence intervals were reported. Compared with no endometriosis, incident endometriosis diagnosis was associated with lower AMH levels (-19.8%; 95% confidence interval, -37.0 to 1.0); however, this association was not statistically significant. Stage III to IV disease was associated with 40.1% lower AMH levels (95% confidence interval, -58.9 to -12.7). Ovarian endometriomas were most strongly associated with lower AMH levels (-54.3%; 95% confidence interval, -69.4 to -31.8), with a more pronounced association among those with infertility (-72.6%; 95% confidence interval, -85.4 to -48.5). Deep (-24.1%; 95% confidence interval, -48.2 to 11.0) and superficial (-15.5%; 95% confidence interval, -34.6 to 9.3) endometriosis also showed a trend toward lower AMH levels, but these findings were not statistically significant. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis was associated with 26.8% lower AMH levels (95% confidence interval, -44.6 to -3.4). Stage III to IV disease was associated with 47.8% lower AMH levels (95% confidence interval, -65.8 to -23.2), and all subtypes of endometriosis were statistically significantly associated with lower levels of AMH compared with a postoperative diagnosis of a normal pelvis (ovarian: -60.8%; 95% confidence interval, -74.4 to -39.9; -34.3%; 95% confidence interval, -56.2 to -1.4; -24.8%; 95% confidence interval, -43.9 to -0.8). Ovarian and moderate to severe (stage III-IV) endometriosis were associated with markedly lower AMH levels compared with no endometriosis. Compared with a postoperative diagnosis of a normal pelvis, incident endometriosis and moderate to severe stages (stage III-IV) were associated with statistically significantly lower AMH levels. Additionally, typology (deep, ovarian, or superficial) was associated with statistically significantly lower AMH levels. However, this association was likely driven by the presence of ovarian endometriomas across all subtypes. These findings are consistent with previous studies and demonstrate that endometriosis lesions themselves, independent of surgical intervention, influence AMH levels.
PregnancySubchorionic HemorrhageProteomic and Transcriptomic AnalysisMachine Learning Biomarker Discovery
Shenoy-Bhangle AS et al., 2026·J Magn Reson Imaging
Endometriosis is a chronic multisystem disease caused by the presence of endometrium-like tissue outside the endometrial canal, inciting inflammation and fibrosis. Transvaginal ultrasound (TVUS) and MRI have replaced diagnostic laparoscopy as the noninvasive imaging modalities of choice for diagnosis and pre-surgical planning. Advanced disease in the pelvis can distort/obliterate anatomic planes and obscure the extent of pelvic organ involvement at laparoscopy. Unlike laparoscopy, MRI is not limited by anatomic distortion and provides accurate multi-compartment assessment of deep pelvic endometriosis involving the uterus and its ligaments, adnexa, bowel, distal ureters, urinary bladder, and pelvic nerves. Additionally, MRI can help detect extra-pelvic organ involvement in the same study. Use of a dedicated MRI protocol and structured reporting template improves multidisciplinary communication and provides a pre-surgical road map; helps patient counseling as well as assessing the need for additional intraoperative organ-specific expertise such as colorectal surgery or urology. Knowledge of MRI and laparoscopic correlation enhances recognition of the key MRI findings to include in the report for optimizing surgical outcomes. This article focuses on the role of MRI in the diagnosis and pre-surgical mapping of pelvic endometriosis, with correlation to laparoscopic findings. 1. 5.
Fertility AwarenessWearable Temperature SensorsDevice ValidationTemperature-Based Methods
Open Access
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 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.
General OB/GYNGut-Brain AxisMicrobiome-Derived BiomarkersNarrative Review
Open Access
Emerging research underscores the pivotal role of the gut–immune–brain axis, a dynamic bidirectional communication system involving intricate interactions between the gut microbiota, immune responses, and the central nervous system. Gut microbes and their metabolites have profound effects on immune and neurological homeostasis, influencing the development and function of multiple physiological systems. Disruption of the composition of the gut microbiota and barrier integrity has been implicated in various neurological and psychiatric disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, depression, and anxiety. Most insights into these host–microbiota interactions come from preclinical models, revealing both the complexity and potential therapeutic opportunities of the gut–brain communication pathways. This review synthesizes the current understanding of these intricate interactions, exploring how microbiota-driven modulation of the gut and brain barriers, immune signaling, and neuronal pathways, such as those through the vagus nerve, contributes to health and disease. We further explore therapeutic implications, including personalized precision microbiota interventions, microbiome-derived biomarkers, and barrier-strengthening strategies. Advancing this field offers transformative potential for developing innovative, personalized therapies tailored to individual microbiomes and immune profiles, ultimately redefining clinical approaches to neurological and immune-mediated diseases.
DiagnosticsUrinary MetabolitesHormonalClinical Outcomes
Open Access
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.
EndometriosisEnvironmental Chemical ExposureTissue Chemical AnalysisPFAS
Open Access
Perand polyfluoroalkyl substances (PFAS) exposure is widespread and has been linked with gynecologic disease. To our knowledge, no study has measured PFAS in endometrial tissue. Eutopic endometrial tissue specimens (n=434) were collected from Investigating Mixtures of Pollutants and Endometriosis in Tissue (IMPLANT) study participants undergoing laparoscopy or laparotomy for any indication (2007-2009). Nine PFAS were measured by high-performance liquid chromatography-tandem mass spectrometry [perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorododecanoic acid (PFDoDA), perfluoroheptanoic acid (PFHpA), perfluorooctanesulfonamide (PFOSA), and perfluoroundecanoic acid (PFUnDA)]. Surgeons diagnosed endometriosis by gold-standard visualization and evaluated the endometriosis staging as moderate and severe (stages 3 and 4) compared to minimal and mild (stages 1 and 2) using American Society of Reproductive Medicine (ASRM) classification. We used modified Poisson regression models adjusted for age (continuous), race (white, all other race/ethnicities), smoking status (serum cotinine >10 ng/mL), study site (Utah, California), and body mass index (continuous) to obtain relative risks (RR) of endometriosis diagnosis and 95% confidence intervals (CIs) for each PFAS. PFAS mixtures were evaluated using Bayesian kernel machine regression. Participants were, on average, 33±7 years old, and 75% of participants were non-Hispanic white. Of the 181 participants with an incident endometriosis diagnosis, 73% had ASRM stage 1 or 2, while 27% had stage 3 or 4. Median [interquartile range (IQR)] eutopic endometrium tissue levels, in nanograms per gram, were 6.58 (6.44) for PFOS, 1.93 (1.71) for PFOA, 0.65 (0.75) for PFHxS, 0.58 (0.52) for PFNA, and 0.12 (0.18) for PFOSA. PFAS in the endometrial tissue was not associated with endometriosis. However, select PFAS in the eutopic tissue were associated with a risk of more advanced (stage 3 or 4 vs. 1 or 2) endometriosis [PFOSA RR=1.25 (95% CI: 1.10, 1.43), PFHxS RR=1.37 (95% CI: 1.12, 1.68), PFOS RR=1.36 (95% CI: 1.02, 1.81)]. PFAS were widely detected in eutopic endometrial tissue. There was no evidence that PFAS in endometrial tissue were associated with a higher risk of endometriosis diagnosis. However, PFOS, PFOSA, and PFHxS in the endometrial tissue were associated with risk of more severe stage of endometriosis. //doi.org/10.1289/EHP15852.
Menstrual CycleCardiac Electrophysiology EffectsCardiovascularMenstrual Cycle Variations
Open Access
Medical gaslighting, in which a patient's concerns are dismissed without proper evaluation, has been described anecdotally in vulvovaginal patient care, but has not been quantified. To use a patient-centered instrument to measure adverse experiences in vulvovaginal care. DESIGN, SETTING, Common themes from National Vulvodynia Association patient testimonials were used to design a mixed-methods measure of patient experience that included both quantitative and qualitative questions. An instrument was created and submitted to officers from the National Vulvodynia Association and Tight-Lipped, another patient advocacy organization, for feedback. The measure was then completed by patients before their first appointment at a vulvovaginal disorder referral clinic from August 2023 to February 2024. Participation in the survey. The primary outcome was the incidence of reported clinician behavior and consequent distress as reported on the survey instrument. Quantitative data were analyzed using simple descriptive statistics (mean [SD], median [IQR], and percentage). Narrative responses provided by patients were analyzed using the clinical-qualitative method for content analysis. A total of 520 patients completed surveys; 5 were eliminated because the patient was younger than 18 years, 6 were eliminated for duplication, 6 were eliminated because they had no past clinician, and 56 were eliminated for completely blank responses. Thus, surveys of 447 patients (mean [SD] age, 41.7 [15.2] years) were analyzed (86% response rate). Patients had a mean (SD) of 5.50 (4.53) past clinicians. Patients reported that a mean (SD) of 43.5% (33.9%) of past practitioners were supportive, 26.6% (31.7%) were belittling, and 20.5% (30.9%) did not believe the patient. In total, 186 patients (41.6%) were told they just needed to relax more, 92 (20.6%) were recommended to drink alcohol, 236 (52.8%) considered ceasing care because their concerns were not addressed, 92 (20.6%) were referred to psychiatry without medical treatment, 72 (16.8%) felt unsafe during a medical encounter, and 176 (39.4%) said they were made to feel crazy, the most distressing surveyed behavior (rated at a mean [SD] of 7.39 [3.06] of 10 on a numerical rating scale of distress). A total of 1150 quotations were analyzed qualitatively; common themes included lack of clinician knowledge (247 quotations) and dismissive behaviors (211 quotations). In this cross-sectional study, a patient-centered measure of adverse experiences in vulvovaginal care was developed. Participants reported common past experiences with gaslighting and substantial distress; they frequently considered ceasing care. There is an urgent need for education supporting a biopsychosocial, trauma-informed approach to vulvovaginal pain and continued development of validated instruments to quantify patient experiences.
Reproductive EndocrinologyVaccine EffectsCOVID-19 VaccinationAMH and AFC
Open Access
This study aimed to elucidate the effects of messenger RNA (mRNA) and inactivated coronavirus disease 2019 (COVID-19) vaccines on ovarian histology and reserve in rats. Thirty female Wistar albino rats, aged 16-24 weeks, were randomly divided into three groups (n = 10): control, mRNA vaccine, and inactivated vaccine groups. Each vaccine group received two doses (on day 0 and day 28) at human-equivalent doses. Four weeks post-second vaccination, ovarian tissues were harvested for analysis. Immunohistochemical analysis was performed to evaluate the expression of transforming growth factor beta-1 (TGF-β1), vascular endothelial growth factor (VEGF), caspase-3, and anti-Müllerian hormone (AMH) in ovarian follicles. Both vaccines induced significant increases in TGF-β1, VEGF, and caspase-3 expression, with more pronounced effects in the mRNA vaccine group. Conversely, AMH expression in the granulosa cells of primary, secondary, and antral follicles showed marked reductions (p < 0.001). The counts of primordial, primary, and secondary follicles decreased significantly in the inactivated vaccine group relative to controls and further in the mRNA vaccine group compared to the inactivated group (p < 0.001). Additionally, the mRNA vaccine group exhibited a decrease in antral and preovulatory follicles and an increase in atretic follicles compared to the other groups (p < 0.05). The serum AMH level was diminished with the mRNA vaccination in comparison with the control and inactivated groups. Our findings suggest that both mRNA and inactivated COVID-19 vaccines may detrimentally impact ovarian reserve in rats, primarily through accelerated follicular loss and alterations in apoptotic pathways during folliculogenesis. Given these observations in a rat model, further investigations into the vaccines' effects on human ovarian reserve are needed.
Menstrual CycleCycle VariabilityUrinary Hormone MonitoringHeat Map Analysis
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. 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.
EndometriosisOvarian Cancer RiskPlasma MicroRNAEarly Cancer Detection
Ectopic pregnancy occurs when a fertilized egg implants outside the uterine cavity, a condition that affects approximately 1% to 2% of pregnancies in the United States. Ectopic pregnancy is a potentially life-threatening condition and accounts for 2.7% of pregnancy-related deaths. Most ectopic pregnancies (approximately 97%) occur within the fallopian tube, commonly linked to underlying fallopian tube abnormalities. Such abnormalities may result from prior infections (eg, gonorrhea or chlamydia), tubal surgeries (including sterilization), prior ectopic pregnancies, or exposure to diethylstilbestrol in utero. Additional risk factors include conception while using intrauterine devices (IUDs) or progesterone-only contraceptives. Although rare, ectopic pregnancies can also occur outside the fallopian tube, such as in the cervix, ovary, abdomen, uterine cornua, or cesarean scars. These extratubal ectopic pregnancies are less likely to be associated with the typical risk factors or tubal pathology, making their diagnosis and management particularly challenging. Regardless of the location, early detection is critical for conservative treatment and improving outcomes. Ectopic pregnancy often causes lower abdominal pain, typically on one side, along with vaginal bleeding. Symptoms like dizziness, fainting, shoulder pain, or severe pelvic pain may indicate a ruptured ectopic pregnancy. However, these signs can mimic other conditions, eg, early normal intrauterine pregnancy, miscarriage, ovarian cyst rupture, or appendicitis. Therefore, differentiating ectopic pregnancy from conditions with similar clinical features can be difficult, making prompt medical evaluation crucial for accurate diagnosis and treatment. Management primarily aims to preserve fertility, improve diagnostic accuracy, and provide psychological support. Treatment varies, depending on clinical stability, ectopic location, beta-human chorionic gonadotropin (β-hCG) levels, and ultrasound findings ranging from expectant management to surgical interventions. In select cases, nonsurgical treatment with methotrexate may be effective, especially when pregnancies are diagnosed early and meet specific criteria. However, medical treatment is less likely to succeed in cases involving larger masses, high β-hCG levels, or visible embryos. Advanced or ruptured cases typically require urgent surgical intervention.
Ethics/PhilosophyRacial Equity in HealthcareAlgorithmic AuditingHealth Equity and Technology
Endometriosis, affecting 11% of reproductive-aged persons, is characterized by ectopic endometrial tissue and chronic inflammation. Prior research suggests those with endometriosis have higher cardiovascular disease risk, but mechanisms remain elusive. The objective of this study is to assess whether endometriosis diagnosis, staging, and typology (superficial endometriosis (SE), ovarian endometriomas (OE), and deep infiltrating endometriosis (DE)) are associated with serum interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-) concentrations. The study analyzed data from 395 premenopausal persons in Utah undergoing gynecologic laparoscopy who participated in the NICHD ENDO study (2007–2009). Post-operative reports determined endometriosis typology (SE, OE, DE) and staging (minimal, mild, moderate, severe) using Revised American Society for Reproductive Medicine classification. Elevated serum cytokine concentrations were defined as IL-6 ≥2pg/mL, IL-8 ≥3pg/mL, and TNF- ≥7.5pg/mL. Generalized linear models generated adjusted prevalence ratios (aPR) 95% CI controlling for age, BMI, marital status, race/ethnicity, and serum cotinine. Participants were on average 32 years (SD=7) at time of gynecologic laparoscopy/laparotomy, non-Hispanic white (79%), married (71%), mean BMI 28 (SD=8) and non-smokers (83% serum cotinine <10ng/mL). Forty-two percent (n=166) were diagnosed with incident endometriosis. We found no differences among those with, compared to without, endometriosis and elevated IL-6, 12% vs 10%, 1.01 (0.97, 1.10), IL-8, 5% vs 8%, 0.99 (0.94, 1.04); and TNF, 16% vs 13%, 1.00 (0.96, 1.04). While there were no statistically significant associations between endometriosis staging or typology and cytokines, those with moderate to severe endometriosis had nonsignificant lower IL-6 and IL-8 (aPR: 0.61 [0.15, 2.52] 0.74 [0.17, 3.20]) but higher TNF- (aPR: 1.27 [0.56, 2.84]), compared to no endometriosis. Individuals with OE and DE had nonsignificant trends of IL-6 and Il-8 (aPR: 0.86 [0.11, 2.52] 0.93 [0.14, 6.43]) but higher TNF- (aPR: 1.93 [0.77, 4.84]). In summary, this study found no clear correlation between endometriosis diagnosis, staging, typology and inflammatory markers IL-6, IL-8, and TNF-. Whether endometriosis severity or typology is associated with TNFshould be explored in future studies with adequate power and more representative samples.
EndometriosisCardiovascular RiskStaging and TypologyLipid Biomarkers
Individuals with endometriosis, a gynecologic condition affecting approximately 11% of people with a uterus, may have an elevated risk for developing cardiovascular disease (CVD) later in life. However, the mechanisms underlying this association are not well understood. We investigated the association between incident endometriosis diagnosis, staging, and typology and lipid biomarkers measured at time of diagnostic surgery among women participating in the NICHD ENDO study (n=395). Endometriosis was categorized using the American Society for Reproductive Medicine staging (I−IV). Endometriosis typology was defined by lesion depth and location and categorized as superficial endometriosis (SE), ovarian endometrioma (OE), and deep infiltrating endometriosis (DE). With no endometriosis as our reference, we evaluated the associations between endometriosis diagnosis, stage (I/II vs III/IV), and typology (SE, OE, DE, OE+DE) and dyslipidemia using standard clinical thresholds (total cholesterol ≥200 mg/dL, high-density lipoprotein (HDL) <50 mg/dL, low-density lipoprotein (LDL) ≥100 mg/dL, triglycerides ≥175 mg/dL, non-HDL ≥130 mg/dL, VLDL ≥30 mg/dL, Apolipoprotein A-1 (APO-A1) <125 mg/dL, Apolipoprotein B (APOB) ≥120 mg/dL; APOB/APO-A1 ratio >0.78). We calculated adjusted prevalence ratios (aPR) and 95% CIs via generalized linear models, controlling for age, race/ethnicity, marital status, BMI, income (poverty level), and serum cotinine as a marker of smoking. At the time of gynecologic surgery, individuals were mean 32 years (SD: 7 years), non-Hispanic white (79%), married (71%), and mean BMI 28 (SD=8). While we found no differences in endometriosis diagnosis or endometriosis staging and dyslipidemia (
Figure 1; Table 1
), a pattern emerged regarding endometriosis typology (
Table 2
). Women with OE+DE, compared to no endometriosis, had increased total cholesterol >200 1.87 (0.99, 3.57); >
175 2.48 (1.34, 4.57); VLDL ≥30 2.08 (1.28, 3.38); and APOB mg/dL ≥120: 2.86 (1.22, 6.66). OE appeared to be driving this association. SE was not associated with dyslipidemia. The association between endometriosis, especially of more severe typology, and subsequent CVD may be through dyslipidemia, which may be detectable at the time of endometriosis diagnosis. Further research in larger, more representative samples is needed before definitive conclusions can be made.
General OB/GYNHypertension ManagementDigital Health InterventionsmHealth EHR Integration
Open Access
Adediran E et al., 2025·Oxford Open Digital Health
Black/African American individuals face twice the risk of hypertension compared to non-Hispanic Whites in the United States (US). A synergistic strategy integrating primary care with Electronic Health Records (EHR) and mobile health (mHealth) technologies may help address hypertension disparities. This unique strategy prioritizes early disease identification, improved care access, and self-management. However, limited research exists on how primary care can effectively integrate these components to reduce hypertension in Black/African American individuals. We aimed to (i) identify characteristics of Black/African American populations represented in EHR-driven mHealth interventions for hypertension management in primary care settings and (ii) identify the specific EHR-driven mHealth interventions. We used the PubMed, Web of Science, and Scopus databases to identify studies conducted in the US. The included articles focused on (i) Black/African American individuals, (ii) EHR and mHealth integration; (iii) primary care setting, and (iv) hypertension or blood pressure as the outcome. We screened 749 studies and synthesized 14. Combined, Black/African American patients were female (61%), 52.6 years on average, with diabetes health comorbidity (35%). Included studies utilized health monitoring devices (n = 14), smartphone applications (n = 11), interactive messaging (n = 8), and patient portals (n = 3). These tools facilitated health monitoring (n = 14), social networking (n = 3), and lifestyle counseling (n = 14). EHR-mHealth technologies in primary care show promise to improve hypertension management in Black/African American populations. Current interventions focus on enhancing health education access, continuous health monitoring, patient–physician communication, and social engagement. Further research is needed to optimize integration into clinical workflow for hypertension management.
EndometriosisTypology and StagingInfertility RiskEndometriosis Staging
Open Access
To determine whether endometriosis typology, namely ovarian endometriomas (OE), deep infiltrating endometriosis (DIE), or superficial endometriosis (SE), correlates with fertility history.
Prospective cohort.
One of fourteen surgical centers in Salt Lake City, Utah (n = 5) or San Francisco, California (n = 9). A total of 473 women (18-44 years) with no prior endometriosis diagnosis, undergoing laparoscopies/laparotomies, irrespective of indication, in Utah or California (2007-2009). Incident endometriosis. Before surgery, we queried women about time to become pregnant for prior planned pregnancies. Generalized linear models were used to calculate adjusted prevalence ratios (aPR) for association between endometriosis typology and infertility, defined as having ever tried >12 months (>6 months for women ≥35 years) to get pregnant. We also generated fecundability odds ratios (aFOR) to capture time to pregnancy. Twenty-five percent (n = 116) of women were diagnosed with SE only, 5% (n = 23) with OE, 6% (n = 29) with DIE, and 5% (n = 22) with OE + DIE, and 60% (n = 283) with no endometriosis. Compared with women with no endometriosis, women with SE had a 1.58 higher aPR (95% confidence interval [CI], 1.16-2.14), although women with OE and/or DIE had a 2.41 higher aPR for subfertility after adjusting for women's age, body mass index, and site. Compared with women with no endometriosis, women with OE and/or DIE had a 53% lower historic fecundability (aFOR, 0.47; 95% CI, 0.24-0.95); however, no association was found among women with SE (aFOR, 0.81; 95% CI, 0.49-1.33). Specific endometriosis typologies may be associated with fecundability, with OE and/or DIE associated with nearly a 150% higher prevalence of subfertility and over a 50% lower historic fecundability.
Chronic endometritis (CE), frequently asymptomatic, is associated with female infertility. Fallopian tube obstruction (FTO) is also one of the factors contributing to female infertility. More than 90% of cases of proximal FTO can be successfully treated after fallopian tubal recanalization (FTR) and the spontaneous pregnancy rate of treated women after FTR is only about 30%. Potential factors affecting the success rate of FTR remain unclear. We speculate that CE may be one of the reasons affecting the recanalization of the fallopian tubes. To identify the correlation between CE and FTO, as well as the influence of CE on pregnancy outcomes following FTR.
Retrospective observational study. We retrospectively analyzed 498 women of childbearing age who underwent laparoscopy and hysteroscopy surgery for infertility. Endometrial samples were collected during surgery for CD138 immunohistochemistry staining for the diagnosis of CE. Based on the results of the tubal patency test, they the fallopian tubal patency group and the proximal FTO group. The prevalence of CE was compared between these two groups. All women with FTO underwent FTR during the operation until successful treatment was achieved. Pregnancy outcomes were assessed after a 12-month follow-up period following the procedures. Logistic regression was used to analyze factors that might affect pregnancy after FTR. The prevalence of CE in women with tubal obstruction was 30.5%, which was significantly higher than that in the fallopian tubal patency group (10.75%), p < 0.001. After FTR, the prevalence of CE in non-pregnant women was 40.18%, which was higher than that in pregnant women (40.18% vs 13.11%), and the difference was significant (p < 0.001). Multiple regression analysis showed that CE was a significant risk factor for FTO (OR: 2.54, 95% CI: 1.368-4.717, p < 0.05). In addition, CE was identified as a risk factor for infertility after FTR (OR: 4.730, 95% CI: 2.012-11.122). The presence of CE seems to decrease the likelihood of achieving spontaneous pregnancy following FTR. This observation underscores the clinical importance of early detection and treatment of CE, emphasizing the necessity for immediate intervention to prevent potential fertility complications.
EndometriosisAdministrative Data ValidationHealth RecordsClaims Data Accuracy
Open Access
How do endometriosis diagnoses and subtypes reported in administrative health data compare with surgically confirmed disease? For endometriosis diagnosis, we observed substantial agreement and high sensitivity and specificity between administrative health data-International Classification of Diseases (ICD) 9 codes-and surgically confirmed diagnoses among participants who underwent gynecologic laparoscopy or laparotomy. Several studies have assessed the validity of self-reported endometriosis in comparison to medical record reporting, finding strong confirmation. We previously reported high interand intra-surgeon agreement for endometriosis diagnosis in the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. STUDY DESIGN, SIZE, In this validation study, participants (n = 412) of the Utah operative cohort of the ENDO Study (2007-2009) were linked to medical records from the Utah Population Database (UPDB) to compare endometriosis diagnoses from each source. The UPDB is a unique database containing linked data on over 11 million individuals, including statewide ambulatory and inpatient records, state vital records, and University of Utah Health and Intermountain Healthcare electronic healthcare records, capturing most Utah residents. PARTICIPANTS/MATERIALS, SETTING, The ENDO operative cohort consisted of individuals aged 18-44 years with no prior endometriosis diagnosis who underwent gynecologic laparoscopy or laparotomy for a variety of surgical indications. In total, 173 women were diagnosed with endometriosis based on surgical visualization of disease, 35% with superficial endometriosis, 9% with ovarian endometriomas, and 14% with deep infiltrating endometriosis. Contemporary administrative health data from the UPDB included ICD diagnostic codes from Utah Department of Health in-patient and ambulatory surgery records and University of Utah and Intermountain Health electronic health records. MAIN For endometriosis diagnosis, we found relatively high sensitivity (0.88) and specificity (0.87) and substantial agreement (Kappa [Κ] = 0.74). We found similarly high sensitivity, specificity, and agreement for superficial endometriosis (n = 143, 0.86, 0.83, Κ = 0.65) and ovarian endometriomas (n = 38, 0.82, 0.92, Κ = 0.58). However, deep infiltrating endometriosis (n = 58) had lower sensitivity (0.12) and agreement (Κ = 0.17), with high specificity (0.99). LIMITATIONS, Medication prescription data and unstructured data, such as clinical notes, were not included in the UPDB data used for this study. These additional data types could aid in detection of endometriosis. Most participants were white or Asian with Hispanic ethnicity reported 11% of the time, which may limit generalizability to some US states. Additionally, given that participants whose administrative health records we utilized were also part of the ENDO Study, the surgeons may have been more vigilant in diagnostic coding due to the operative forms they completed for the ENDO Study, which may have led to increased validity. However, the codes compared in the UPDB would have been entered by medical coders as part of standard clinical practice. We observed substantial agreement between administrative health data and surgically confirmed endometriosis diagnoses overall, and for superficial and ovarian endometrioma subtypes. These findings may provide reassurance to researchers using administrative healthcare records to assess risk factors and long-term health outcomes of endometriosis. Our findings corroborate prior research that demonstrates high specificity but low sensitivity for deep infiltrating endometriosis, indicating deep infiltrating endometriosis is not reliably annotated in administrative healthcare data. This suggests that medical record-based deep infiltrating endometriosis diagnoses may be suitable for etiologic studies but not for surveillance or detection studies. STUDY FUNDING/COMPETING INTEREST(S): The original ENDO Study was funded by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contracts NO1-DK-6-3428; NO1-DK-6-3427; 10001406-02). We acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah's program in Personalized Health and Center for Clinical and Translational Science. This research was also supported by the NCRR grant, 'Sharing Statewide Health Data for Genetic Research' (R01 RR021746, G. Mineau, PI) with additional support from the Utah Department of Health and Human Services, University of Utah. Additionally, this research was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. Research reported in this publication was also supported by the National Institutes of Health (Award Numbers R01HL164715 [to L.V.F., K.C.S., and A.Z.P.] and K01AG058781 [to K.C.S.]), by the Huntsman Cancer Institute's Breast and Gynecologic Cancers Center, and by the Doris Duke Foundation's COVID-19 Fund to Retain Clinical Scientists funded by the American Heart Association. A.C.K. was supported by Training Grant Number 5T15LM007124 from the National Library of Medicine to K.E. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other sponsors. There are no competing interests among any of the authors. N/A.
DiagnosticsAMH for POIScreeningAMH Biomarker
Open Access
Premature ovarian insufficiency/failure (POI/POF) is a significant issue for women of reproductive age. Anti-Müllerian hormone (AMH) is a potential biomarker of ovarian reserve, but its clinical value in diagnosing and predicting POI/POF remains unclear. This study aimed to analyze the correlation between AMH and basal follicle-stimulating hormone (FSH) levels in women aged 18 to 40 and evaluate AMH's predictive value for POI/POF. A total of 21,143 participants aged 18-40 who visited the gynecology department or underwent physical examinations at the International Peace Maternity and Child Health Hospital in Shanghai, China, from July 2016 to June 2021 were enrolled. Demographic information and laboratory test results were collected, including age, FSH, AMH, E2 and test dates. Participants were grouped by FSH and AMH levels, and subgroup analyses were performed to investigate the relationship between these hormones and age. The AMH level associated with POI risk was evaluated using restricted cubic splines (RCS) and logistic regression. Clinical benefit was assessed by decision curve analysis (DCA). Participants with higher FSH levels had significantly lower median AMH levels and vice versa(p<0.001). At AMH ≥ 0.5 ng/mL, FSH levels were normal or slightly elevated with age. At AMH level below 0.5ng/ml,basal FSH increased significantly with age. At FSH <10 IU/L, AMH levels show a trend of rising and then decreasing with age, reaching a peak at approximately 25 years old and gradually decreasing with age. At FSH ≥10 IU/L, AMH levels show a gradual downward trend with age, and at FSH >40 IU/L, AMH levels remain very low to undetectable values. The RCS showed that the risk of POI/POF in the overall population sharply increased until serum AMH reached a low level (below 0.5ng/ml). DCA showed that a low AMH level had good clinical diagnostic utility in predicting POI/POF. Our analysis of a large dataset suggests that serum AMH levels are inversely correlated with FSH levels and that AMH is a good predictor of POI until it drops to a low level.
InfertilityEndometrial PolypsVitamin D and Reproductive HealthEndometrial Pathology Detection
Are serum vitamin D levels associated with the incidence of endometrial polyps (EPs) in infertile patients? Serum 25(OH)D levels were nonlinearly correlated with the incidence of EPs in infertile women. EPs are a common condition that may affect the receptivity of the endometrium in women of reproductive age. Vitamin D regulates cell proliferation and differentiation, apoptosis, angiogenesis, anti-inflammation, and immunomodulation, in addition to its well-known functions in balancing calcium and phosphorus. Previous studies have shown that vitamin D concentrations are associated with reproductive outcomes, and that low vitamin D levels are associated with the incidence of colorectal polyps and nasal polyps. There is little evidence regarding the relationship between EPs and serum vitamin D levels. STUDY DESIGN, SIZE, We conducted a cross-sectional study using data from Guangdong Women and Children Hospital from January 2019 to October 2023, enrolling 3107 patients. PARTICIPANTS/MATERIALS, SETTING, A total of 3107 infertile patients who underwent hysteroscopy were included in this study; 642 patients had endometrial polyps and 2465 had a normal uterine cavity. Hysteroscopy findings included risk of EPs, polyp size, percentage of multiple polyps, and incidence of chronic endometritis (CE). Serum vitamin D were assessed by measuring total 25(OH)D using chemiluminescence. According to international guideline recommendations for vitamin D deficiency, patients the <50 nmol/l group and the ≥50 nmol/l group. Univariable and multivariable logistic regression models, stratified analyses, and smooth curve fitting were used to examine the relationship between serum 25(OH)D levels and risk of EPs. MAIN Of all patients, 23.8% (740/3107) were vitamin D deficient (<50 nmol/l). The incidence of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group (24.9% vs 19.3%; P = 0.001). However, there were no differences in polyp size, proportion of multiple polyps, and presence of CE between the two groups. After controlling for confounders, 25(OH)D ≥ 50 nmol/l (compared with <50 nmol/l) was negatively associated with risk of EPs (adjusted OR, 0.733; 95% CI, 0.598-0.898). Other variables that had an impact on polyp incidence included BMI, type of infertility, CA125, and CD138-positive plasma cells. In addition, a linear regression model between age and serum 25(OH)D levels showed a positive linear association. Subgroup analyses were performed for different age groups, and the risk of EPs was significantly higher in the 25(OH)D < 50 nmol/l group than in the ≥50 nmol/l group, both in the younger subgroup (23.8% vs 19.1%) and in the older subgroup (28.0% vs 19.9%). The smooth curve fitting model showed a nonlinear correlation between 25(OH)D levels and risk of EPs (nonlinear P-value = 0.020), with an optimal threshold of 51.8 nmol/l for 25(OH)D levels. Moreover, subgroup smooth curve fitting models showed a nonlinear correlation between 25(OH)D levels and polyp risk in patients aged <35 years (nonlinear P-value = 0.010), whereas a linear correlation between 25(OH)D levels and polyp risk was found in patients aged ≥35 years (nonlinear P-value = 0.682). LIMITATIONS, Caution should be exercised in interpreting our findings as this is a correlational study and causality cannot be inferred from our results. In addition, because of strict inclusion and exclusion criteria, our results may not be generalizable to unselected populations, including premenopausal women or women of other races. This study demonstrated for the first time that vitamin D deficiency is an independent risk factor for the incidence of EPs in infertile patients. Identifying modifiable risk factors (e.g. vitamin D deficiency) can help in the development of new strategies for treating polyps or to protect against polyp development. Further clinical intervention trials and laboratory studies are needed to evaluate the effect of vitamin D on the development of EPs and to elucidate the mechanisms. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Natural Science Foundation of China (82101718) and Natural Science Foundation of Guangdong Province, China (2022A1515010776). No competing interest was involved in this study. N/A.
Could the risk of subsequent pregnancy loss be predicted based on the risk factors of recurrent pregnancy loss (RPL) patients? A nomogram, constructed from independent risk factors identified through multivariate logistic regression, serves as a reliable tool for predicting the likelihood of subsequent pregnancy loss in RPL patients. Approximately 1-3% of fertile couples experience RPL, with over half lacking a clear etiological factor. Assessing the subsequent pregnancy loss rate in RPL patients and identifying high-risk groups for early intervention is essential for pregnancy counseling. Previous prediction models have mainly focused on unexplained RPL, incorporating baseline characteristics such as age and the number of previous pregnancy losses, with limited inclusion of laboratory and ultrasound indicators. STUDY DESIGN, SIZE, The retrospective study involved 3387 RPL patients who initially sought treatment at the Reproductive Immunology Clinic of Renji Hospital, Shanghai Jiao Tong University School of Medicine, between 1 January 2020 and 31 December 2022. Of these, 1153 RPL patients met the inclusion criteria and were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, RPL was defined as two or more pregnancy losses (including biochemical pregnancy loss) with the same partner before 28 weeks of gestation. Data encompassing basic demographics, laboratory indicators (autoantibodies, peripheral immunity coagulation, and endocrine factors), uterine and endometrial ultrasound results, and subsequent pregnancy outcomes were collected from enrolled patients through initial questionnaires, post-pregnancy visits fortnightly, medical data retrieval, and telephone follow-up for lost patients. R software was utilized for data cleaning, dividing the data into a training cohort (n = 808) and a validation cohort (n = 345) in a 7:3 ratio according to pregnancy success and pregnancy loss. Independent predictors were identified through multivariate logistic regression. A nomogram was developed, evaluated by 10-fold cross-validation, and compared with the model incorporating solely age and the number of previous pregnancy losses. The constructed nomogram was evaluated using the AUC, calibration curve, decision curve analysis (DCA), and clinical impact curve analysis (CICA). Patients were then categorized into lowand high-risk subgroups. MAIN We included age, number of previous pregnancy losses, lupus anticoagulant, anticardiolipin IgM, anti-phosphatidylserine/prothrombin complex IgM, anti-double-stranded DNA antibody, arachidonic acid-induced platelet aggregation, thrombin time and the sum of bilateral uterine artery systolic/diastolic ratios in the nomogram. The AUCs of the nomogram were 0.808 (95% CI: 0.770-0.846) in the training cohort and 0.731 (95% CI: 0.660-0.802) in the validation cohort, respectively. The 10-fold cross-validated AUC ranged from 0.714 to 0.925, with a mean AUC of 0.795 (95% CI: 0.750-0.839). The AUC of the nomogram was superior compared to the model incorporating solely age and the number of previous pregnancy losses. Calibration curves, DCAs, and CICAs showed good concordance and clinical applicability. Significant differences in pregnancy loss rates were observed between the lowand high-risk groups (P < 0.001). LIMITATIONS, This study was retrospective and focused on patients from a single reproductive immunology clinic, lacking external validation data. The potential impact of embryonic chromosomal abnormalities on pregnancy loss could not be excluded, and the administration of medication to all cases impacted the investigation of risk factors for pregnancy loss and the model's predictive efficacy. This study signifies a pioneering effort in developing and validating a risk prediction nomogram for subsequent pregnancy loss in RPL patients to effectively stratify their risk. We have integrated the nomogram into an online web tool for clinical applications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Natural Science Foundation of China (82071725). All authors have no competing interests to declare. N/A.
General OB/GYNUterine NicheCesarean Scar Niche DetectionCesarean Scar Defect and Fertility
Open Access
The increasing prevalence of cesarean section (CS) deliveries globally has sparked apprehension regarding potential long-term complications, notably the emergence of uterine niches. CS results in a scar that in certain patients, inadequate healing of that scar results in the development of a uterine niche. While most small niches show no symptoms, large cesarean scar niches in nonpregnant women can give rise to cesarean scar disorder syndrome. This syndrome is characterized by abnormal uterine bleeding, dysmenorrhea, and secondary infertility. In pregnant women, the presence of substantial niches may be linked to potentially life-threatening complications, including cesarean scar dehiscence, uterine rupture, placenta accreta spectrum disorders, placenta previa, and cesarean scar ectopic pregnancy.
Given the potential dangers associated with uterine niche occurrence, numerous studies in recent years have delved into the concept of cesarean scar niche, exploring its risk factors, diagnostic approaches, and treatment options. Various diagnostic modalities, such as twoor three-dimensional transvaginal ultrasonography, twoand three-dimensional sono-hysterography, hysterosalpingography, hysteroscopy, or magnetic resonance imaging, can be employed to detect uterine niches. However, none of these diagnostic methods is universally accepted as the “gold standard,” and there remains a lack of unequivocal guidelines on certain aspects related to the diagnosis of cesarean scar niche. These niches, characterized by hypoechoic regions within the myometrium at the site of a previous CS scar, pose diagnostic complexities and provoke inquiries into their prevalence, factors influencing their development, clinical presentations, and appropriate therapeutic approaches.
As CS rates rise, this review aims to understand and address uterine niches and mitigate their impact on maternal health and reproductive outcomes.
EndometriosisNoninvasive BiomarkersGastrointestinal Myoelectrical ActivityGI Involvement
Open Access
Endometriosis represents substantial direct and indirect healthcare costs impacted by an absence of uniformly accurate, non-invasive diagnostic tools. We endeavored to demonstrate gastrointestinal myoelectrical activity (GIMA) biomarkers, unique to endometriosis, will allow non-invasive, uniformly accurate diagnosis or exclusion of endometriosis. Prospective open-label comparative study of 154 patients, age ≥ 18, with or without diagnosed endometriosis. Population included 62 non-endometriosis controls (Cohort 1), 43 subjects with surgically/histologically confirmed endometriosis (Cohort 2), and 49 subjects with abdominal pain and negative imaging (Cohort 3). Non-invasive electroviscerography (EVG) recorded GIMA biomarkers from three abdominal electrodes before and 30 min post water load protocol. Cohort 2 had postoperative EVG and Cohort 3 had preoperative EVG. Calculated specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and predictive probability or C-statistic used univariate, multivariate, linear, and logistical regression analyses of the area under the curve (AUC) at all frequency and time points, including age and pain covariants. The non-endometriosis cohort differed significantly from the endometriosis cohorts (p < 0.001) for median (IQR) and AUC percent frequency distribution of power at baseline, 10 min, 20 min, and 30 min post water 15-20 cpm, 30-40 cpm, and 40-50 cpm. The endometriosis cohorts were statistically similar (p > 0.05). GIMA biomarker threshold scoring demonstrated 95%/91% sensitivity and PPV, 96%/95% specificity and NPV, and a C-statistic of >99%/98%, respectively, for age subsets. GIMA biomarkers in Cohort 3 predicted 47/49 subjects positive and 2/49 negative for endometriosis, confirmed surgically. Hormonal therapy, surgical stage, nor pain score affected diagnostic accuracy. EVG with GIMA biomarker detection distinguished participants with and without endometriosis based upon endometriosis-specific GIMA biomarkers threshold scoring.
AndrologyOverview and EvaluationCauses and TreatmentSemen Analysis
Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse. It affects about 15% of all couples in the United States and at least 180 million couples worldwide. Male infertility is defined by the World Health Organization (WHO) as the inability of a male to make a fertile female pregnant for a minimum of at least 1 year of regular unprotected intercourse. The male is solely responsible for about 20% of cases and is a contributing factor in another 30% to 40% of all infertility cases. As male and female causes often co-exist, it is essential that both partners are investigated for infertility and managed together. Overall, the male factor substantially contributes to about 50% of all cases of infertility. There are several reasons for male fertility, including both reversible and irreversible conditions. Other factors can influence each partner, including age, medications, surgical history, exposure to environmental toxins, genetic problems, and systemic diseases. The key purpose for evaluating a male for infertility is to identify his contributing factors, offer treatment for those that are reversible, determine if he is a candidate for assisted reproductive techniques (ART), and provide counseling for irreversible and untreatable conditions. Up to 6% of men evaluated for male infertility will be found to have more serious underlying pathology, such as cancer. This is an additional reason to do a comprehensive evaluation of the male partners of infertile couples so that any significant, underlying medical conditions can be identified and treated.
EndometriosisPain CharacterizationPain PhenotypingClinical Applications
Open Access
Endometriosis is a debilitating, chronic disease that is estimated to affect 11% of reproductive-age women. Diagnosis of endometriosis is difficult with diagnostic delays of up to 12 years reported. These delays can negatively impact health and quality of life. Vague, nonspecific symptoms, like pain, with multiple differential diagnoses contribute to the difficulty of diagnosis. By investigating previously imprecise symptoms of pain, we sought to clarify distinct pain symptoms indicative of endometriosis, using an artificial intelligence-based approach. We used data from 473 women undergoing laparoscopy or laparotomy for a variety of surgical indications. Multiple anatomical pain locations were clustered based on the associations across samples to increase the power in the probability calculations. A Bayesian network was developed using pain-related features, subfertility, and diagnoses. Univariable and multivariable analyses were performed by querying the network for the relative risk of a postoperative diagnosis, given the presence of different symptoms. Performance and sensitivity analyses demonstrated the advantages of Bayesian network analysis over traditional statistical techniques. Clustering grouped the 155 anatomical sites of pain into 15 pain locations. After pruning, the final Bayesian network included 18 nodes. The presence of any pain-related feature increased the relative risk of endometriosis (p-value < 0.001). The constellation of chronic pelvic pain, subfertility, and dyspareunia resulted in the greatest increase in the relative risk of endometriosis. The performance and sensitivity analyses demonstrated that the Bayesian network could identify and analyze more significant associations with endometriosis than traditional statistical techniques. Pelvic pain, frequently associated with endometriosis, is a common and vague symptom. Our Bayesian network for the study of pain-related features of endometriosis revealed specific pain locations and pain types that potentially forecast the diagnosis of endometriosis.
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.
PregnancyIron and Vitamin D StatusAntenatal DepressionMicronutrient Assessment in Pregnancy
Open Access
The maternal status of multiple micronutrients during pregnancy and postpartum and their potential associations with maternal health outcomes are largely undescribed. This study aimed to examine associations between maternal iron and vitamin D status, individually and in combination, on depression symptoms in pregnant individuals. The Alberta Pregnancy Outcomes and Nutrition cohort study included pregnant participants and their children from Calgary and Edmonton, Canada. Iron biomarkers (serum ferritin [SF], soluble transferrin receptor, and hepcidin) were measured via immunoassays and vitamin D [25-hydroxyvitamin D3 (25(OH)D3) and 3-epi-25-hydoxyvitamin D3 (3-epi-25(OH)D3)] metabolites were quantifed using liquid chromatography with tandem mass spectroscopy. Four categories of maternal iron and vitamin D status during the second trimester were conceptualized using concentrations of SF and total 25-hydoxyvitamin D [25(OH)D], respectively. Maternal Edinburgh Postnatal Depression Scale (EPDS) scores during the third trimester (n = 1920) and 3 mo postpartum (n = 1822) were obtained. Concentrations of maternal 25(OH)D3, 3-epi-25(OH)D3, and the ratio of both metabolites were significantly higher during the second trimester compared with their status at 3 mo postpartum. Higher second trimester maternal concentrations of SF (β: -0.8; 95% confidence interval [CI]: -1.5, -0.01), hepcidin (β: -0.5; 95% CI: -0.9, -0.2), and 25(OH)D3 (β: -0.01; 95% CI: -0.02, -0.004) predicted lower maternal EPDS scores during the third trimester. Pregnant individuals with a low iron (SF <15 μg/L) and replete vitamin D (25(OH)D ≥75 nmol/L) (β: 1.1; 95% CI: 0.03, 2.1) or low iron (SF <15 μg/L) and vitamin D (25(OH)D <75 nmol/L) (β: 2.2; 95% CI: 0.3, 4.2) status during midpregnancy had higher third trimester EPDS scores compared with those that were replete in both micronutrients. A higher midpregnancy maternal iron and vitamin D status, independently or in combination, predicted fewer maternal depression symptoms in the third trimester. Concentrations of maternal 25(OH)D3 and 3-epi-25(OH)D3 may be lower in the postpartum period compared with midpregnancy.
PregnancyRecurrent Preterm BirthPlacental PathologyProgesterone Supplementation for Preterm Birth
Spontaneous preterm birth significantly increases the risk for a recurrent preterm birth. Only a few identifiable clinical risk factors can be referenced in counseling for recurrent preterm birth. Furthermore, treatment using progesterone supplementation has not consistently prevented preterm birth among high-risk patients, but it may be effective in a subset of those patients. Placental pathology from a previous pregnancy may be used to predict which patients will experience a recurrent preterm birth or to identify a subset of patients more likely to respond to treatment with antenatal progesterone. This study aimed to determine if histologic patterns are associated with recurrent preterm birth among patients with an index spontaneous preterm birth. A secondary objective was to determine if placental histologic types and/or progesterone receptor density in the decidua are associated with the response to progesterone supplementation with intramuscular 17-hydroxyprogesterone caproate. This was a retrospective cohort study at a single institution of women with singleton pregnancies with an index spontaneous preterm birth and a subsequent birth within the same hospital system between 2009 and 2019. Patients were included if placental pathology was available for the index spontaneous preterm birth. A logistic regression was used to determine if there were independent associations between 4 histologic types (acute inflammation, maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammation) and recurrent preterm birth. For the secondary endpoint, 17-hydroxyprogesterone caproate response was defined as prolonging gestation by >3 weeks beyond the gestational age at delivery in the index pregnancy. Patients who delivered <3 weeks beyond the gestational age in the index pregnancy but at ≥39 weeks' gestation were excluded. A logistic regression was used to assess the independent association between placental histology and 17-hydroxyprogesterone caproate response. Sensitivity analyses were completed using only patients with an index birth <36 weeks' gestation, and then excluding those with medically indicated preterm birth in a subsequent pregnancy. A nested case-control immunohistochemical study was done among 20 patients with a subsequent term birth and 20 patients with a subsequent spontaneous preterm birth. The percentage of cells in the maternal decidua positive for progesterone receptors was correlated with the subsequent pregnancy outcome. A total of 352 patients were included. Acute inflammation was the most common histologic type seen among patients with spontaneous preterm birth (44.1%), followed by chronic inflammation (40.9%) and maternal vascular malperfusion (31.3%). No histologic type was independently associated with recurrent preterm birth. A total of 155 patients received 17-hydroxyprogesterone caproate in a second pregnancy. Low-grade acute inflammation was significantly associated with a decreased likelihood of 17-hydroxyprogesterone caproate response. Low-grade maternal vascular malperfusion among those with an index pregnancy delivered at <36 weeks' gestation was significantly associated with a more than 4 times increased likelihood of 17-hydroxyprogesterone caproate response when excluding those with a subsequent iatrogenic preterm birth. Progesterone receptor staining was not associated with recurrent preterm birth. Although acute inflammation was prevalent among spontaneous preterm births, more than half of the spontaneous preterm births were not associated with acute inflammation. Low-grade acute inflammation was associated with a significantly decreased response to 17-hydroxyprogesterone caproate supplementation. Low-grade maternal vascular malperfusion was associated with a 4-fold increased likelihood of 17-hydroxyprogesterone caproate response among those with index deliveries <36 weeks' gestation. Further work is needed to determine if placental pathologic examination can be used to target treatment in subsequent pregnancies to prevent recurrent preterm birth.
Reproductive EndocrinologyThyroid Autoimmunity and IVFIVF Outcomes and Thyroid FunctionTSH Thresholds in Fertility
Open Access
This study aimed to investigate the impact of thyroid autoantibodies and serum TSH levels on clinical IVF outcomes. This study included 260 Korean women scheduled for their first IVF between 2013 and 2017. Serum levels of thyroid hormone, TSH, and antibody for thyroid peroxidase and thyroglobulin were measured just before the first ovarian stimulation. Clinical pregnancy rate (PR), ongoing PR, and miscarriage rate were analyzed according to thyroid autoimmunity and serum TSH levels. The primary outcome was ongoing PR beyond 12 weeks of gestation. The ongoing PR and miscarriage rates were similar between women with positive (n = 29) and negative autoantibodies (n = 186). In women with subclinical hypothyroidism (serum TSH ≥4.2 μIU/mL), ongoing PR was significantly lower than euthyroid women (22.2%, vs. 44.7%, p = 0.045), but miscarriage rate was similar. The group with serum TSH ≥3.4 μIU/mL showed a significantly lower ongoing PR (23.9% vs. 46.7%, p = 0.005) and significantly higher miscarriage rate (38.9% vs. 14.1%, p = 0.020). In multivariate logistic regression analysis, serum TSH ≥3.4 μIU/mL was an independent unfavorable predictor for ongoing PR (odds ratio 0.375, p = 0.013). Thyroid autoantibodies did not affect clinical IVF outcomes, but women with serum TSH ≥3.4 μIU/mL demonstrated poor IVF outcomes.
PregnancyFirst Trimester Anatomy UltrasoundFetal Anatomy Assessment in ObesityPrenatal Imaging
Second-trimester ultrasound is the standard technique for fetal anatomy evaluation in the United States despite international guidelines and literature that suggest that first-trimester timing may be superior in patients with obesity. First-trimester imaging performs well in cohorts of participants with obesity. Our aim was to compare the completion rate of a first-trimester fetal anatomy ultrasound scan with that of a second-trimester fetal anatomy ultrasound scan among pregnant people with a body mass index ≥35 kg/m(2). This randomized controlled trial enrolled participants with a body mass index ≥35 kg/m(2) with a singleton gestation and who presented before 14+0/7 weeks of gestation. Participants were randomized to receive an ultrasound assessment of anatomy at either 12+0/7 to 13+6/7 weeks or at 18+0/7 to 22+6/7 weeks. The primary outcome was completion rate (percentage of scans that optimally imaged all the required fetal structures). Secondary outcomes included the necessity of a transvaginal approach, completion rates for each individual view, number of anomalies identified and missed in each group, scan duration, and patient perspectives. A 1-year pilot sample was analyzed using Bayesian methods for the primary outcome with a neutral prior and frequentist analyses for the remaining outcomes. A total of 128 participants were enrolled, and 1 withdrew consent; 62 subjects underwent a first-trimester ultrasound scan and 62 underwent a second-trimester ultrasound scan. A total of 2 participants did not attend the research visits, and 1 sought termination of pregnancy. In the first-trimester group, 66% (41/62) of ultrasound scans were completed in comparison with 53% (33/62) in the second-trimester ultrasound group (Bayesian relative risk, 1.20; 95% credible interval, 0.91-1.73). When compared with a second-trimester scan plus a follow-up ultrasound, a first-trimester ultrasound plus a second-trimester ultrasound was equally successful in completing the anatomy views (76%). First-trimester anatomy ultrasound scans required a transvaginal approach in 63% (39/62) of cases and had a longer duration than a second-trimester ultrasound scan. No anomalies were missed in either group. First-trimester ultrasound participants who responded to a survey described that they were very satisfied with the technique. In pregnant subjects with a body mass index ≥35 kg/m(2), a single first-trimester anatomy ultrasound scan was more likely to obtain all the recommended anatomic views than a single second-trimester ultrasound scan. An evaluation of anatomy at 12+0/7 to 13+6/7 weeks' gestation plus an evaluation at 18+0/7 to 22+6/7 led to complete anatomic evaluation 4 weeks earlier than 2 second trimester scans. Assessment of ultrasound duration in a clinical setting is needed to ensure feasibility outside of a research setting.
EndometriosisPCOS Co-OccurrenceEndometriosis OverlapEndometriosis vs PCOS
Open Access
Polycystic ovarian syndrome and endometriosis are 2 of the most common reproductive disorders among women but are thought to be unrelated. This study aimed to examine the overlap and common symptoms of polycystic ovarian syndrome and endometriosis. The study population included the Endometriosis, Natural History, Diagnosis, and Outcomes Study (2007-2009) 473 women, aged 18 to 44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at 1 of 14 surgical centers located in Salt Lake City, Utah, or San Francisco, California, in addition to a population cohort composed of 127 women from the surgical centers' catchment areas. Age and site-adjusted multinomial regression models were used to estimate adjusted prevalence ratios and 95% confidence intervals of reproductive history characteristics among women with endometriosis only, women with polycystic ovarian syndrome only, and women with both endometriosis and polycystic ovarian syndrome. Among the operative cohort, 35% had endometriosis only, 9% had polycystic ovarian syndrome only, and 5% had endometriosis and polycystic ovarian syndrome. Among the population cohort, 10% had endometriosis only, 8% had polycystic ovarian syndrome only, and 2% had endometriosis and polycystic ovarian syndrome. In the operative cohort, a history of subfertility was associated with a higher adjusted probability of having both conditions (adjusted prevalence ratio, 10.33; 95% confidence interval, 3.94-27.08), followed by having endometriosis only (adjusted prevalence ratio, 2.45; 95% confidence interval, 1.56-3.84) or polycystic ovarian syndrome only (adjusted prevalence ratio, 1.15; 95% confidence interval, 0.51-2.61), than having neither condition. In addition, experiencing chronic pelvic pain within the past 12 months was associated with a higher probability of having both conditions (adjusted prevalence ratio, 2.53; 95% confidence interval, 1.07-6.00) than having neither condition. Among a cohort of women undergoing gynecologic laparoscopy or laparotomy, our study found that nearly 1 in 20 women had both an incident endometriosis diagnosis and symptoms consistent with polycystic ovarian syndrome. Among a population cohort of women not seeking gynecologic care, polycystic ovarian syndrome and endometriosis overlap prevalence was approximately 1 in 50 women.
General OB/GYNFetal Anatomy UltrasoundUltrasound ChallengesUltrasound Completion Rates
As maternal body mass index (BMI) increases, fetal anatomy ultrasound becomes more challenging, less sensitive, and less likely to be complete. We sought to report our experience of incomplete evaluation of anatomy in patients with BMI of 50 kg/m(2) or greater. This is a retrospective cohort of singleton gestations in mothers with BMI of 50 kg/m(2) or greater, undergoing anatomy evaluations between 2017 and 2021 at 9 maternal-fetal-medicine sites in Houston, TX. Patient variables and scan results were collected throughout pregnancy to provide a longitudinal assessment of the primary outcome, completion rate (percent of all scans which optimally captured 24 American Institute of Ultrasound in Medicine-recommended images). Secondary outcomes included the rate of optimal capture of each individual structure. In total, 293 patients with BMI ≥50 kg/m(2) were identified. Only 28% of initial scans were complete, but over the entire pregnancy, a complete anatomic evaluation was achieved in 76% of women, largely due to weekly ultrasounds done for antenatal testing later in pregnancy. Neither BMI, placental location, nor amniotic fluid volume affected completion rate. The most difficult views are the outflow tracts, 4-chamber view, and spine. One quarter of women with BMI of 50 kg/m(2) or greater will not have a complete fetal anatomic evaluation by the end of pregnancy, since even basic fetal anatomic views are technically challenging to complete. Solutions deserve further attention, and may include first trimester imaging, transvaginal imaging, and optimization of ultrasound machine settings.
PregnancyMaternal Mental HealthDepression and Anxiety ScreeningPerinatal Depression
Perinatal depression and anxiety are major causes of maternal morbidity, and are more common in high-risk pregnancies compared to low-risk pregnancies. This study used validated screening tools to assess the prevalence of depression and anxiety symptoms in pregnant patients who transferred their obstetric care to a specialized fetal center for fetal anomaly. This is a prospective cohort of patients with a fetal anomaly prompting transfer of obstetric care to Texas Children's Hospital Fetal Center between January 2021 and February 2022. The primary outcome was a self-assessed Edinburgh Postnatal Depression Scale score of 13 or higher, either antepartum or postpartum ("ever-positive EPDS"). Secondary outcomes included self-assessed Perinatal Anxiety Screening Scale (PASS) scores of 21 or higher ("ever-positive PASS"), obstetric outcomes, and neonatal outcomes. A frequentist analysis was performed. Of 149 women who transferred to Texas Children's Hospital during the study period, 94 enrolled in this study. Twenty-six percent of women had an ever-positive EPDS; 20% of patients had an ever-positive PASS. Patients were more likely to have an ever-positive EPDS if they were single (46% compared to 20%, p = 0.025). Women who had an ever-positive EPDS were more likely to be referred to psychiatry (46% compared to 14%, p = 0.004) and psychotherapy (29% compared to 1%, p < 0.001). Surprisingly, patients were more likely to have an ever-positive PASS if they reported good social support (p = 0.03). Antepartum EPDS and PASS scores had no relationship with postpartum EPDS scores. Women who transfer care to a tertiary setting have positive EPDS scores at double the rate of the general population, but tend to experience this either antepartum or postpartum (not both). Fetal centers should be prepared to screen for mental health symptoms before and after delivery and provide appropriate referral or treatment.
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
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.
Dominguez JA et al., 2023·Ultrasound Obstet Gynecol
The purpose of this State-of-the-Art Review was to provide a strategic analysis, in terms of strengths, weaknesses, opportunities and threats (SWOT analysis), of the current evidence regarding the management of uterine isthmocele (Cesarean scar defect). Strengths include the fact that isthmocele can be diagnosed on two-dimensional transvaginal ultrasound, and that surgical repair may restore natural fertility potential and prevent secondary infertility, as well as reduce the risk of miscarriage and other obstetric complications. However, there is a lack of high-quality evidence regarding the best diagnostic method and criteria, as well as the potential benefits of surgical repair with respect to fertility. There is a need for experienced surgeons skilled in the various isthmocele repair techniques. Isthmocele repair does not prevent the need for Cesarean delivery in subsequent pregnancies. There is increasing awareness regarding the accuracy of transvaginal ultrasound in diagnosing isthmocele. This may lead to surgical correction and prevention of obstetric and perinatal complications in subsequent pregnancies, including Cesarean scar pregnancy. Regarding threats, the existence of different surgical techniques means that there is a risk of selecting an inadequate approach if the type of isthmocele and the patient's characteristics are not considered. There is a risk of overtreatment when asymptomatic defects are repaired surgically. Finally, there is an absence of cost-effectiveness analyses to justify routine repair. Thus, while there are many data suggesting that isthmocele has an adverse effect on both natural fertility and the outcome of assisted reproduction techniques, high-quality evidence to support surgical isthmocele repair in all asymptomatic patients desiring future fertility are lacking. There is increasing agreement to recommend hysteroscopic repair of isthmocele as a first-line approach as long as the residual myometrial thickness is at least 2.5-3.0 mm.
The presence of adenomyosis is traditionally confirmed by histopathologic examination of the uterine specimen. Today, it could be diagnosed by magnetic resonance imaging or ultrasound. Ultrasound diagnosis was previously less precise. However, with the advances in ultrasound technology including 3 dimensional ultrasound, the specificity and sensitivity of ultrasound to diagnose adenomyosis have increased. In addition, it has led to a clear increase in the prevalence of adenomyosis.
Alabdullatif N et al., 2022·Int J Environ Res Public Health
Effective patient-provider communication improves mammography utilization. Using information technology (IT) promotes health outcomes. However, there are disparities in access to IT that could contribute to disparities in mammography utilization. This study aims to assess the association between IT-based health care communication and mammography utilization and to evaluate if this effect is modified by race/ethnicity and age. To this end, this study was conducted using the National Health Interview Survey from 2011 to 2018. A total of 94,290 women aged 40 years and older were included. Multiple logistic regression models were used, and odds ratios were reported. The study found that all IT-based healthcare communication strategies were significantly associated with mammography utilization in all years from 2011 to 2018. In 2018, women who looked up health information on the internet, scheduled a medical appointment on the internet, and communicated with providers by email had a significantly higher chance to use mammography (p ≤ 0.005 for all strategies across all years). White women and women aged 50 years and older benefited the most from IT-based healthcare communication. In conclusion, facilitating access to IT may help increase mammography utilization, which may contribute to eliminating disparities in breast cancer mortality.
This systematic review and meta-analysis aims to evaluate the impact of chronic endometritis (CE) and its therapy on in vitro fertilization (IVF) outcome. Additionally, we aim to investigate whether various degrees of CE severity may exert a different effect on IVF outcome. Ongoing-pregnancy rate/live-birth-rate (OPR/LBR), clinical-pregnancy rate (CPR), and miscarriage rate (MR) were calculated. A total number of 4145 patients (from ten studies) were included. Women with CE had lower OPR/LBR (OR 1.97, p = 0.02) and CPR (OR 2.28, p = 0.002) compared to those without CE. CE cure increased OPR/LBR (OR 5.33, p < 0.0001) and CPR (OR 3.64, p = 0.0001). IVF outcome was comparable between women with cured CE and those without CE (OPR/LBR, p = ns). Women with severe CE had lower OPR/LBR (OR 0.43, p = 0.003) and CPR (OR 0.40, p = 0.0007) compared to those mild CE. Mild CE showed no influence on the IVF outcome as compared to women without CE (OPR/LBR, p = ns). Based on this data analysis, CE significantly reduces OPR/LBR and CPR in women undergoing IVF. Importantly, CE resolution after antibiotic therapy may improves IVF outcome, leading to similar OPR/LBR and CPR as compared to unaffected patients. The negative effects of CE on IVF outcome may be restricted to severe disease, whereas mild CE may have no influence on IVF success.
Endometriosis is a benign disease that can cause pain and infertility in women. Debate exists over how endometriosis should best be diagnosed. On one hand, endometriosis can be diagnosed by directly examining pelvic anatomy via a surgical procedure known as diagnostic laparoscopy. On the other hand, the disease can be diagnosed via non-surgical means such as using medical imaging, the symptoms described by the patient and whether the patient responds to non-surgical therapies such as medication. In this debate article, we argue in favour of diagnostic laparoscopy. We review the safety of the procedure, compare the ability of diagnostic laparoscopy vs medical imaging to detect endometriosis and consider the benefits of formally diagnosing or ruling out the condition.
The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin (MET), Gonadotropin-releasing hormone agonist (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET). Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. The extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis. After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD = -1.43, 95% CI: -2.05 to -0.80, P < 0.00001). After MET treatment, the serum AMH decreased in polycystic ovary syndrome (PCOS) patients (WMD = -1.79, 95% CI: -2.32 to -1.26, P < 0.00001), in both obese and non-obese patients. GnRH-a treatment in endometriosis patients led to dynamic changes in the serum AMH levels, that is, ascent at 1 month (P = 0.05), and descent at 3 months (P = 0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD = 0.18, 95% CI: 0.09 to 0.27, P < 0.0001). After VD treatment the serum AMH increased, and it was obvious in non-PCOS patients (WMD = 0.78, 95% CI: 0.34 to 1.21, P = 0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD = -1.24, 95% CI: -1.87 to -0.61, P = 0.0001). Serum AMH levels may be affected in the short term after drug application. Specifically, OC, MET and CC lead to decreased AMH level, DHEA and VD lead to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medications should be taken into consideration when AMH is used as a marker of ovarian reserve.
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. 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. 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.
Biochemical markers of spermatogenesis and fertility assessment are important in the practical management of infertile males and the determination of an individual’s prognosis. We performed an analysis on 100 males with a male infertility factor. The following study inclusion seminogram, FSH, LH, testosterone, estradiol, prolactin, TSH, and inhibin B concentrations. The patients were subsequently treated by reproductive endocrinologists in accordance with AUA/ASRM and EAU guidelines. The reproductive status was evaluated over a period of 3 years. We found a strong correlation of sperm count with inhibin B (r = 0.74, p < 0.001) and FSH concentration levels (r = −0.46, p < 0.001). Among 95 patients at follow-up, pregnancies occurred for 59 of their partners (48 spontaneous, 5 after IVF−ET, and 6 after IUI). Thirty-six patients remained childless despite the therapy. Sperm count and inhibin B level were the best predictors of natural fertilization (ROC 0.86 and 0.84; 2.7 mln/mL and 45 pg/mL). Although inhibin B and FSH can be used to evaluate spermatogenesis and fertility, the initial sperm concentration appeared to be the best predictor of success. Pregnancy was achieved in a surprisingly large proportion of patients with a very low concentration of inhibin B and a low initial sperm count. It is noteworthy that 81% of the pregnancies were achieved without medically assisted reproduction.
The purpose is to accurately identify women at high risk of developing cervical cancer so as to optimize cervical screening strategies and make better use of medical resources. However, the predictive models currently in use require clinical physiological and biochemical indicators, resulting in a smaller scope of application. Stacking-integrated machine learning (SIML) is an advanced machine learning technique that combined multiple learning algorithms to improve predictive performance. This study aimed to develop a stacking-integrated model that can be used to identify women at high risk of developing cervical cancer based on their demographic, behavioral, and historical clinical factors. The data of 858 women screened for cervical cancer at a Venezuelan Hospital were used to develop the SIML algorithm. The screening data were randomly split into training data (80%) that were used to develop the algorithm and testing data (20%) that were used to validate the accuracy of the algorithms. The random forest (RF) model and univariate logistic regression were used to identify predictive features for developing cervical cancer. Twelve well-known ML algorithms were selected, and their performances in predicting cervical cancer were compared. A correlation coefficient matrix was used to cluster the models based on their performance. The SIML was then developed using the best-performing techniques. The sensitivity, specificity, and area under the curve (AUC) of all models were calculated. The RF model identified 18 features predictive of developing cervical cancer. The use of hormonal contraceptives was considered as the most important risk factor, followed by the number of pregnancies, years of smoking, and the number of sexual partners. The SIML algorithm had the best overall performance when compared with other methods and reached an AUC, sensitivity, and specificity of 0.877, 81.8%, and 81.9%, respectively. This study shows that SIML can be used to accurately identify women at high risk of developing cervical cancer. This model could be used to personalize the screening program by optimizing the screening interval and care plan in highand low-risk patients based on their demographics, behavioral patterns, and clinical data.
NaProTECHNOLOGYBiophysical PropertiesCervical MucusFertile Window Detection
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.
Polycystic Ovarian Syndrome (PCOS), the most common reproductive endocrine disorder affecting premenopausal women, is frequently associated with central obesity and pancreatic β-cell dysfunction. Aniridia, a rare congenital eye disorder with haploinsufficiency of the PAX6 gene, was observed to co-occur with PCOS in a proband. This study investigates eye health and PAX6 genotypes of women with PCOS and controls. This is a cross-sectional study of 203 premenopausal women (100 healthy controls, 103 with PCOS) conducted at an academic medical center in Vancouver, Canada. Ophthalmological exams and detailed medical histories were obtained from each participant. DNA extracted from saliva was Sanger-sequenced for the exons, intron-exon boundaries, and untranslated regions of PAX6. Women with PCOS had eye abnormalities, including abnormalities of the anterior segment, optic nerve, and retina, that were not observed in controls (p = 0.0002). Myopia prevalence was similar in both groups. Dry eye syndrome, by history, was markedly more prevalent in women with PCOS (22.3%) than controls (5%), p = 0.004. PAX6 genotype did not significantly differ between the two groups, nor was it associated with the greater prevalence of eye anomalies observed in women with PCOS. This is the first study to systematically perform an ophthalmological examination in women with PCOS, who were found to have a higher prevalence of potentially serious eye health problems compared with controls. These data suggest that ophthalmological-metabolic-genetic connections in women with PCOS require further investigation. Confirmation of these data and increased attention to eye health in women with PCOS appears warranted.
Chronic endometritis (CE) and endometrial polyps (EPs) are common conditions in reproductive age women. CE is an infectious disorder of the endometrium characterized by signs of chronic inflammation at hysteroscopic and histological analyses. EPs are abnormal endometrial growths containing glands, stroma and blood vessels projecting from the lining of the uterus. During the last years, different authors have investigated the correlation between CE and EPs, with controversial results. The aim of this study was to summarize available evidence on the potential correlation between CE and EPs.
Systematic literature review and meta-analysis. Observational-studies were identified by searching electronic databases from their inception to September 2021. Only studies on pre-menopausal women were included. Statistical analysis was performed using MedCalc 16.4.3 (Ostend, Belgium) and Review Manager version 5.3 (Nordic Cochrane Centre, Cochrane Collaboration). The summary measures were reported as pooled proportion or odds ratio (OR) with 95% confidence interval (CI). The primary outcome was to evaluate the prevalence of CE in women with EPs. The secondary outcome was to determine the prevalence of CD-138-positive EPs among EPs. Tertiary outcomes were to compare the prevalence of CE in women with EPs versus women with a non-polypoid endometrium and to compare the prevalence of CE in women with a single EP versus women with multiple EPs. Eight observational studies (n = 3225 patients) were included in quantitative synthesis. Pooled prevalence of CE among women with EPs was 51.35% (95% CI, 27.24-75.13%). Pooled proportion of CD-138-positive EPs among EPs was 70.73% (95% CI, 55.73-83.68%). Women with EPs showed higher prevalence of CE compared to women without EPs (OR 3.07, 95% CI 1.59-5.95). Women with ≥3 EPs had higher prevalence of CE then women with a single EP (OR 3.43, 95% CI 1.83-6.46). In pre-menopausal women, CE and EPs may have a dependent relationship and may represent two consequent steps of a common pathological process.
The (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.
SurgeryScar ComplicationsCesarean Scar PregnancyUterine Scar Assessment
Open Access
The definition of a cesarean scar pregnancy (CSP) is the localization of the gestational sac (GS) in the cicatrix tissue, which is created in the front wall of the uterus after a previous cesarean section (CS). The worldwide prevalence of CSP has been growing rapidly. However, there are no general recommendations regarding prophylaxis and treatment of the abnormalities of the anterior wall of the uterus discovered in a non-pregnant myometrium, or how to deal with existing cases of CSP. We present the latest knowledge, a holistic approach to the biology, histology, imaging, and management concerning post-CS scars based on our cases, which were treated in the Department of Pregnancy and Pathology of Pregnancy in the Medical University of Lublin, Poland. In our study, we present images of tissue samples of areas with a cicatrix in the uterus, and ultrasound and MRI images of CSP. We discuss the advances in the biology of the post-CS scar tissue, the prevention techniques used to repair the scar defect (niche) before the pregnancy, and the treatment of different complications of CSP, such as the rupture of the gravid uterus or the dehiscence of the myometrium.
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.
Thiamine or vitamin B1 is an essential, water-soluble vitamin required for mitochondrial energetics-the production of adenosine triphosphate (ATP). It is a critical and rate-limiting cofactor to multiple enzymes involved in this process, including those at the entry points and at critical junctures for the glucose, fatty acid, and amino acid pathways. It has a very short half-life, limited storage capacity, and is susceptible to degradation and depletion by a number of products that epitomize modern life, including environmental and pharmaceutical chemicals. The RDA for thiamine is 1.1-1.2 mg for adult females and males, respectively. With an average diet, even a poor one, it is not difficult to meet that daily requirement, and yet, measurable thiamine deficiency has been observed across multiple patient populations with incidence rates ranging from 20% to over 90% depending upon the study. This suggests that the RDA requirement may be insufficient to meet the demands of modern living. Inasmuch as thiamine deficiency syndromes pose great risk of chronic morbidity, and if left untreated, mortality, a more comprehensive understanding thiamine chemistry, relative to energy production, modern living, and disease, may prove useful.
Bone HealthDiagnosticsPerimenopause/Menopause
Open Access
Glomerulations are not specific for interstitial cystitis/bladder pain syndrome (IC/BPS). Controversy exists about whether cystoscopic findings differ between patients with and without lower urinary tract symptoms. We sought to compare the prevalence of cystoscopic findings in women with "no or minimal" urinary symptoms to those with a "high" symptom burden. This is a secondary analysis of a prospective cohort study performed at a University Educational Facility. Participants in this study were part of a larger prospective study, in which female patients scheduled to undergo routine gynecologic procedures were all consented for cystoscopy with hydrodistension (CWHD). We defined the "minimally symptomatic group" as those with ≤1 on each of the O'Leary/Sant Interstitial Cystitis Symptom Index (ICSI) subscores and without history of IC/BPS. The "highly symptomatic" cohort of women had composite ICSI score ≥12 and a Burning/Pain subscore of 4 or 5. All were non-smokers. A total of 84 women underwent CWHD, with 33 having minimal symptoms and 51 being highly symptomatic. The two groups were not statistically different when assessing for 'any glomerulations' compared to 'no glomerulations.' However, minimally symptomatic women had an eight-fold lower prevalence of significant glomerulations than highly symptomatic women (3.0% minimally symptomatic vs. 23.5% highly symptomatic, P<0.05.). Extensive glomerulations (≥10 in 3 or 4 quadrants) are rare in women with minimal urinary symptoms. These findings contrast with prior limited prospective data which quoted similar incidence of glomerulations in IC/BPS patients and asymptomatic patients. This study highlights the importance of evaluating objective evidence on CWHD and merits further investigation as part of the ongoing conversation regarding the definition of bladder health and pathology.
To investigate and propose a new simple tridimensional (3D) ultrasonographic method to diagnose a T-shaped uterus (Class U1a). A multicenter non-experimental case-control diagnostic accuracy study was conducted between January 2018 and December 2019, including 50 women (cases) diagnosed with T-shaped uterus (U1a class) and 50 women with a "normal uterus" (controls). All the enrolled women underwent 3D ultrasound, drawing four lines and recording the length draw and measure the interostial line (R0); draw from the midpoint of R0 a perpendicular line length 20 mm; draw and measure in the uterine cavity a line parallel to R0 at 10 mm below R0 (R10) and a second line parallel to R0 at 20 mm below R0 (R20). The diagnostic performance of all sonographic parameters statistically significantly different between T-shaped and normal uteri was estimated using the receiver operator characteristic (ROC) curve analysis. R10 and R20 were statistically significantly shorter in the T-shaped than the normal uterus. R10 reported the highest diagnostic accuracy with an area under the ROC curve of 0.973 (95% CI 0.940-1.000). R10 length maximizing the Youden's J statistic was 10.5 mm. Assuming R10 length equal to or shorter than 10 mm as the cut off value for defining a woman as having a T-shaped uterus, the new ultrasonographic method following the proposed protocol (R0, R10, and R20) reported sensitivity for T-shaped uterus of 91.1% (95% CI 0.78-0.97%) and a specificity of 100% (95% CI 0.89-100%). The positive likelihood ratio was higher than 30, and the negative likelihood ratio was 0.09 (95% CI 0.04-0.26). Measuring the length of the intracavitary line parallel to the interostial line at 10 mm from it and using a length ≤ of 10 mm as cut off value (the "Rule of 10") appears a simple and accurate 3D ultrasonographic method for the diagnosis of a T-shaped uterus.
Saliba Thorne C et al., 2021·Diabetes Res Clin Pract
In diabetic foot ulceration, a correlation between pressure and skin temperature is suspected. The aim of this systematic review is to provide a more rigorous analysis of existing literature related to the various technologies used to read and measure both in-shoe plantar pressures, and in-shoe skin temperatures simultaneously. A systematic review of the literature related to the topic was searched in database sources such as Medline OVID, Cochrane Library, PubMed, CONAHL, PROSPERO, and Elsevier. Outcome measures of interest included validity, reliability and responsiveness of in-shoe temperature and/or pressure mapping device used, and characteristics and quantity of sensors used, anatomical landmarks and statistical analysis used to interpret the data. Quality of evidence and risk of bias was evaluated using the QUADAS-2. Nineteen studies were identified and included in this review. The majority of studies used a small sample size (mean n = 17) and recruited healthy participants. All studies have shown excellent validity but only a few tested for the reliability of the device. None of the studies tested for responsiveness of the device. Quality assessment results scored high risk in view of 'patient selection', 'use of reference standard' and 'applicability', and low risk in view of 'use if index test' and 'flow and timing'. The data outlined in this review confirms that further improvement, reliability testing and clinical validation of the developed systems is required despite the results of excellent performance in detecting changes of in-shoe skin temperature and pressure.
AndrologyDNA FragmentationDiagnostic GuidelinesDNA Integrity Assessment
Open Access
Prostate cancer remains one of the most prevalent malignancies among men worldwide, with early and accurate diagnosis being critical for improving outcomes [...]
Reproductive EndocrinologyMenstrual CycleDiagnostics
Open Access
Saei Ghare Naz M et al., 2021·Int J Endocrinol Metab
Menstrual cycle is considered the fifth vital sign among women. This study aimed to summarize the menstrual disturbances in different endocrine disorders.
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.
Low-level light therapy (LLLT) is a recent addition to the pantheon of light-based therapeutic interventions. The absorption of red/near-infrared light energy, a process termed "photobiomodulation," enhances mitochondrial ATP production, cell signaling, and growth factor synthesis, and attenuates oxidative stress. Photobiomodulation is now highly commercialized with devices marketed directly to the consumer. In the gray area between the commercial and therapeutic sectors, harnessing the clinical potential in reproducible and scientifically measurable ways remains challenging. The aim of this article was to summarize the clinical evidence for photobiomodulation and discuss the regulatory framework for this therapy. A review of the clinical literature pertaining to the use of LLLT for skin rejuvenation (facial rhytids and dyschromias), acne vulgaris, wound healing, body contouring, and androgenic alopecia was performed. A reasonable body of clinical trial evidence exists to support the role of low-energy red/near-infrared light as a safe and effective method of skin rejuvenation, treatment of acne vulgaris and alopecia, and, especially, body contouring. Methodologic flaws, small patient cohorts, and industry funding mean there is ample scope to improve the quality of evidence. It remains unclear if light-emitting diode sources induce physiologic effects of compararable nature and magnitude to those of the laser-based systems used in most of the higher-quality studies. LLLT is here to stay. However, its ubiquity and commercial success have outpaced empirical approaches on which solid clinical evidence is established. Thus, the challenge is to prove its therapeutic utility in retrospect. Well-designed, adequately powered, independent clinical trials will help us answer some of the unresolved questions and enable the potential of this therapy to be realized.
Bone HealthVertebral Fracture AssessmentVertebral Fracture ClassificationFracture Epidemiology
Study purposeMorphometric methods categorize potential osteoporotic vertebral fractures (OVF) on the basis of loss of vertebral height. A particular example is the widely used semiquantitative morphometric tool proposed by Genant (GSQ). A newer morphologic algorithm-based qualitative (mABQ) tool focuses on vertebral end-plate damage in recognizing OVF. We used data from both sexes in the Canadian Multicentre Osteoporosis Study (CaMos) to compare the 2 methods in identifying OVF at baseline and during 10 years of follow-up. We obtained lateral thoracic and lumbar spinal radiographs (T4-L4) 3 times, at 5-year intervals, in 828 participants of the population-based CaMos. Logistic regressions were used to study the association of 10-year changes in bone mineral density (BMD) with incident fractures. At baseline, 161 participants had grade 1 and 32 had grade 2 GSQ OVF; over the next 10 years, only 9 of these participants had sustained incident GSQ OVF. Contrastingly, 21 participants at baseline had grade 1 and 48 grade 2 mABQ events; over the next 10 years, 79 subjects experienced incident grade 1 or grade 2 mABQ events. Thus, incident grades 1 and 2 morphologic fractures were 8 times more common than morphometric deformities alone. Each 10-year decrease of 0.01 g/cm2 in total hip BMD was associated with a 4.1% (95% CI: 0.7-7.3) higher odds of having an incident vertebral fracture. This analysis further suggests that morphometric deformities and morphologic fractures constitute distinct entities; morphologic fractures conform more closely to the expected epidemiology of OVF.
We herein summarise the evidence concerning the impact of sperm DNA fragmentation in various clinical infertility scenarios and the advances on sperm DNA fragmentation tests. The collected evidence was used to formulate 41 recommendations. Of these, 13 recommendations concern technical aspects of sperm DNA fragmentation testing, including pre-analytical information, clinical thresholds and interpretation of results. The remaining 28 recommendations relate to indications for sperm DNA fragmentation testing and clinical management. Clinical scenarios like varicocele, unexplained infertility, idiopathic infertility, recurrent pregnancy loss, intrauterine insemination, in vitro fertilisation/intracytoplasmic sperm injection, fertility counselling for men with infertility risk factors and sperm cryopreservation have been contemplated. The bulk evidence supporting the recommendations has increased in recent years, but it is still of moderate to low quality. This guideline provides clinicians with advice on best practices in sperm DNA fragmentation testing. Also, recommendations are provided on possible management strategies to overcome infertility related to sperm DNA fragmentation, based on the best available evidence. Lastly, we identified gaps in knowledge and opportunities for research and elaborated a list of recommendations to stimulate further investigation.
Compared to other genital cancers, cervical cancer is the most prevalent and the main cause of mortality in females in third-world countries, affected by different factors, including smoking, poor nutritional status, immune-deficiency, long-term use of contraceptives and so on. The present study was conducted to predict cervical cancer and identify its important predictors using machine learning classification algorithms. In a cross-sectional study, the data of 145 patients with 23 attributes, which referred to Shohada Hospital Tehran, Iran during 2017-2018, were analyzed by machine learning classification algorithms which included SVM, QUEST, C&R tree, MLP and RBF. The criteria measurement used to evaluate these algorithms included accuracy, sensitivity, specificity and area under the curve (AUC). The accuracy, sensitivity, specificity and AUC of Quest and C&R tree were, respectively 95.55, 90.48, 100, and 95.20, 95.55, 90.48, 100, and 95.20, those of RBF 95.45, 90.00, 100 and 91.50, those of SVM 93.33, 90.48, 95.83 and 95.80 and those of MLP 90.90, 90.00, 91.67 and 91.50 percentage. The important predictors in all the algorithms were found to comprise personal health level, marital status, social status, the dose of contraceptives used, level of education and number of caesarean deliveries. This investigation confirmed that ML can enhance the prediction of cervical cancer. The results of this study showed that Decision Tree algorithms can be applied to identify the most relevant predictors. Moreover, it seems that improving personal health and socio-cultural level of patients can be causing cervical cancer prevention.
Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p'-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.
No Authors Listed, 2020·LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]
Naltrexone is a synthetic opioid antagonist used in prevention of relapse of opiate addiction and alcoholism. Naltrexone has been associated with low rates of serum enzyme elevations during therapy and with rare instances of clinically apparent liver injury.
Contraception/ComparisonOvarian Reserve EffectsAMH and AFCContraceptive Impact on Markers
Landersoe SK et al., 2019·Eur J Contracept Reprod Health Care
The aim of the study was to assess whether the ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) were lower among women using the progestin-only pill (POP) or levonorgestrel-releasing intrauterine system (LNG-IUS) and similar to the decrease observed in combined oral contraceptive (COC) pill users. This retrospective study comprised 565 hormonal contraceptive users (COC, POP, LNG-IUS or contraceptive vaginal ring) and 983 non-hormonal contraceptive users, who were seen in two Danish fertility assessment and counselling clinics between 2015 and 2019. Adjusted multiple regression analysis was used to examine the differences in AMH and AFC between hormonal and non-hormonal contraceptive users. Compared with non-hormonal contraceptive users, AMH was 31.1% lower among COC users [95% confidence interval (CI) -39.6%, -25.9%; p < 0.001], 35.6% lower among POP users (95% CI -49.0%, -18.6%; p < 0.001) and 17.1% lower among LNG-IUS users (95% CI -31.4%, 0.002%; p = 0.052); no significant differences were seen among vaginal ring users. Compared with non-hormonal contraceptive users, AFC was 31.3% lower among COC users (95% CI -35.0%, -25.3%; p < 0.001) and 29.7% lower among POP users (-39.1%, -17.9%; p < 0.001); no significant differences were seen among LNG-IUS or vaginal ring users. Ovarian volume was more than 50% reduced among COC and vaginal ring users (p < 0.001) but was unchanged among POP and LNG-IUS users. Assessment of ovarian reserve markers among users of all types of hormonal contraception should be interpreted cautiously and the type of contraceptive method considered.
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.
Reproductive EndocrinologyHistological DatingNoyes CriteriaEndometrial Dating
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.
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.
SurgeryCesarean Scar Defect RepairTransvaginal UltrasoundIsthmocele
Open Access
An isthmocele, a cesarean scar defect or uterine niche, is any indentation representing myometrial discontinuity or a triangular anechoic defect in the anterior uterine wall, with the base communicating to the uterine cavity, at the site of a previous cesarean section scar. It can be classified as a small or large defect, depending on the wall thickness of the myometrial deficiency. Although usually asymptomatic, its primary symptom is abnormal or postmenstrual bleeding, and chronic pelvic pain may also occur. Infertility, placenta accrete or praevia, scar dehiscence, uterine rupture, and cesarean scar ectopic pregnancy may also appear as complications of this condition. The risk factors of isthmocele proven to date include retroflexed uterus and multiple cesarean sections. Nevertheless, factors such as a lower position of cesarean section, incomplete closure of the hysterotomy, early adhesions of the uterine wall and a genetic predisposition may also contribute to the development of a niche. As there are no definitive criteria for diagnosing an isthmocele, several imaging methods can be used to assess the integrity of the uterine wall and thus diagnose an isthmocele. However, transvaginal ultrasound and saline infusion sonohysterography emerge as specific, sensitive and cost-effective methods to diagnose isthmocele. The treatment includes clinical or surgical management, depending on the size of the defect, the presence of symptoms, the presence of secondary infertility and plans of childbearing. Surgical management includes minimally invasive approaches with sparing techniques such as hysteroscopic, laparoscopic or transvaginal procedures according to the defect size.
To evaluate the diagnostic performance of several biochemical predictors of insulin resistance (IR).
A total of 90 nondiabetic subjects were tested with both the pancreatic suppression test (PST) and the oral glucose tolerance test (OGTT). Of them, 53 were non-insulin-resistant (NIR) subjects and the remaining 37 were insulin resistant subjects. All glucose and insulin values from the OGTT were positively correlated with the steady-state plasma glucose (SSPG) value of the PST. Among the OGTT values, basal insulin (I0) displayed a stronger correlation with SSPG (r = 0.604). Receiver operating characteristic analysis of the OGTT data demonstrated that I0 exhibited the highest area under the receiver operating characteristic curve (AUROC), compared with the rest of the OGTT data. However, the reduced sensitivity of this predictor precluded its clinical use.We then tested six potential predictors of IR derived from the OGTT values. Of them, the I0*G60 had a correlation coefficient of 0.697 with the SSPG and an AUROC of 0.867, surpassing the respective values of the traditional biochemical predictors of IR. Its cutoff predicting IR was >1110 mg/dL*μΙU/mL (>428 nM*pM), its sensitivity was 0.865, and its global accuracy was 0.822. We then selected the six best biochemical predictors of IR according to their posttest probability ratio. I0*G60, ISI composite, AUC-Gl*In/', quantitative insulin sensitivity check index, homeostatic model assessment 1 (HOMA1), and HOMA2. We conclude that the I0*G60 is a promising, inexpensive, and easily calculable predictor of IR that outperforms the predictive power of the traditional predictors of IR, including the insulin sensitivity index composite.
Ovulation confirmation is a fundamental component of the evaluation of infertility. To inform the design of a larger clinical trial to determine the effectiveness of a new home-based pregnanediol glucuronide (PDG) urine test to confirm ovulation when compared with the standard of serum progesterone. In this observational prospective cohort study (single group assignment) in an urban setting (stage 1), a convenience sample of 25 women (aged 18-42 years) collected daily first morning urine for luteinisinghormone (LH), PDG and kept a daily record of their cervical mucus for one menstrual cycle. Serum progesterone levels were measured to confirm ovulation. Sensitivity and specificity were used as the main outcome measures. Estimation of number of ultrasound (US)-monitored cycles needed for a future study was done using an exact binomial CI approach. Recruitment over 3 months was achieved (n=28) primarily via natural fertility regulation social groups. With an attrition rate of 22%, specificity of the test was 100% for confirming ovulation. Sensitivity varied depending on whether a peak-fertility mucus day or a positive LH test was observed during the cycle (85%-88%). Fifty per cent of participants found the test results easy to determine. A total of 73 US-monitored cycles would be needed to offer a narrow CI between 95% and 100%. This is first study to clinically evaluate this test when used as adjunct to the fertility awareness methods. While this pilot study was not powered to validate or test efficacy, it helped to provide information on power, recruitment and retention, acceptability of the procedures and ease of its use by the participants. Given this test had a preliminary result of 100% specificity, further research with a larger clinical trial (stage 2) is recommended to both improve this technology and incorporate additional approaches to confirm ovulation. NCT03230084.
Anti-Müllerian hormone (AMH) levels are used worldwide as a screening tool for the duration of the female reproductive lifespan. Although AMH levels are associated with age at menopause, individual predictions of menopause with a single AMH measurement are unreliable. This study investigated whether individual AMH decline patterns can improve the prediction of menopause compared with a single measurement.
The study population comprised 2434 premenopausal women from the population-based Doetinchem Cohort Study. Participants were followed up every 5 years for a total of 20 years, and AMH was measured in 6699 plasma samples with the picoAMH assay. Longitudinal statistical modeling was combined with time varying Cox modeling, to integrate multiple AMH measurements per woman. The mean age at menopause was 50 years, and 7.4% of the women who reached menopause during follow-up did so before age 45 years. For a 25-year-old, the AMH decline rate between ages 20 and 25 years increased the C-statistic of menopause prediction from 0.64 to 0.69. Beyond that age, the AMH decline rate did not improve predictions of menopause or early menopause. For women younger than age 30 years, for whom menopause prediction is arguably most relevant, the models underestimated the risk of early menopause. These results suggest that knowledge of the AMH decline rate does not improve the prediction of menopause. Based on the low discriminative ability and underestimation of the risk of early menopause, the use of AMH as a screening method for the timing of menopause cannot currently be advocated.
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.
Bone HealthVertebral Fracture AssessmentRadiographic DiagnosisVertebral Morphometry vs Morphology
Until recently there has been little evidence available to validate any method by which to make an accurate diagnosis of an osteoporotic vertebral fractures (OVFs) from plain radiographs. In part this reflects a lack of a completely satisfactory "gold standard," but primarily it relates to the absence of well-designed prospective studies in this context. Historically, OVFs were recognized by evidence of macroscopic structural failure in vertebrae using the criteria applied elsewhere in the skeleton. This comprised altered alignment, fragmentation, cortical disruptions, and breaks, among other changes. However, these morphological criteria were replaced by vertebral morphometry, referring to the use of quantitative or quasi-quantitative measurement tools for fracture diagnosis. Vertebral morphometry emerged as an understanding of and treatment for osteoporosis evolved, mainly in response to the need for expeditious assessments of large numbers of spine images for epidemiological and pharmaceutical purposes. Although most of the descriptions of such morphometric tools have stressed that they were not to be applied to clinical diagnosis with respect to individual patients, this constraint has been widely disregarded. Here we review the major attempts to develop a diagnostic strategy for OVF and describe their characteristics in adults and children. Recent evidence suggests that morphometric (quantitative; ie, based on measurement of dimensions and shape description) criteria are inferior to morphologic (qualitative; ie, based on structural integrity) vertebral damage assessment in identifying people with low bone density and at an increased risk of future fracture. Thus there is now an evidentiary basis for suggesting that morphological assessment is the preferred strategy for use in diagnosing OVF from radiographs.
InfertilityUltrasound SafetyBioeffects and SafetyUltrasound Exposure
Abramowicz JS, 2019·Ultrasound Imaging in Reproductive Medicine
Ultrasound is a form of energy with effects in tissues it traverses (bioeffects). The major bioeffects are a rise in temperature (thermal effects) and some effects secondary to the alternating positive and negative pressures of the ultrasound wave (nonthermal or mechanical effects). Two on-screen indices, the thermal index (TI) and the mechanical index (MI), give the end user an indication of possible thermal and nonthermal changes occurring in real time during the ultrasound scan. No harmful effects have been described in epidemiological studies in humans, but some deleterious results have been demonstrated in animals. While intensities produced by B-mode, gray-scale ultrasound are, most likely, safe, the use of Doppler involves much higher levels of energy. In addition, the very early fetus is known to be very vulnerable to external influences or insults. Information on susceptibility of the ovum, preor postfertilization, is virtually inexistent. In addition, knowledge regarding bioeffects and safety of ultrasound by clinical end users is grossly inadequate. In vivo exposure to ultrasound at spatial average intensities below 1 W/cm2, which is, arguably, almost always the case in ART as well as early gestation, does not adversely affect oocytes/embryos/fetuses. It is advocated to utilize ultrasound only when medically indicated, for the shortest time and at the lowest intensity compatible with accurate diagnosis. The TI and MI should be kept below 1. Further prospective studies on ultrasound safety in ART and pregnancy are highly recommended, as is education of the end users.
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.
DiagnosticsLow-Dose Naltrexone Therapeutic ReviewOpioid Antagonist TherapyOff-Label Drug Applications
Open Access
Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.
Menstrual CycleClassification SystemsFIGO StandardsAbnormal Uterine Bleeding
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.
DiagnosticsLaser vs LED Therapy ComparisonLight-Based TherapeuticsPhotobiomodulation Applications
Open Access
Photobiomodulation (PBM) is a treatment method based on research findings showing that irradiation with certain wavelengths of red or near-infrared light has been shown to produce a range of physiological effects in cells, tissues, animals and humans. Scientific research into PBM was initially started in the late 1960s by utilizing the newly invented (1960) lasers, and the therapy rapidly became known as "low-level laser therapy". It was mainly used for wound healing and reduction of pain and inflammation. Despite other light sources being available during the first 40 years of PBM research, lasers remained by far the most commonly employed device, and in fact, some authors insisted that lasers were essential to the therapeutic benefit. Collimated, coherent, highly monochromatic beams with the possibility of high power densities were considered preferable. However in recent years, non-coherent light sources such as light-emitting diodes (LEDs) and broad-band lamps have become common. Advantages of LEDs include no laser safety considerations, ease of home use, ability to irradiate a large area of tissue at once, possibility of wearable devices, and much lower cost per mW. LED photobiomodulation is here to stay.
Menstrual CycleLuteinized Unruptured Follicle SyndromeNSAIDs and OvulationFollicular Development and Ovulation
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.
Fertility AwarenessHome Fertility Hormone MonitoringUrinary Hormone Self-TestingQuantitative Home Immunoassay
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.
Bone HealthVertebral Morphometry MethodsVertebral Fracture AssessmentOsteoporotic Fracture Classification
We read with interest the editorial by Cummings and Eastell,1 A History of Pivotal Advances in Clinical Research in Bone and Mineral Diseases, published in a recent issue of the JBMR. In discussing such advances, they include spinal morphometry, and specifically refer to and illustrate the Genant semiquantitative (GSQ) paradigm,2 although also referring to the algorithm-based qualitative (ABQ) method3 of vertebral evaluation in the diagnosis of osteoporotic vertebral fractures (OVFs). Although in its day the GSQ method was a credible attempt at structured reporting, recent data suggest that GSQ grade 1 lesions, the most common, relate less well to bone density and fracture risk than comparable fractures diagnosed using the ABQ tool.4-6 Although morphometric methods may serve for understanding the epidemiology of osteoporotic fractures in large populations, it is much less certain that the GSQ method provides a basis for the care of individual patients. In a multidisciplinary context such as is served by this Journal, the endorsement of the GSQ method by the authors, without qualification, may well prove misleading. It is potentially invalid at the bedside and this should have been made explicit. We have observed a reluctance to give the presence of one or more vertebral fractures the importance they should be accorded because of confusion and ambiguity in the descriptive criteria and terminology used (eg, “wedging,” “deformity”) to define them. Perhaps the lack of a clear understanding of what might or might not constitute an OVF contributes to this disarray among radiologists and clinicians alike, again as noted recently by Szulc.7 Most of the many authors describing or reviewing “systems of morphometry,”8-12 such as in the current ASBMR primer,10 have cautioned that they are only to be used for epidemiological purposes. Moreover, most such reviews caution that positive findings should ideally be re-assessed by an “expert.” The danger, recognized by such constraints, is that of false-positive diagnoses from the clinical use of morphometry. In our experience, it is all too common for the iconic diagram provided by Dr. Genant to serve as a guide for the clinical evaluation of spinal images when that was not its intent. In the relevant article, Genant and colleagues2 were at pains to emphasize the importance of recognizing end-plate damage as evidence of OVF, but it has proved deceptively simple for readers to see only the diagram which Cummings and Eastell1 reproduce without noting these constraints. Historically the GSQ method was proposed as an attempt at structured diagnosis in fracture evaluation when such a concept was uncommon. Nevertheless it needs to be seen in perspective and it may have now outlived its usefulness. A great amount of admirable effort has gone into a structured understanding and diagnosis of atypical femoral fractures by the ASBMR.13 Those are, however, very rare events. Perhaps it is time to develop a comparable understanding of the much more common problem of OVF diagnosis to an extent the evidence allows. A taxonomy of such lesions is overdue. At present there are large differences in reported OVF incidence and prevalence for any given population. That fact probably reflects, at least in part, the method of diagnosis used, as much as any real insights into disease. None.
Fertility AwarenessCalendar and App-Based MethodsLH Surge and Cycle Length VariabilityCycle Tracking App Accuracy
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 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. NCT01577147. www.clinicaltrials.gov .
General OB/GYNLow-Dose Naltrexone for Crohn DiseaseInflammatory Bowel Disease TreatmentOpioid Antagonist Anti-Inflammatory Use
Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. A systematic search of MEDLINE, Embase, PubMed, CENTRAL, and the Cochrane IBD Group Specialized Register was performed from inception to 15 January 2018 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also screened.
Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.3.5). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty-one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy-two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). AUTHORS' Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children.
Chronic endometritis is a persistent inflammation of the endometrial mucosa caused by bacterial pathogens such as Enterobacteriaceae, Enterococcus, Streptococcus, Staphylococcus, Mycoplasma, and Ureaplasma. Although chronic endometritis can be asymptomatic, it is found in up to 40% of infertile patients and is responsible for repeated implantation failure and recurrent miscarriage. Diagnosis of chronic endometritis is based on hysteroscopy of the uterine cavity, endometrial biopsy with plasma cells being identified histologically, while specific treatment is determined based on microbial culture. However, not all microorganisms implicated are easily or readily culturable needing a turnaround time of up to 1 week. We sought to develop a molecular diagnostic tool for chronic endometritis based on real-time polymerase chain reaction equivalent to using the 3 classic methods together, overcoming the bias of using any of them alone. Endometrial samples from patients assessed for chronic endometritis (n = 113) using at least 1 or several conventional diagnostic methods namely histology, hysteroscopy, and/or microbial culture, were blindly evaluated by real-time polymerase chain reaction for the presence of 9 Chlamydia trachomatis, Enterococcus, Escherichia coli, Gardnerella vaginalis, Klebsiella pneumoniae, Mycoplasma hominis, Neisseria gonorrhoeae, Staphylococcus, and Streptococcus. The sensitivity and specificity of the molecular analysis vs the classic diagnostic techniques were compared in the 65 patients assessed by all 3 recognized classic methods. The molecular method showed concordant results with histological diagnosis in 30 samples (14 double positive and 16 double negative) with a matching accuracy of 46.15%. Concordance of molecular and hysteroscopic diagnosis was observed in 38 samples (37 double positive and 1 double negative), with an accuracy of 58.46%. When the molecular method was compared to microbial culture, concordance was present in 37 samples (22 double positive and 15 double negative), a matching rate of 56.92%. When cases of potential contamination and/or noncultivable bacteria were considered, the accuracy increased to 66.15%. Of these 65 patients, only 27 patients had consistent histological + hysteroscopic diagnosis, revealing 58.64% of nonconcordant results. Only 13 of 65 patients (20%) had consistent histology + hysteroscopy + microbial culture results. In these cases, the molecular microbiology matched in 10 cases showing a diagnostic accuracy of 76.92%. Interestingly, the molecular microbiology confirmed over half of the isolated pathogens and provided additional detection of nonculturable microorganisms. These results were confirmed by the microbiome assessed by next-generation sequencing. In the endometrial samples with concordant histology + hysteroscopy + microbial culture results, the molecular microbiology diagnosis demonstrates 75% sensitivity, 100% specificity, 100% positive and 25% negative predictive values, and 0% false-positive and 25% false-negative rates. The molecular microbiology method describe herein is a fast and inexpensive diagnostic tool that allows for the identification of culturable and nonculturable endometrial pathogens associated with chronic endometritis. The results obtained were similar to all 3 classic diagnostic methods together with a degree of concordance of 76.92% providing an opportunity to improve the clinical management of infertile patients with a risk of experiencing this ghost endometrial pathology.
InfertilitySubclinical Hypothyroidism and TSHTSH Threshold for FertilityThyroid Screening in Infertility Workup
Orouji Jokar T et al., 2017·J Clin Endocrinol Metab
Unexplained infertility (UI), defined as the inability to conceive after 12 months of unprotected intercourse with no diagnosed cause, affects 10% to 30% of infertile couples. An improved understanding of the mechanisms underlying UI could lead to less invasive and less costly treatment strategies. Abnormalities in thyroid function and hyperprolactinemia are well-known causes of infertility, but whether thyrotropin (TSH) and prolactin levels within the normal range are associated with UI is unknown. To compare TSH and prolactin levels in women with UI and women with a normal fertility evaluation except for an azoospermic or severely oligospermic male partner. DESIGN, SETTING, Cross-sectional study including women evaluated at a large academic health system between 1 January 2000 and 31 December 2012 with normal TSH (levels within the normal range of the assay and ≤5 mIU/L) and normal prolactin levels (≤20 ng/mL) and either UI (n = 187) or no other cause of infertility other than an azoospermic or severely oligospermic partner (n = 52). TSH and prolactin. Women with UI had significantly higher TSH levels than controls [UI: TSH 1.95 mIU/L, (1.54, 2.61); TSH 1.66 mIU/L, (1.25, 2.17); P = 0.003]. This finding remained significant after we controlled for age, body mass index, and smoking status. Nearly twice as many women with UI (26.9%) had a TSH ≥2.5 mIU/L compared with controls (13.5%; P < 0.05). Prolactin levels did not differ between the groups. Women with UI have higher TSH levels compared with a control population. More studies are necessary to determine whether treatment of high-normal TSH levels decreases time to conception in couples with UI.
Fertility AwarenessSelf-Tracking App Ovulation AnalysisApp-Based Population DataMobile App Menstrual Cycle Protocols
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.
Fertility AwarenessWrist Wearable Temperature MonitoringContinuous Temperature TrackingOvulation Detection Validation
Open Access
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.
Down syndrome (trisomy 21) is a well-known cause of mental retardation. It can be diagnosed in early pregnancy. Scientists have made great strides in outlining the pathophysiologic mechanisms of mental retardation in Down syndrome. Much less has been published on human therapy. To our knowledge, these are the first published cases of fetal therapy for Down syndrome. Reports of three cases. In all cases, treatment was both biochemical (e.g. nutritional) and educational. In all cases, treatment was both before and after birth. All children lacked the characteristic faces usually seen in the children with Down syndrome. This suggests a treatment effect before birth. All children had better than expected development. Enhancement of development is proposed as a new therapeutic principle. Developing neurons exchange neurotrophic factors during development when they give or receive stimulation from other neurons. Neurons which receive neurotrophic stimulation survive, and those, which do not, are lost to apoptosis. The developmental therapeutic principle seeks to optimize brain development. Biochemical inputs (neurotransmitters, drugs, hormones, nutrients) and functional stimulation are integrated to optimize the growth and survival of neurons individually; other cells; subcellular organelles; and the brain as a whole. Treatment may be before and after birth, both biochemical and functional. These principles may be applied to Down syndrome, other conditions, and normal fetuses or children. Baggot PJ and Baggot RM (2014). Fetal Report of three cases and review of the literature. J Am Phys Surg 19(1):20-24.
Despite lack of evidence of their utility, biomarkers of ovarian reserve are being promoted as potential markers of reproductive potential. To determine the associations between biomarkers of ovarian reserve and reproductive potential among women of late reproductive age. DESIGN, SETTING, Prospective time-to-pregnancy cohort study (2008 to date of last follow-up in March 2016) of women (N = 981) aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, recruited from the community in the Raleigh-Durham, North Carolina, area. Early-follicular-phase serum level of antimüllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and urinary level of FSH. The primary outcomes were the cumulative probability of conception by 6 and 12 cycles of attempt and relative fecundability (probability of conception in a given menstrual cycle). Conception was defined as a positive pregnancy test result. A total of 750 women (mean age, 33.3 [SD, 3.2] years; 77% white; 36% overweight or obese) provided a blood and urine sample and were included in the analysis. After adjusting for age, body mass index, race, current smoking status, and recent hormonal contraceptive use, women with low AMH values (<0.7 ng/mL [n = 84]) did not have a significantly different predicted probability of conceiving by 6 cycles of attempt (65%; 95% CI, 50%-75%) compared with women (n = 579) with normal values (62%; 95% CI, 57%-66%) or by 12 cycles of attempt (84% [95% CI, 70%-91%] vs 75% [95% CI, 70%-79%], respectively). Women with high serum FSH values (>10 mIU/mL [n = 83]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (63%; 95% CI, 50%-73%) compared with women (n = 654) with normal values (62%; 95% CI, 57%-66%) or after 12 cycles of attempt (82% [95% CI, 70%-89%] vs 75% [95% CI, 70%-78%], respectively). Women with high urinary FSH values (>11.5 mIU/mg creatinine [n = 69]) did not have a significantly different predicted probability of conceiving after 6 cycles of attempt (61%; 95% CI, 46%-74%) compared with women (n = 660) with normal values (62%; 95% CI, 58%-66%) or after 12 cycles of attempt (70% [95% CI, 54%-80%] vs 76% [95% CI, 72%-80%], respectively). Inhibin B levels (n = 737) were not associated with the probability of conceiving in a given cycle (hazard ratio per 1-pg/mL increase, 0.999; 95% CI, 0.997-1.001). Among women aged 30 to 44 years without a history of infertility who had been trying to conceive for 3 months or less, biomarkers indicating diminished ovarian reserve compared with normal ovarian reserve were not associated with reduced fertility. These findings do not support the use of urinary or blood follicle-stimulating hormone tests or antimüllerian hormone levels to assess natural fertility for women with these characteristics.
DiagnosticsX-Ray Detector Material ScienceLead Oxide Characterization
Open Access
We investigated the electronic structure of Lead Oxide (PbO) - one of the most promising photoconductor materials for direct conversion x-ray imaging detectors, using soft x-ray emission and absorption spectroscopy. Two structural configurations of thin PbO layers, namely the polycrystalline and the amorphous phase, were studied, and compared to the properties of powdered α-PbO and β-PbO samples. In addition, we performed calculations within the framework of density functional theory and found an excellent agreement between the calculated and the measured absorption and emission spectra, which indicates high accuracy of our structural models. Our work provides strong evidence that the electronic structure of PbO layers, specifically the width of the band gap and the presence of additional interband and intraband states in both conduction and valence band, depend on the deposition conditions. We tested several model structures using DFT simulations to understand what the origin of these states is. The presence of O vacancies is the most plausible explanation for these additional electronic states. Several other plausible models were ruled out including interstitial O, dislocated O and the presence of significant lattice stress in PbO.
General OB/GYNRetained Products of ConceptionPelvic Imaging
Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.
Fertility AwarenessMenstrual CycleDiagnostics
Open Access
An affordable, user-friendly fertility-monitoring tool remains an unmet need. We examine in this study the correlation between pulse rate (PR) and the menstrual phases using wrist-worn PR sensors. 91 healthy, non-pregnant women, between 22-42 years old, were recruited for a prospective-observational clinical trial. Participants measured PR during sleep using wrist-worn bracelets with photoplethysmographic sensors. Ovulation day was estimated with "Clearblue Digital-Ovulation-urine test". Potential behavioral and nutritional confounders were collected daily. 274 ovulatory cycles were recorded from 91 eligible women, with a mean cycle length of 27.3 days (±2.7). We observed a significant increase in PR during the fertile window compared to the menstrual phase (2.1 beat-per-minute, p < 0.01). Moreover, PR during the mid-luteal phase was also significantly elevated compared to the fertile window (1.8 beat-per-minute, p < 0.01), and the menstrual phase (3.8 beat-per-minute, p < 0.01). PR increase in the ovulatory and mid-luteal phase was robust to adjustment for the collected confounders. There is a significant increase of the fertile-window PR (collected during sleep) compared to the menstrual phase. The aforementioned association was robust to the inter- and intra-person variability of menstrual-cycle length, behavioral, and nutritional profiles. Hence, PR monitoring using wearable sensors could be used as one parameter within a multi-parameter fertility awareness-based method.
Bani Mohammad M et al., 2017·Asian Pac J Cancer Prev
The polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and a notable proportion of women of reproductive age are affected. It may constitute a risk factor for cancer development. Different factors could result in different manifestations and many of these are related to predispositions. It is essential to establish criteria to achieve an exact diagnosis of PCOS, especially among adolescent patients because of the overlap between features of PCO syndrome and physiological findings in puberty. Day by day the technology of ultrasonography is improving and accuracy is increasing, but remains dependent on the specific equipment available. Some factors are inter-related in determining PCOS prognosis. Serum AMH is synthesized by small antral follicles, which are precisely those seen on ultrasound and could help us to diagnose PCOS but there are many aspects that still require elucidation. In this minireview we have attempted to identify some of these correlations.
Chronic endometritis (CE) is a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium. A majority of CE cases produce no noticeable signs or mild symptoms, and the prevalence rate of CE has been found to be approximately 10%. Gynecologists and pathologists often do not focus much clinical attention on CE due to the time-consuming microscopic examinations necessary to diagnose CE, its mild clinical manifestations, and the benign nature of the disease. However, the relationship between CE and infertility-related conditions such as repeated implantation failure and recurrent miscarriage has recently emerged as an area of inquiry. In this study, we reviewed the literature on the pathophysiology of CE and how it may be associated with infertility, as well as the literature regarding the diagnosis and treatment of CE. In addition, we discuss the value of hysteroscopic procedures in the diagnosis and treatment of CE.
To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially.
Inter-rater agreement study.
Five urban surgical centres. Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. Laparoscopies were diagnosed, digitally recorded, and reassessed. Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.
We review the general topic of traumatic brain injury (TBI) and our research utilizing transcranial photobiomodulation (tPBM) to improve cognition in chronic TBI using red/near-infrared (NIR) light-emitting diodes (LEDs) to deliver light to the head. tPBM improves mitochondrial function increasing oxygen consumption, production of adenosine triphosphate (ATP), and improving cellular energy stores. Nitric oxide is released from the cells increasing regional blood flow in the brain. In our previously published study, 11 chronic TBI patients with closed-head TBI caused by different accidents (motor vehicle accident, sports-related, improvised explosive device blast injury) and exhibiting long-lasting cognitive dysfunction received 18 outpatient treatments (Monday, Wednesday, Friday for 6 weeks) starting at 10 months to 8 years post-TBI. LED therapy is nonthermal, painless, and noninvasive. An LED-based device classified as nonsignificant risk (FDA cleared) was used. Each LED cluster head (5.35 cm diameter, 500 mW, 22.2 mW/cm(2)) was applied for 9 min 45 sec (13 J/cm(2)) using 11 midline from front-to-back hairline and bilaterally on frontal, parietal, and temporal areas. Testing was performed before and after transcranial LED (tLED; at 1 week, 1 month, and at 2 months after the 18th treatment) and showed significant improvements in executive function and verbal memory. There were also fewer post-traumatic stress disorder (PTSD) symptoms reported. Ongoing, current studies involve TBI patients who have been treated with tLED using either 26 J/cm(2) per LED location on the head or treated with intranasal only (iLED) using red (633 nm) and NIR (810 nm) diodes placed into the nostrils. The NIR iLED is hypothesized to deliver photons to the hippocampus, and the red 633 nm iLED is believed to increase melatonin. Results have been similar to the previously published tLED study. Actigraphy sleep data showed increased time asleep (on average one additional hour per night) after the 18th tLED or iLED treatment. LED treatments may be performed in the home. Sham-controlled studies with veterans who have cognitive dysfunction from Gulf War Illness, blast TBI, and TBI/PTSD are currently ongoing.
The Zika virus has spread rapidly in the Americas since its first identification in Brazil in early 2015. Prenatal Zika virus infection has been linked to adverse pregnancy and birth outcomes, most notably microcephaly and other serious brain anomalies. To determine whether Zika virus infection during pregnancy causes these adverse outcomes, we evaluated available data using criteria that have been proposed for the assessment of potential teratogens. On the basis of this review, we conclude that a causal relationship exists between prenatal Zika virus infection and microcephaly and other serious brain anomalies. Evidence that was used to support this causal relationship included Zika virus infection at times during prenatal development that were consistent with the defects observed; a specific, rare phenotype involving microcephaly and associated brain anomalies in fetuses or infants with presumed or confirmed congenital Zika virus infection; and data that strongly support biologic plausibility, including the identification of Zika virus in the brain tissue of affected fetuses and infants. Given the recognition of this causal relationship, we need to intensify our efforts toward the prevention of adverse outcomes caused by congenital Zika virus infection. However, many questions that are critical to our prevention efforts remain, including the spectrum of defects caused by prenatal Zika virus infection, the degree of relative and absolute risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy, and factors that might affect a woman’s risk of adverse pregnancy or birth outcomes. Addressing these questions will improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy.
PCOSMetabolic SyndromeRotterdam CriteriaVisceral Adiposity Index
It is unknown which phenotype of polycystic ovary syndrome (PCOS) has a greater metabolic risk and how to detect this risk. The aim of this study was therefore to compare the incidence of metabolic syndrome (MetS) and metabolic risk profile (MRP) for different phenotypes. A total of 100 consecutive newly diagnosed PCOS women in a tertiary referral hospital were recruited. Patients were classified into four phenotypes according to the Rotterdam criteria, on the presence of at least two of the three criteria hyperandrogenism (H), oligo/anovulation (O) and PCO appearance (P): phenotype A, H + O + P; phenotype B, H + O; phenotype C, H + P; phenotype D, O + P. Prevalence of MetS and MRP were compared among the four groups. Based on Natural Cholesterol Education Program Adult Treatment Panel III diagnostic criteria, MetS prevalence was higher in phenotypes A and B (29.6% and 34.5%) compared with the other phenotypes (10.0% and 8.3%; P < 0.001). Although the prevalence of obesity was similar, the number of patients with homeostatic model assessment insulin resistance index (HOMA-IR) >3.8 was significantly higher in androgenic PCOS phenotypes. After logistic regression analysis, visceral adiposity index (VAI) was the only independent predictor of MetS in PCOS (P = 0.002). VAI was also significantly higher in phenotype B, when compared with the others (P < 0.01). Phenotypes A and B had the highest risk of MetS among the four phenotypes, and VAI may be a predictor of metabolic risk in PCOS women.
Petousis S et al., 2016·J Matern Fetal Neonatal Med
To compare the expression of progesterone receptors (A + B) and type-B progesterone receptors in the epithelial and stromal cells of fertile and infertile women. Women were divided into two groups, the group of fertile controls (group 1) and the group of infertile women (group 2) and were set on regular ultrasound imaging in order to detect ovulation. An endometrial biopsy was obtained on the seventh or eighth post-ovulatory day. Immunohistochemistry was performed to measure percentage of positive nuclei, intensity of staining and h-score for progesterone receptors (PgR) (A + B) as well as type-B progesterone receptors in epithelial and stromal cells. Secondary outcomes included endometrial tissue dating, the rate of tissues being out-of-phase and endometrial thickness. Endometrial issue was obtained from 15 fertile and 30 infertile women. Expression of PgR (A + B) and PgR type-B was significantly lower in the epithelial cells of infertile women. PgR (A + B) h-score was 220.0 ± 18.5 for fertile versus 147.3 ± 18.0 for infertile women (p = 0.02). PgR type-B h-score in epithelial cells was 166.8 ± 30.7 for fertile versus 90.8 ± 20.6 for infertile (p = 0.04). No significant difference was observed in stromal cells. Expression levels of PgR (A + B) as well as type-B receptors are significantly lower in the epithelial cells of infertile women during implantation window.
Vissenberg R et al., 2016·Eur J Obstet Gynecol Reprod Biol
Thyroid dysfunction has been described as a possible risk factor for having an abnormal fetal position at birth. In this study we aim to determine the association between thyroid function in early pregnancy and breech presentation at term. We used data from the Amsterdam Born Children and their Development (ABCD) cohort. 3347 pregnant women were included between January 2003 and March 2004 in Amsterdam, the Netherlands. Thyroid function tests were performed between 5 and 37 weeks gestational age (median 12.9 weeks). The main outcome measure was the association between thyroid function in early pregnancy and breech presentation at term. Univariate and multivariate analysis were performed to determine the association between thyroid function and breech presentation. Increased TSH in pregnancy, defined as thyroid stimulating hormone (TSH) >97.5th percentile (>3.53mIU/L), was associated with a higher risk for breech presentation at term (aOR 2.32, CI 1.1-4.8, p=0.02) compared to euthyroidism (TSH between 2.5th and 97.5th percentile). After exclusion of overt hypothyroidism and hyperthyroidism the aOR was 2.34 (CI 1.1-5.0, p=0.03). Trimester specific analysis showed a significant association of increased TSH levels (>3.68mIU/L) in the second trimester with breech presentation (aOR 3.7, CI 1.7-7.8, p=0.001). In the second trimester low free thyroxine (FT4) <2.5th percentile (<6.7pmol/L) was also associated with breech presentation (aOR 2.5, CI 1.0-6.3, p=0.04). Increased TSH and decreased FT4 in the second trimester of pregnancy are associated with an increased risk for breech presentation at term. The association of abnormal thyroid parameters in the first of third trimester is still unclear.
General OB/GYNInterstitial CystitisSjögren Syndrome Urinary Complications
We report a case of interstitial cystitis (IC) associated with primary Sjögren's syndrome (SS) successfully controlled with combination therapy of tacrolimus and a corticosteroid. In 2011, a 69-year-old female, who had been diagnosed with primary SS 23 years ago, developed IC and was successfully treated with tacrolimus and prednisolone combination therapy. The mechanism of IC, including the involved autoimmunity, has not been elucidated. Clinical observation studies suggest a potential association between SS and IC. However, IC is currently thought to be underdiagnosed in patients with SS as well as in the general population. Based on our case and others reported previously, IC associated with SS responds well to immunosuppressive therapy. In particular, a combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with a corticosteroid seems to be highly effective. The possibility of IC in patients with SS complaining of lower urinary tract symptoms without features of infection or other identifiable causes should be given attention.
Fertility AwarenessUrinary Hormone MonitoringBBT and Cervical Mucus ValidationPregnanediol Glucuronide Threshold
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 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.
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.
Chronic endometritis (CE) is a local inflammatory disease characterized by unusual plasmacyte infiltration in the endometrial stromal areas. CE has been neglected in gynecologic practice, as it is a less symptomatic benign disease that requires demanding and time-consuming histopathologic examinations for the definite diagnosis. Recent studies, however, suggest the association of CE with infertility and obstetric and neonatal complications. In this review article, we aimed to update the knowledge on epidemiology, etiology, and pathogenesis of CE as well as discuss its clinical management from diagnosis to treatment.
Thyroid autoimmunity with normal thyroid function is associated with recurrent miscarriage (RM), but the association with live birth is less clear. Therefore, we determined the association between thyroid peroxidase antibodies (TPO-Ab) and live-birth rate (LBR) in a retrospective cohort of euthyroid women with unexplained RM. We included 202 women of which 28 were TPO-Ab positive (13.9%) and 174 were TPO-Ab negative. TPO-Ab positive women (n = 10) without levothyroxine treatment had a lower LBR (29%) compared to TPO-Ab negative women (51%) (HR 0.23, 0.07-0.72, p = 0.012). The LBR in women with TPO-Ab receiving levothyroxine was not different compared women without TPO-Ab (60% versus 51%, p = 0.50). In conclusion, TPO-Ab are associated with a lower LBR in euthyroid women with unexplained RM and these women may benefit from treatment with levothyroxine.
Menstrual CycleEndocrine CausesProlactin and Thyroid ScreeningMenstrual Dysfunction
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.
Reproductive EndocrinologyAMH and AFC AssessmentEffects on Fertility MarkersConfounding Factors
To what extent does oral contraception (OC) impair ovarian reserve parameters in women who seek fertility assessment and counselling to get advice on whether their remaining reproductive lifespan is reduced? Ovarian reserve parameters defined by anti-Müllerian hormone (AMH), antral follicle count (AFC) and ovarian volume were found to be significantly decreased by 19% (95% CI 9.1-29.3%), 18% (95% CI 11.2-24.8%) and 50% (95% CI 45.1-53.7%) among OC users compared with non-users. AMH and AFC have proved to be reliable predictors of ovarian ageing. In women, AMH declines with age and data suggest a relationship with remaining reproductive lifespan and age at menopause. OC may alter parameters related to ovarian reserve assessment but the extent of the reduction is uncertain. STUDY DESIGN, SIZE, A cross-sectional study of 887 women aged 19-46 attending the Fertility Assessment and Counselling Clinic (FACC) from 2011 to 2014 comparing ovarian reserve parameters in OC users with non-OC users. PARTICIPANTS/MATERIALS, SETTING, The FAC Clinic was initiated to provide individual fertility assessment and counselling. All women were examined on a random cycle day by a fertility specialist. Consultation included; transvaginal ultrasound (AFC, ovarian volume, pathology), a full reproductive history and AMH measurement. Women were grouped into non-users and users of OC (all combinations of estrogen-progestin products and the contraceptive vaginal ring). Non-users included women with an intrauterine device (IUD) or no hormonal contraception. MAIN Of the 887 women, 244 (27.5%) used OC. In a linear regression analyses adjusted for age, ovarian volume was 50% lower (95% CI 45.1-53.7%), AMH was 19% lower (95% CI 9.1-29.3%), and AFC was 18% lower (95% CI 11.2-24.8%) in OC users compared with non-users. Comparison of AMH at values of <10 pmol/l OC was found to have a significant negative influence on AMH (OR 1.6, 95% CI 1.1; 2.4, P = 0.03). Furthermore, we found a significant decrease in antral follicles sized 5-7 mm (P < 0.001) and antral follicles sized 8-10 mm (P < 0.001) but an increase in antral follicles sized 2-4 mm (P = 0.008) among OC users. The two groups (OC users versus non-users) were comparable regarding age, BMI, smoking and maternal age at menopause. LIMITATIONS, The study population comprised women attending the FAC Clinic. Recruitment was based on self-referral, which could imply a potential selection bias. Ovarian reserve was examined at a random cycle day. However, both AMH and AFC can be assessed independently of the menstrual cycle. The accuracy in predicting residual reproductive lifespan is still needed in both users and non-users of OC. OC has a major impact on the ovarian volume, and a moderate impact on AFC and AMH with a shift towards the smaller sized antral follicle subclasses. The most evident reduction occurs in the antral follicles of 5-7 and 8-10 mm with the highest number of AMH secreting granulosa cells. It is essential to be aware of the impact of OC use on ovarian reserve parameters when guiding OC users on their fertility status and reproductive lifespan. The FAC Clinic was established in 2011 as part of the ReproHigh collaboration. This study received funding through the Capital Region Research Fund and by EU-regional funding. There are no competing interests. The biobank connected to FAC Clinic is approved by the Scientific Ethical Committee (H-1-2011-081).
What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, The study population for these analyses includes the ENDO Study (2007-2009) 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.
General OB/GYNCentral HypothyroidismLevothyroxine ReplacementThyroid Hormone Levels
Although it has been recommended that serum free thyroxine (FT4) levels should be targeted to middle-upper normal levels during levothyroxine (l-T4) replacement therapy in patients with central hypothyroidism (CeH), the rationale has not been clarified. A retrospective single-center study enrolled 116 patients with hypothyroidism (CeH, n=32; total thyroidectomy (Tx), n=22; primary hypothyroidism (PH), n=33; and control benign thyroid nodule (C), n=29). The patients had received L-T4 therapy at the Kobe University Hospital between 2003 and 2013. They were stratified according to serum FT4 level (≥ 1.10 or <1.10 ng/dl), and body temperature (BT), serum free triiodothyronine (FT3) levels, FT3/FT4 ratio, and lipid profiles were compared. The effect of GH replacement therapy on thyroid function was also analyzed. FT3 levels and FT3/FT4 ratios were significantly lower in patients with CeH than in patients with PH (P<0.05) or C (P<0.05). In patients with FT4 <1.10 ng/dl, BT was significantly lower in patients with CeH (P=0.002) and Tx (P=0.005) than in patients with PH, whereas no differences were found in patients with FT4 ≥ 1.10 ng/dl. In patients with CeH, FT3 levels were higher in those with GH replacement therapy (P=0.018). In CeH, patients with median-lower normal levels of serum FT4 exhibited lower serum FT3 levels and lower BT. These results support the target levels of serum FT4 as middle-upper normal levels during l-T4 replacement therapy in patients with CeH.
To evaluate the efficacy of an association of N-acetyl cystein, alpha-lipoic acid, and bromelain (NAC/LA/Br) in the treatment of endometriosis we set up a new in vivo murine model. We explored the anti-inflammatory and proapoptotic effect of this combination on human endometriotic endothelial cells (EECs) and on endothelial cells isolated from normal uterus (UtMECs). We implanted fragments of human endometriotic cysts intraperitoneally into SCID mice to evaluate the efficacy of NAC/LA/Br treatment. UtMECs and EECs, untreated or treated with NAC/LA/Br, were activated with the proinflammatory stimulus TNF-α and their response in terms of VCAM1 expression was evaluated. The proapoptotic effect of higher doses of NAC/LA/Br on UtMECs and EECs was measured with a fluorogenic substrate for activated caspases 3 and 7. The preincubation of EECs with NAC/LA/Br prior to cell stimulation with TNF-α prevents the upregulation of the expression of the inflammatory "marker" VCAM1. Furthermore NAC/LA/Br were able to induce EEC, but not UtMEC, apoptosis. Finally, the novel mouse model allowed us to demonstrate that mice treated with NAC/LA/Br presented a lower number of cysts, smaller in size, compared to untreated mice. Our findings suggest that these dietary supplements may have potential therapeutic uses in the treatment of chronic inflammatory diseases like endometriosis.
AndrologyTotal Motile Sperm CountPrognostic IndicatorsWHO Classification vs TMSC
Does the prewash total motile sperm count (TMSC) have a better predictive value for spontaneous ongoing pregnancy (SOP) than the World Health Organization (WHO) classification system? The prewash TMSC shows a better correlation with the spontaneous ongoing pregnancy rate (SOPR) than the WHO 2010 classification system. According to the WHO classification system, an abnormal semen analysis can be diagnosed as oligozoospermia, astenozoospermia, teratozoospermia or combinations of these and azoospermia. This classification is based on the fifth percentile cut-off values of a cohort of 1953 men with proven fertility. Although this classification suggests accuracy, the relevance for the prognosis of an infertile couple and the choice of treatment is questionable. The TMSC is obtained by multiplying the sample volume by the density and the percentage of A and B motility spermatozoa. STUDY DESIGN, SIZE, We analyzed data from a longitudinal cohort study among unselected infertile couples who were referred to three Dutch hospitals between January 2002 and December 2006. Of the total cohort of 2476 infertile couples, only the couples with either male infertility as a single diagnosis or unexplained infertility were included (n = 1177) with a follow-up period of 3 years. PARTICIPANTS/MATERIALS, SETTING, In all couples a semen analysis was performed. Based on the best semen analysis if more tests were performed, couples were grouped according to the WHO classification system and the TMSC range, as described in the Dutch national guidelines for male infertility. The primary outcome measure was the SOPR, which occurred before, during or after treatments, including expectant management, intrauterine insemination, in vitro fertilization or intracytoplasmic sperm injection. After adjustment for the confounding factors (female and male age, duration and type of infertility and result of the postcoital test) the odd ratios (ORs) for risk of SOP for each WHO and TMSC group were calculated. The couples with unexplained infertility were used as reference. MAIN A total of 514 couples did and 663 couples did not achieve a SOP. All WHO groups have a lower SOPR compared with the unexplained group (ORs varying from 0.136 to 0.397). Comparing the couples within the abnormal WHO groups, there are no significant differences in SOPR, except when oligoasthenoteratozoospermia is compared with asthenozoospermia [OR 0.501 (95% CI 0.311-0.809)] and teratozoospermia [OR 0.499 (95% CI: 0.252-0.988)], and oligoasthenozoospermia is compared with asthenozoospermia [OR 0.572 (95% CI: 0.373-0.877)]. All TMSC groups have a significantly lower SOPR compared with the unexplained group (ORs varying from 0.171 to 0.461). Couples with a TMSC of <1 × 10(6) and 1-5 × 10(6) have significantly lower SOPR compared with couples with a TMSC of 5-10 × 10(6) [respectively, OR 0.371 (95% CI: 0.215-0.64) and OR 0.505 (95% CI: 0.307-0.832)]. LIMITATIONS, To include all SOPs during the follow-up period of 3 years, couples were not censured at the start of treatment. Roughly, three prognostic couples with a TMSC <5, couples with a TMSC between 5 and 20 and couples with a TMSC of more than 20 × 10(6) spermatozoa. We suggest using TMSC as the method of choice to express severity of male infertility. None.
Fertility AwarenessFertile Window DetectionCervical Mucus PatternsUltrasound Validation of Biomarkers
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?
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, 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.
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.
Selenium supplementation in people with Hashimoto's thyroiditis might reduce antibody levels and result in a decreased dosage of levothyroxine (LT4) and may provide other beneficial effects (e.g. on mood and health-related quality of life). The aim of our systematic review was to assess the effects of selenium supplementation on Hashimoto's thyroiditis. We searched The Cochrane Library, MEDLINE, EMBASE and Web of Science for randomized controlled trials. Study selection, data extraction, assessment of risk of bias and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. Four studies rated at unclear to high risk of bias comprising 463 participants were included. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (RR 4.67, 95% CI 1.61-13.50). Selenomethionine 200 μg as a single treatment or combined with LT4 reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo (or placebo plus LT4) in three studies (p < 0.001). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. In conclusion, the results of these four studies, assessed at unclear to high risk of bias, show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete and not reliable to help inform clinical decision making.
EndometriosisMenstrual Symptoms as BiomarkersPremenstrual Spotting AssociationPremenstrual Spotting Predictive Value
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.
This report updates CDC's 2002 recommendations regarding screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections (CDC. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections-2002. MMWR 2002;51[No. RR-15]) and provides new recommendations regarding optimal specimen types, the use of tests to detect rectal and oropharyngeal C. trachomatis and N. gonorrhoeae infections, and circumstances when supplemental testing is indicated. The recommendations in this report are intended for use by clinical laboratory directors, laboratory staff, clinicians, and disease control personnel who must choose among the multiple available tests, establish standard operating procedures for collecting and processing specimens, interpret test results for laboratory reporting, and counsel and treat patients. The performance of nucleic acid amplification tests (NAATs) with respect to overall sensitivity, specificity, and ease of specimen transport is better than that of any of the other tests available for the diagnosis of chlamydial and gonococcal infections. Laboratories should use NAATs to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls and when evaluating a potential gonorrhea treatment failure, in which case culture and susceptibility testing might be required. NAATs that have been cleared by the Food and Drug Administration (FDA) for the detection of C. trachomatis and N. gonorrhoeae infections are recommended as screening or diagnostic tests because they have been evaluated in patients with and without symptoms. Maintaining the capability to culture for both N. gonorrhoeae and C. trachomatis in laboratories throughout the country is important because data are insufficient to recommend nonculture tests in cases of sexual assault in prepubescent boys and extragenital anatomic site exposure in prepubescent girls. N. gonorrhoeae culture is required to evaluate suspected cases of gonorrhea treatment failure and to monitor developing resistance to current treatment regimens. Chlamydia culture also should be maintained in some laboratories to monitor future changes in antibiotic susceptibility and to support surveillance and research activities such as detection of lymphogranuloma venereum or rare infections caused by variant or mutated C. trachomatis.
To evaluate the association between endometriosis and chronic endometritis. Endometrial specimens were obtained from 71 patients, 34 with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group), who underwent hysterectomy, and the specimens were immunostained for the plasmacyte marker CD138. The rate of chronic endometritis was compared between the endometriosis group and the non-endometriosis group. Furthermore, the 71 patients were also divided into two groups, 28 with chronic endometritis (chronic endometritis group) and 43 without chronic endometritis (non-chronic endometritis group). Logistic regression analysis was performed with variables including age, body mass index (BMI), gravidity and parity, and diagnoses of leiomyoma, adenomyosis, and endometriosis on pathology to examine the independent effect of each variable on chronic endometritis. Patients suffering from cervical invasive carcinoma, endometrial carcinoma, and endometrial polyps or treated with gonadotropin-releasing hormone agonists, progestins, or oral contraceptives before surgery were excluded. Chronic endometritis was identified in 52.94% of the endometriosis group and 27.02% of the non-endometriosis group (p<0.05). Logistic regression analysis revealed that endometriosis was associated with chronic endometritis. This result suggests a strong association between endometriosis and chronic endometritis.
To determine the variability in the recognition of normal sperm and various sperm defects using the strict criteria recommended by the World Health Organization (5th edition, 2010). Sperm morphologic assessment by three experienced evaluators. Image processing laboratory and reproduction research institute. PATIENT(S): Semen donors from a sperm bank. INTERVENTION(S): The morphology of 5,296 sperm was evaluated using statistical analyses of variability. MAIN OUTCOME MEASURE(S): The proportion and coefficients of variation (CVs) of normal sperm, defects of specific parts, and the categories of defects were measured. The degree of agreement between any two of the three evaluators was calculated. The multiple anomalies index, teratozoospermia index, sperm deformity index, and the CVs were also measured. RESULT(S): The CVs of normal sperm, multiple anomalies index, teratozoospermia index, and sperm deformity index were 4.80%, 4.14%, 5.75%, and 6.81%, respectively. A broader range (4.80%-132.97%) of CVs was observed for the recognition of various defects. The coefficients of the degree of agreement concerning specific morphologic parts of sperm varied (0.387-0.607), with lower relative values for the head and mid-piece than for the tail and cytoplasm. CONCLUSION(S): The sperm head is more difficult to evaluate than the other parts using the criteria recommended by the World Health Organization in 2010. The degree of agreement concerning specific parts and various defects varied in broad ranges. A stricter definition for each defect is needed.
Fertility AwarenessDiagnosticsMenstrual Cycle
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.
There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18-44 years were recruited into an operative cohort, along with 131 similarly aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research.
Caesarean sections are the most commonly performed surgical procedures involving the uterus in fertile women. Typically, this surgery involves a transverse incision in the anterior lower uterine segment. The incidence of caesarean sections is on the increase worldwide, and consequently, the complications associated with them are becoming more common. One such complication that is gaining more attention is previous lower uterine segment caesarean scar defect (PCSD). In this review, we sought to explore the definition, aetiology, presentation, diagnosis and management of PCSD.
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, 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.
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 (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. (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.
We sought to identify risk factors for endometriosis and their consistency across study populations Natural History, Diagnosis, and Outcomes (ENDO) Study. In this prospective matched, exposure cohort design, 495 women aged 18-44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an ageand residence-matched population cohort of 131 women (unexposed to surgery, population cohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort. The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3-4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3-4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57-3.76) and population (AOR, 7.91; 95% CI, 1.69-37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28-4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44-5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32-0.75), parity (AOR, 0.42; 95% CI, 0.28-0.64), and body mass index (AOR, 0.95; 95% CI, 0.93-0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor. An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.
Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease.
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.
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.
General OB/GYNAbnormal Uterine BleedingUterine Bleeding Evaluation
The majority of miscarriages are sporadic and most result from genetic causes that are greatly influenced by maternal age. Recurrent pregnancy loss (RPL) is defined by two or more failed clinical pregnancies, and up to 50% of cases of RPL will not have a clearly defined etiology.
To estimate the interrater and intrarater reliability of endometriosis diagnosis and severity of disease among gynecologic surgeons viewing operative digital images. The study population comprised a random sample (n=148 [36%]) of women who participated Natural History, Diagnosis and Outcomes study. Four academic expert and four local, specialized expert surgeons reviewed the images, diagnosed the presence or absence of endometriosis for each woman, and rated severity using the revised American Society for Reproductive Medicine (ASRM) criteria. Interrater-level and intrarater-level agreement were calculated for both endometriosis diagnosis and staging. The interrater reliability for endometriosis diagnosis among the Fleiss κ=0.69 (95% confidence interval [CI] 0.64-0.74). Surgeons agreed on revised ASRM endometriosis staging criteria after experienced assessment in a majority of cases (mean 61%, range 52-75%) with moderate Fleiss κ=0.44 (95% CI 0.41-0.47). The intrarater reliability for experienced assessment compared with computer-assisted revised ASRM staging was almost perfect (mean weighted κ=0.95, range 0.89-0.99). Substantial reliability was found for revised ASRM endometriosis diagnosis, whereas moderate reliability was observed for staging. Almost perfect reliability was observed for surgeons' rating of disease severity compared with computerized-assisted, checklist-based staging. Findings suggest that reliability in endometriosis diagnosis is not greatly altered by location or composition of surgeons, supporting the conduct of multisite studies or compilation of endometriosis data across clinical centers. Although surgeons appear to be skilled at assessing endometriosis stage intuitively, how staging of disease burden correlates with clinical outcomes remains to be developed.
Chronic autoimmune thyroiditis (CAT) is the most common cause of acquired hypothyroidism, which requires lifelong levothyroxine replacement therapy. Currently, no effective therapy is available for CAT. Thus, the objective of this study was to evaluate the efficacy of low-level laser therapy (LLLT) in patients with CAT-induced hypothyroidism by testing thyroid function, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and ultrasonographic echogenicity. A randomized, placebo-controlled trial with a 9-month follow-up was conducted from 2006 to 2009. Forty-three patients with a history of levothyroxine therapy for CAT-induced hypothyroidism were randomly assigned to receive either 10 sessions of LLLT (830 nm, output power of 50 mW, and fluence of 707 J/cm(2); L group, n=23) or 10 sessions of a placebo treatment (P group, n=20). The levothyroxine was suspended 30 days after the LLLT or placebo procedures. Thyroid function was estimated by the levothyroxine dose required to achieve normal concentrations of T3, T4, free-T4 (fT4), and thyrotropin after 9 months of postlevothyroxine withdrawal. Autoimmunity was assessed by measuring the TPOAb and TgAb levels. A quantitative computerized echogenicity analysis was performed preand 30 days postintervention. The results showed a significant difference in the mean levothyroxine dose required to treat the hypothyroidism between the L group (38.59 ± 20.22 μg/day) and the P group (106.88 ± 22.90 μg/day, P<0.001). Lower TPOAb (P=0.043) and greater echogenicity (P<0.001) were also noted in the L group. No TgAb difference was observed. These findings suggest that LLLT was effective at improving thyroid function, promoting reduced TPOAb-mediated autoimmunity and increasing thyroid echogenicity in patients with CAT hypothyroidism.
Reproductive EndocrinologyInfertilityDiagnostics
Open Access
A reliable indirect measure of ovarian reserve for the individual woman remains a challenge for reproductive specialists. Using descriptive statistics from a large-scale study of ovarian volumes, we have developed a normative model for healthy females for ages 25 through 85. For average values, this model has a strong and positive correlation (r = 0.89) with our recent model of nongrowing follicles (NGFs) in the human ovary for ages 25 through 51. When both models are log-adjusted, the correlation increases to r = 0.99, over the full range of ovarian volume. Furthermore we can deduce that an ovary of 3 cm(3) volume (or less) contains approximately 1000 NGF (or fewer). These strong correlations indicate that ovarian volume is a useful factor in the indirect estimation of human ovarian reserve for the individual woman.
Use of selective salpingography (SS) and fallopian tube catheterization (TC) has revolutionized the diagnosis and treatment of proximal tubal infertility. To evaluate results of women treated for proximal tubal obstruction by selective salpingography and tubal catherization. Selective salpingography was performed in women with proximal bilateral tubal obstructions. Follow-up ranged from 4 to 12 months. twelve patients had been shown to have bilateral proximal obstruction of the fallopian tube. After SS/TC, patency was achieved in 8 cases. Spontaneous conceptions occurred in 4 women. SS and TC should be used more widely because it is simple and effective in case of proximal tubal blockage.
InfertilitySperm-Oviduct InteractionElectron Microscopy Reproductive TractSperm Transport and Reservoir
The oviduct is an important organ for successful mammalian reproduction. In this work, human oviducts were inseminated and their explants analyzed using scanning electron microscopy in order to study, at a finer ultrastructual level, the interaction between spermatozoon and oviduct in vitro. Results show unequivocally a spermatozoon tightly attached through the acrosomal region of its head to several cilia of the human tubal epithelial cells. This finding proves that spermatozoa do indeed adhere to the endosalpinx, a fact of utmost relevance for the physiology of the reproductive process, since it supports the idea of a spermatozoa reservoir being formed in the oviduct, which is also briefly discussed.
The RAND Interstitial Cystitis Epidemiology survey estimated that 2.7% to 6.5% of United States women have urinary symptoms consistent with a diagnosis of interstitial cystitis/bladder pain syndrome. We describe the demographic and clinical characteristics of the symptomatic community based RAND Interstitial Cystitis Epidemiology cohort, and compare them with those of a clinically based interstitial cystitis/bladder pain syndrome cohort. Subjects included 3,397 community women who met the criteria for the RAND Interstitial Cystitis Epidemiology high sensitivity case definition, and 277 women with an interstitial cystitis/bladder pain syndrome diagnosis recruited from specialist practices across the United States (clinical cohort). Questions focused on demographic information, symptom severity, quality of life indicators, concomitant diagnoses and treatment. Average symptom duration for both groups was approximately 14 years. Women in the clinical cohort reported worse baseline pain and maximum pain, although the absolute differences were small. Mean Interstitial Cystitis Symptom Index scores were approximately 11 for both groups, but mean Interstitial Cystitis Problem Index scores were 9.9 and 13.2 for the clinical cohort and the RAND Interstitial Cystitis Epidemiology cohort, respectively (p <0.001). The RAND Interstitial Cystitis Epidemiology subjects were more likely to be uninsured. The RAND Interstitial Cystitis Epidemiology community cohort was remarkably similar to an interstitial cystitis/bladder pain syndrome clinical cohort with respect to demographics, symptoms and quality of life measures. In contrast to other chronic pain conditions for which clinical cohorts typically report worse symptoms and functional status than population based samples, our data suggest that many measures of symptom severity and functional impact are similar, and sometimes worse, in the RAND Interstitial Cystitis Epidemiology cohort. These findings suggest that interstitial cystitis/bladder pain syndrome is significantly burdensome, and likely to be underdiagnosed and undertreated in the United States.
Fertility AwarenessUrinary Hormone MetabolitesHome-Based Hormone TestingEstrogen and Progesterone Profiles
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 24 and 35 days, respectively), a mean follicular phase of 14.8 ± 3.1 days (n = 107; 5th and 95th 11 and 21 days) and a mean luteal phase length of 13.3 ± 1.5 days (n = 106; 5th and 95th 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.
EndometriosisEnvironmental Toxicants and POPsExposure Assessment MethodologyEnvironmental Pollutant Biospecimen Selection
Persistent organic pollutants (POPs) have been associated with endometriosis, though with equivocal results possibly reflecting choice of biospecimen. We sought to assess this ...
General OB/GYNEndometrial PolypsTransvaginal UltrasonographyPolypectomy
This review article summarizes the salient literature on the diagnosis and management of endometrial polyps. Electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE were searched with the MeSH terms including all subheadings and keywords endometrial polyps, abnormal uterine bleeding, polypectomy, polyp management, polyp and diagnosis, and polyp and malignancy. There is a paucity of level I evidence in the literature on the diagnosis and management of this common gynecologic disease. Noninvasive investigations such as transvaginal ultrasonography, with or without the use of 3-dimensional ultrasonography and contrast techniques remain the mainstay of first-line investigation. Hysteroscopic resection is the most effective management for endometrial polyps and allows histologic assessment, whereas blind biopsy or curettage has low diagnostic accuracy and should not be performed. This article will review the cause, epidemiology, clinical presentation, diagnostic investigations, and management of endometrial polyps.
To estimate the incidence of endometriosis in an operative cohort of women seeking clinical care and in a matched population cohort to delineate more fully the scope and magnitude of endometriosis in the context of and beyond clinical care.
Matched-exposure cohort design.
Surgical centers in the Salt Lake City, Utah, and San Francisco, California, areas. PATIENT(S): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy between 2007 and 2009, and the population cohort comprised 131 women from the surgical centers' catchment areas. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Incidence of endometriosis by diagnostic method in the operative cohort and by pelvic magnetic resonance imaged (MRI) disease in the population cohort. RESULT(S): Endometriosis incidence in the operative cohort ranged by two orders of 0.7% for only histology, 7% for only MRI, and 41% for visualized disease. Endometriosis staging was skewed toward minimal (58%) and mild disease (15%). The incidence of MRI-diagnosed endometriosis was 11% in the population cohort. CONCLUSION(S): Endometriosis incidence is dependent on the diagnostic method and choice of sampling framework. Conservatively, 11% of women have undiagnosed endometriosis at the population level, with implications for the design and interpretation of etiologic research.
The WHO fracture risk assessment tool (FRAX(®)) estimates an individual's 10-yr major osteoporotic and hip fracture probabilities. When bone mineral density (BMD) is included in the FRAX calculation, only the femoral neck measurement can be used. Recently, a procedure was reported for adjusting major osteoporotic fracture probability from FRAX with femoral neck BMD based on the difference (offset) between the lumbar spine and the femoral neck T-score values. The objective of the current analysis was to independently evaluate this algorithm in a population-based cohort of 4575 women and 1813 men aged 50 yr and older from the Canadian Multicentre Osteoporosis Study. For women and men combined, there was a 15% (95% confidence interval 7-24%) increase in major osteoporotic fracture risk for each offset T-score after adjusting for FRAX probability calculated with femoral neck BMD. The effect was stronger in women than men, but a significant sex interaction was not detected. Among the full cohort, 5.5% had their risk category reclassified after using the offset adjustment. Sexand age-dependent offsets (equivalent to an offset based on Z-scores) showed improved risk classification among individuals designated to be at moderate risk with the conventional FRAX probability measurement. In summary, the T-score difference between the lumbar spine and femoral neck is an independent risk factor for major osteoporotic fractures that is independent of the FRAX probability calculated with femoral neck BMD.
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.
General OB/GYNVitamin D SupplementationVitamin D Serum LevelsDescriptive Cohort Study
Studies indicate that intake of vitamin D in the range from 1,100 to 4,000 IU/d and a serum 25-hydroxyvitamin D concentration [25(OH)D] from 60-80 ng/ml may be needed to reduce cancer risk. Few community-based studies allow estimation of the dose-response relationship between oral intake of vitamin D and corresponding serum 25(OH)D in the range above 1,000 IU/d. A descriptive study of serum 25(OH)D concentration and self-reported vitamin D intake in a community-based cohort (n = 3,667, mean age 51.3 ± 13.4 y). Serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion, with no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml). Unsupplemented all-source input was estimated at 3,300 IU/d. The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d. Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.
PregnancyThyroid Dysfunction and Pregnancy LossTSH Reference Ranges in PregnancyFirst Trimester TSH Thresholds
The definition of what constitutes a normal TSH during pregnancy is in flux. Recent studies suggested that the first trimester upper limit of normal for TSH should be 2.5 mIU/liter. The objective of the study was to evaluate the pregnancy loss and preterm delivery rate in first-trimester thyroid peroxidase antibody-negative women with TSH values between 2.5 and 5.0 mIU/liter. The present study is a component of a recently published large-scale prospective trial that evaluated the impact of levothyroxine treatment on maternal and neonatal complications in thyroid peroxidase-positive women with TSH levels above 2.5 mIU/liter. The present study evaluated 4123 thyroid peroxidase antibody-negative women with TSH levels at or below 5.0 mIU/liter. Women were divided into two groups group A, TSH level below 2.5 mIU/liter, excluding hyperthyroid women defined as an undetectable TSH with an elevated free T(4), and group B, TSH level between 2.5 and 5.0 mIU/liter. The study was conducted at two ambulatory clinics of community hospitals in southern Italy. A total of 4123 women were evaluated. There was no intervention. The incidence of pregnancy loss and preterm delivery in group A as compared with group B was measured. The rate of pregnancy loss was significantly higher in group B as compared with group A (6.1 vs. 3.6% respectively, P = 0.006). There was no difference in the rate of preterm delivery between the two groups. The increased incidence of pregnancy loss in pregnant women with TSH levels between 2.5 and 5.0 mIU/liter provides strong physiological evidence to support redefining the TSH upper limit of normal in the first trimester to 2.5 mIU/liter.
The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [χ(2)(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 ± 0.59) and black (pH 4.7 ± 1.04) women as compared with Asian (pH 4.4 ± 0.59) and white (pH 4.2 ± 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.
Chronic plasmacytic endometritis (CPE) is an infectious or reactive process with multiple etiologies. The lesion is reportedly often associated with pelvic inflammatory disease and intermenstrual bleeding. However, the clinical significance of the diagnosis when found incidentally and whether particular pathologic findings are associated with clinically important CPE have not been evaluated. We reviewed 105 chronic endometritis cases that had been diagnosed earlier and 130 controls to examine the pathologic and clinical associations in a diverse population.A pathology database was searched for endometrial biopsies diagnosed as CPE, and 105 cases were found. Systematic randomized sampling identified 130 control cases (biopsies not diagnosed as CPE). Slides were carefully reviewed to assess 10 histopathologic features. Clinical records were reviewed for 15 clinical parameters. Analysis was performed using chi tests and SAS software.Few patients (3%) received antibiotics or further clinical intervention after the diagnosis of CPE was rendered. The clinical data trended toward fewer menstrual abnormalities as plasma cells increased. The intensity of inflammation showed no association with patient age or symptom duration. Evaluation of controls revealed 17 cases with missed diagnosis of CPE, representing an overall 16% underdiagnosis rate.In CPE, there are no specific clinical features that correlate with the intensity of pathologic findings; the most specific histologic feature is the presence of plasma cells, and it is predominantly identified in weakly proliferative endometrium. There is a clinically insignificant 16% pathologic underdiagnosis rate. In contrast to the findings of past studies, only a small percentage of patients had pelvic inflammatory disease (4%).
To study the relationship between suboptimal maternal thyroid function during gestation and breech presentation at term. Prospective follow-up study during three trimesters of gestation. A total of 1058 Dutch Caucasian healthy pregnant women were prospectively followed from 12 weeks gestation until term (>or=37 weeks) delivery. Maternal thyroid parameters [TSH, free T4 (FT4) and auto-antibodies to thyroid peroxidase] were assessed at 12, 24 and 36 weeks gestation as well as foetal presentation at term. At term, 58 women (5.5%) presented in breech. Compared with women with foetuses in the cephalic position, those women who presented in breech at term had significantly higher TSH concentrations, but only at 36 weeks gestation (P = 0.007). No between group differences were obtained for FT4 level at any assessment. The prevalence of breech presentation in the subgroup of women with TSH >or= 2.5 mIU/l (90th percentile) at 36 weeks gestation was 11%, compared with 4.8% in the women with TSH < 2.50 mIU/l (P = 0.006). Women with TSH below the 5th percentile had no breech presentations. Breech position was significantly and independently related to high maternal TSH concentration (>or=2.5 mIU/l) at 36 weeks gestation (O.R.: 2.23, 95% CI: 1.14-4.39), but not at 12 and 24 weeks gestation. Women with TSH levels above 2.5 mIU/l during end gestation are at risk for breech presentation, and as such for obstetric complications.
Fertility AwarenessBasal Body TemperatureTemperature Analysis MethodsProgesterone Confirmation Methods
Jennifer L Bedford 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 (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.
To examine whether thin endometria can be improved by increasing uterine radial artery (uRA) blood flow. A prospective observational study. University hospital and city general hospital. PATIENT(S): Sixty-one patients with a thin endometrium (endometrial thickness [EM] <8 mm) and high radial artery-resistance index of uRA (RA-RI >or=0.81). INTERVENTION(S): Vitamin E (600 mg/day, n = 25), l-arginine (6 g/day, n = 9), or sildenafil citrate (100 mg/day, intravaginally, n = 12) was given. MAIN OUTCOME MEASURE(S): EM and RA-RI were assessed by transvaginal color-pulsed Doppler ultrasound. RESULT(S): Vitamin E improved RA-RI in 18 (72%) out of 25 patients and EM in 13 (52%) out of 25 patients. L-arginine improved RA-RI in eight (89%) out of nine patients and EM in six (67%) patients. Sildenafil citrate improved RA-RI and EM in 11 (92%) out of 12 patients. In the control group (n = 10), who received no medication to increase uRA-blood flow, only one (10%) patient improved in RA-RI and EM. The effect of vitamin E was histologically examined in the endometrium (n = 5). Vitamin E improved the glandular epithelial growth, development of blood vessels, and vascular endothelial growth factor protein expression in the endometrium. CONCLUSION(S): Vitamin E, l-arginine, or sildenafil citrate treatment improves RA-RI and EM and may be useful for the patients with a thin endometrium.
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 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.
Vertebral fractures are the most common osteoporotic fracture, and patients with prevalent vertebral fractures have a greater risk of future fractures. However, radiographically determined vertebral fractures are not identified as a distinct risk factor in the World Health Organization (WHO) fracture risk assessment tool. The objective of this study was to evaluate and compare potential risk factors including morphometric spine fracture status and the WHO risk factors for predicting 5-yr fracture risk. We hypothesized that spine fracture status provides prognostic information in addition to consideration of the WHO risk factors alone. A randomly selected, population-based community cohort of 2761 noninstitutionalized men and women > or =50 yr of age living within 50 km of one of nine regional centers was enrolled in the Canadian Multicentre Osteoporosis Study (CaMOS), a prospective and longitudinal cohort study following subjects for 5 yr. Prevalent and incident spine fractures were identified from lateral spine radiographs. Incident nonvertebral fragility fractures were determined by an annual, mailed fracture questionnaire with validation, and nonvertebral fragility fracture was defined by investigators as a fracture with minimal trauma. A model considering the WHO risk factors plus spine fracture status provided greater prognostic information regarding future fracture risk than a model considering the WHO risk factors alone. In univariate analyses, age, BMD, and spine fracture status had the highest gradient of risk. A model considering these three risk factors captured almost all of the predictive information provided by a model considering spine fracture status plus the WHO risk factors and provided greater predictive information than a model considering the WHO risk factors alone. The use of spine fracture status along with age and BMD predicted future fracture risk with greater simplicity and higher prognostic accuracy than consideration of the risk factors included in the WHO tool.
Over the past decade, significant advances have occurred in the diagnosis and treatment of reproductive disorders. In this review, we discuss the routine testing performed to diagnose unexplained infertility. We also discuss additional testing, such as assessment of ovarian reserve, and the potential role of laparoscopy in the complete workup of unexplained infertility. Finally, we outline the available therapeutic options and discuss the efficacy and the cost-effectiveness of the existing treatment modalities. The optimal treatment strategy needs to be based on individual patient characteristics such as age, treatment efficacy, side-effect profile, and cost considerations.
Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (677C>T, 1298A>C) cause elevated plasma homocysteine concentrations and have been linked to fatal outcomes after nitrous oxide anesthesia. This study tested the hypothesis that patients with common MTHFR 677C>T or 1298A>C mutations develop higher plasma homocysteine concentrations after nitrous oxide anesthesia than wild-type patients. In this prospective, observational cohort study with blinded, mendelian randomization, the authors included 140 healthy patients undergoing elective surgery. All patients received 66% nitrous oxide for at least 2 h. The main outcome variable, plasma total homocysteine, and folate, vitamin B12, and holotranscobalamin II were measured before, during, and after surgery. After completion of the study, all patients were tested for their MTHFR 677C>T or 1298A>C genotype. Patients with a homozygous MTHFR 677C>T or 1298A>C mutation (n = 25) developed higher plasma homocysteine concentrations (median [interquartile range], 14.9 [10.0-26.4] microm) than wild-type or heterozygous patients (9.3 [7.5-15.5] microm; n = 115). The change in homocysteine after nitrous oxide anesthesia was tripled in homozygous patients compared with wild-type (5.6 microm [+60%] vs. 1.8 microm [+22%]). Only homozygous patients reached average homocysteine levels considered abnormal (> 15 microm). Plasma 5-methyl-tetrahydrofolate concentrations increased uniformly by 20% after nitrous oxide anesthesia, indicating the inactivation of methionine synthase and subsequent folate trapping. Holotranscobalamin II concentrations remained unchanged, indicating no effect of nitrous oxide on vitamin B12 plasma concentrations. This study shows that patients with a homozygous MTHFR 677C>T or 1298A>C mutation are at a higher risk of developing abnormal plasma homocysteine concentrations after nitrous oxide anesthesia.
To report the novel technique of periumbilical ultrasound-guided saline infusion (PUGSI).
Prospective study of two noninvasive diagnostic tests to detect obliterating subumbilical adhesions.
Tertiary care center. PATIENT(S): One hundred fifty patients were included in the study. Patients without risk factors for adhesions were used as a control group (n = 38), whereas the study group had risk factors for intra-abdominal adhesions (n = 112). INTERVENTION(S): Preoperative examination with the visceral slide and the PUGSI. MAIN OUTCOME MEASURE(S): The presence of obliterating subumbilical adhesions in the high-risk patient and the ability of the PUGSI to detect them preoperatively. RESULT(S): There were no obliterating umbilical adhesions in the control group. The prevalence of obliterating umbilical adhesions in the risk group was 3.6%. The visceral slide test had an accuracy of 96.4%, a sensitivity of 50%, and a specificity of 98.1%, with a negative predictive value of 98.1% and a positive predictive value of 50%. The PUGSI test was able to detect all cases of obliterating subumbilical adhesions, demonstrating sensitivity and specificity of 100%. CONCLUSION(S): The PUGSI test has excellent negative and positive predictive values and is useful in determining patients who have obliterating subumbilical adhesions. Use of both tests preoperatively appears to be helpful in identifying patients at risk for visceral injury during laparoscopic surgery.
General OB/GYNInterstitial CystitisUTI DetectionCase-Control Study
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease primarily in women that is of low incidence and unknown etiology and manifests as bladder pain and urinary symptoms. Acute urinary tract infection (UTI) is of high incidence in women, presents as dysuria and urinary symptoms, and is caused by uropathogenic bacteria. We hypothesized that UTI is present at the onset of IC/PBS in some women. For a case-control study seeking risk factors for IC/PBS, women with IC/PBS symptoms of 12 months or less were recruited and evaluated by interview and medical record review. The date of symptom onset was identified by a six-step process. Three evidence-based methods using culture, urinalysis, and symptoms were used separately and in combination to diagnose UTI at IC/PBS onset. Of 1177 screened women, 314 with recent-onset IC/PBS, including numerous confirming characteristics, were enrolled in the study; 98% of the requested medical records were obtained and reviewed. Evidence of a UTI at the onset of IC/PBS was found in 18% to 36% of women. Common UTI features not used in its diagnosis (short interval to medical care, hematuria, antibiotic treatment, and improvement after antibiotics) were significantly more common in those with onset UTI than in those without. These retrospective data suggest that a proportion, probably a minority, of women at IC/PBS onset had evidence of UTI or inflammation. Our results indicate that UTI is present at the onset of IC/PBS in some women and might reveal clues to IC/PBS pathogenesis.
Fertility AwarenessFertile Window EstimationVariability and DurationE3G and LH Detection
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.
Bone HealthISCD GuidelinesPerimenopausal BMD ScreeningTechnical Standards
At the 2007 Position Development Conference, the Dual-Energy X-ray Absorptiometry Technical Task Force investigated three major areas of bone density testing. Although bone mineral density (BMD) testing in men had previously been reviewed at the 2005 Position Development Conference, we reviewed the most recent data in men to develop appropriate indications for bone density testing in men. We continue to recommend screening at age 70 and discuss the clinical risk factors that may be an appropriate indication for earlier BMD testing. Menopausal transition (perimenopause) was considered an important time to consider BMD evaluation because bone loss may be significant prior to menopause. However, because fracture risk is inherently low in women of this age without other risk factors, screening BMD testing is not appropriate. We discuss the risk factors that are strong indicators of fracture risk that may be increased during the menopause transition. The presence of these risk factors are appropriate indications for BMD testing with applicability of WHO diagnostic categorization. The issue of establishing a high threshold for BMD was investigated thoroughly and the current literature was reviewed. Despite the fact there is agreement that all BMD values greater than T-score -1.0 are not normal, it was felt that because of the paucity of sensitivity data and confounding factors such as high body mass index, an upper threshold could not be established or recommended at this time. This was felt to be an important area for further research.
General OB/GYNInterstitial CystitisBladder AutoimmunityAutoantibodies
The cause of interstitial cystitis, a chronic disease that affects the bladder, is unknown. Autoantibodies, such as those against nuclear and bladder epithelium antigens, have been found in patients with interstitial cystitis, but these are likely to be secondary to the disease. No data support a direct causal role of autoimmune reactivity in the pathogenesis of interstitial cystitis. Indirect evidence, however, does support a possible autoimmune nature of interstitial cystitis, such as the strong female preponderance and the clinical association between interstitial cystitis and other known autoimmune diseases within patients and families. The strongest association occurs between interstitial cystitis and Sjögren's syndrome. Increasing evidence suggests a possible role of autoantibodies to the muscarinic M3 receptor in Sjögren's syndrome. The M3 receptor is also located on the detrusor muscle cells of the bladder and mediates cholinergic contraction of the urinary bladder and other smooth muscle tissues. Autoantibodies to the M3 receptor might be important in both the early noninflammatory and the late inflammatory features of interstitial cystitis.
The prevalence of endometriosis is estimated to be around 10%. Diagnosis is through visualisation of the lesions, mostly via laparoscopy. Studies reveal that there is an average delay in the diagnosis of endometriosis of between 8 and 12 years. Little is known about the reasons for delays in diagnosis women's experiences of primary care prior to diagnosis. To investigate women's experiences of endometriosis from first presentation to diagnosis. Retrospective analysis of data collected from primary care records in four general practices. General practice in south-east England. Women with a Read Code diagnosis of endometriosis were recruited to the study. Details of consultations, investigations, and referrals related to endometriosis were recorded from the notes. Data were analysed using descriptive statistics. The prevalence of endometriosis in women aged over 16 years was 1.44%. A third of women had consulted their GP six or more times before being diagnosed. Ultrasound was frequently requested by GPs, but was helpful in diagnosing endometriosis in only 10.6% of women who underwent a scan. Thirty-nine per cent of women were referred to gynaecologists two or more times before a positive diagnosis was made. The median time from first presentation with symptoms to diagnosis was 9.0 years (interquartile range = 4.5-13.5 years). Repeated consultations and negative investigations contribute to a median delay of 9.0 years before diagnosis of endometriosis. Further research into GPs' interpretation of symptoms and patients' experiences of negative investigations and consultations may lead to a more positive outcome for women with this condition.
Fertility AwarenessDay-Specific Conception ProbabilitiesBiomarkers and Proxy MeasuresPericonceptional Window Assessment
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 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.
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.
Menstrual CyclePhase Length DistributionOvulation Day EstimationElectronic Fertility Monitors
Fehring RJ et al., 2006·J Obstet Gynecol Neonatal Nurs
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. 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.
AndrologyDNA IntegrityChemotherapy Effects on FertilityChromatin Analysis
While (partial) recovery of spermatogenesis, observed by means of standard semen analysis, has been seen in testicular cancer patients after chemotherapy with cisplatin, sperm genomic integrity and its implication for the patient's fertility are poorly understood. Semen and serum from 22 patients treated for testicular cancer were analysed preand post-chemotherapy. Besides routine semen analysis, sperm samples were evaluated by computerized karyometric image analysis (CKIA), chromomycin-A3 assay (CMA3, chromatin condensation) and TdT-mediated dUTP nick-end labelling assay (TUNEL, DNA damage). Serum FSH, LH and testosterone concentrations were measured. Ejaculate volume decreased post-chemotherapy (P<0.05). External sperm characteristics (CKIA morphometry) and sperm counts did not deteriorate after chemotherapy. An improvement in DNA condensation was assessed after chemotherapy (37 versus 50% and 47.5 versus 63.7% for CMA3 and CKIA respectively; both P<0.005); yet a high percentage of TUNEL-positive sperm was found in the samples (21 versus 25% for preand post-chemotherapy samples respectively). These values were significantly higher than those of a convenience sample of normozoospermic males attending pre-IVF screening. Serum FSH and LH (IU/l) increased after chemotherapy compared with pretreatment levels (8.1 versus 16.7 and 4.5 vs 6.8; both P<0.05, respectively). Despite the improvement in sperm chromatin packaging after chemotherapy, an abnormally high percentage of DNA-damaged sperm was found in these samples. As sperm quality does not reach normal levels after treatment, it remains difficult to outline the best strategy and guidance concerning fertility potential of testicular cancer patients.
Menstrual CycleUltrastructureScanning Electron MicroscopyCervical Mucus Patterns
Two main types of cervical mucus have been described 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 analyze IVF outcomes in patients with a history of one or more elevations in basal FSH who have a normal basal FSH at the start of their IVF cycle, compared with the general IVF population.
Retrospective clinical study.
University hospital. PATIENT(S): General IVF patient population. INTERVENTION(S): Patients received standard IVF gonadotropin protocols, oocyte retrieval, and embryo transfer. MAIN OUTCOME MEASURE(S): Oocyte yield, fertilization, implantation, clinical pregnancy, and cancellation rate. RESULT(S): Oocyte yields were lower in patients with a history of elevated basal FSH, for all age groups, and showed an age-dependent decline in all patients. Over the age of 40 years, both implantation and clinical pregnancy rates were lower in these patients, with no significant difference observed in patients under the age of 40 years. No pregnancies were observed in patients with a history of three or more elevated FSH levels, regardless of age. CONCLUSION(S): A history of elevated basal FSH levels in patients under the age of 40 years predicts a lower oocyte yield in IVF cycles with normal basal FSH levels but does not translate to either lower pregnancy or implantation rates. Patients aged >40 years with prior elevations in basal FSH levels have both compromised ovarian response and compromised embryo quality relative to those with normal FSH levels, as illustrated by lower oocyte yield, higher cancellation rates, and lower implantation and pregnancy rates.
General OB/GYNThyroid and Celiac AssociationAntigliadin and Thyroid AutoantibodiesAutoimmune Thyroiditis
To investigate the presence of the antigliadin antibodies in the patients with Graves' disease and Hashimoto's thyroiditis. Four hundred patients with autoimmune thyroid disease (280 Graves' disease and 120 Hashimoto's thyroiditis ) were included in the study. The patients with celiac sprue patients were excluded. For the diagnosis of autoimmune thyroiditis, blood levels of thyrotropin (TSH), free thyroxine (FT4), and the titration of thyroid autoantibodies (TgAb and TmAb) were measured, and the thyroid gland was ultrasonographycally evaluated. After the diagnosis of autoimmune thyroid disease was established, the titration of antigliadin antibodies (Ig A and B) were routinely detected. Twenty two patients (5.5 per cent) with autoimmune thyroiditis had positive antigliadin antibodies. Polyglandular endocrine syndrome was diagnosed in most of these patients. We claim that polyglandular endocrine syndrome is the commonest cause of positivity of antigliadin antibodies in the patients with autoimmune thyroid disease.
Experimental data suggest that placental growth factor (PlGF), a member of the vascular endothelial growth factor family, acts as a primary inflammatory instigator of atherosclerotic plaque instability and thus may be useful as a risk-predicting biomarker in patients with acute coronary syndromes (ACS). To determine whether blood levels of PlGF predict risk for death or nonfatal myocardial infarction in patients with acute chest pain. DESIGN, SETTING, Measurement of PlGF levels as well as levels of markers of myocardial necrosis (troponin T [TnT]), platelet activation (soluble CD40 ligand [sCD40L]), and inflammation (high-sensitivity C-reactive protein [hsCRP]) in an inception cohort of 547 patients with angiographically validated ACS participating in the CAPTURE (c7E3 Fab Anti-Platelet Therapy in Unstable Refractory Angina) trial and in a heterogeneous cohort of 626 patients presenting with acute chest pain to an emergency department in Germany between December 1996 and March 1999. Risk for death or nonfatal myocardial infarction after 30 days. In patients with ACS, elevated PlGF levels (>27.0 ng/L; 40.8% of patients) indicated a markedly increased risk of events at 30 days (14.8% vs 4.9%; unadjusted hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.79-6.24; P<.001). In a multivariable model, elevated levels of TnT (HR, 1.83; 95% CI, 1.05-3.86; P =.03), sCD40L (HR, 2.65; 95% CI, 1.41-4.99; P =.002), and PlGF (HR, 3.03; 95% CI, 1.54-5.95; P<.001) were independent predictors, while elevated hsCRP level was not (HR, 0.98; 95% CI, 0.53-1.98; P =.94). In patients with acute chest pain, elevated levels of PlGF predicted risk (21.2% vs 5.3%) (unadjusted: HR, 4.80; 95% CI, 2.81-8.21; P<.001; HR, 3.00; 95% CI, 1.68-5.38; P<.001). Patients negative for all 3 markers (TnT, sCD40L, and PlGF) were at very low cardiac risk (7 no event; 30 2.1% event rate). Plasma PlGF levels may be an independent biomarker of adverse outcome in patients with suspected ACS. A single initial measurement of plasma PlGF appears to extend the predictive and prognostic information gained from traditional inflammatory markers.
Fertility AwarenessClearplan Easy Fertility MonitorComparison with Hormonal MarkersElectronic Monitors vs Biomarkers
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 determine the positive predictive value of the combined symptoms of severe dysmenorrhea with the sign of tenderness and/or nodularity of the cul-de-sac and/or uterosacral ligament(s) in diagnosing endometriosis clinically. In this prospective study, 116 patients with severe dysmenorrhea, after excluding urinary and gastrointestinal disease, underwent pelvic examination by the same investigator. Women having adnexal mass on pelvic examination were excluded Tenderness, and also nodularity, of the cul-de-sac, right and left uterosacral ligament were recorded separately. The laparoscopist did not know the findings of the pelvic examination. The diagnosis of endometriosis was made visually when lesions were typical and all other lesions were biopsied. The prevalence of endometriosis was 78.4%. Tenderness, nodularity, tenderness and nodularity, and also tenderness or nodularity of cul-de-sac and/or uterosacral ligament(s) were all statistically significantly associated with the presence of endometriosis (P = .048, .005, .004, and .004 respectively). The positive predictive values were 85.5%, 94.0%, 94.6% and 86.7%, respectively. The positive predictive value of severe dysmenorrhea with nodularity of the cul-de-sac and/or uterosacral ligament(s) was 94.0%.
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.
Bone HealthBone Density MeasurementOsteoporosis PreventionBone Densitometry
Osteoporosis has lately become recognized as an important disease on two accounts. On one hand, demographic change has resulted in a greatly increased and increasing burden of morbidity and mortality due to osteoporotic fracturing. On the other hand, lifestyle changes and preventive measures have become recognized as important factors in prevention of both osteoporosis and osteoporotic fractures, while several effective drug treatments have recently become available to treat osteoporosis by increasing bone density and reducing fracture incidence. Because bone density is, with age, the best predictor of fracture risk, its measurement has become central to the care of those potentially at risk. When a clinician refers a person for a bone density examination, the clinician should be concerned less with an "imaging diagnosis" than with the requirement that the laboratory has procedures in place for rigorous quality assurance and precision measurements, as well as for education of the staff involved. Implementation of these measures and an understanding of their clinical relevance in diagnosis and follow-up, as well as communication with clinicians in this context, are more important than any diagnostic insight that might be provided by "interpreting" a bone density study.
Perimenopause/MenopauseVasomotor and Breast Tenderness CyclicityBasal Body Temperature MethodsDaily Perimenopause Diary
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.
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.
Laparoscopy is the standard method to visually identify endometriotic lesions under magnification within and outside the minor pelvis. The aim of this study was to analyze the accuracy of laparoscopic visualization in diagnosing the various endometriotic sites as confirmed histologically. Presumed endometriotic sites were observed in 164 patients operated on under the clinical suspicion of endometriosis. Targeted biopsies were performed for histologic corroboration, comparing the laparoscopic findings and diagnosis to the histological results. The histological reports of the biopsies confirmed the presence of endometriosis in 138 patients (84.1%), but in 26 patients (15.9%), no evidence of endometriosis was observed. 100% of "red" lesions, 92% of "black" lesions, and 31% of "white" lesions turned out to be endometriosis. Of the 264 various suspected endometriotic sites observed, 142 (53.8%) were confirmed histologically. The most accurate diagnosis was in lesions on the parietal peritoneum of the pelvis, confirmed in 9/9 cases (100%); the ovarian fossa, confirmed in 8/12 cases (66.7%); and the uterosacral ligaments and posterior surface of the broad ligament, confirmed in 83/138 cases (60.1%). As for the other sites, the histologic confirmation rates in the ovarian surface, bowel serosa, and vesicouterine fold of the peritoneum were 48%, 40%, and 13%, respectively. Endometriosis has a multiple appearance, and the lesions may be confused with nonendometriotic lesions. It is clear that a nonhistology-based diagnosis may lead to unnecessary prolonged medical treatment and operations and may delay the proper treatment measures from being applied. Therefore, a meticulous histological confirmation should still be the first step in the laparoscopic diagnosis and treatment of suspected endometriosis.
Adrenomedullin (AM) gains its bioactivity by amidation at its C-terminal, forming "mature AM." The mature AM and the expression of AM receptor component mRNAs, receptor activity-modifying protein 2 and calcitonin receptor-like receptor, from feto-maternal tissues of normal pregnant women and women with histologic chorioamnionitis were examined to clarify the pathophysiological features of this intrauterine infection. Samples of the placenta and fetal membranes were obtained from 10 normal pregnant women and eight women with histologic chorioamnionitis under informed consent. Mature AM in the fetal membranes was significantly lower in patients with chorioamnionitis than in normal pregnant women. On the other hand, there were no differences in mature AM levels in the placenta between the two groups. The total AM levels as a sum of mature and immature AM were not significantly different between the two groups in either area. The ratio of mature AM/total AM was significantly decreased in the fetal membranes of the patients with chorioamnionitis compared with normal pregnancies, but not in the placenta. Also, levels of mature AM were negatively correlated with C-reactive protein concentrations. The present results thus suggested that mature AM may have some role in chorioamnionitis.
EndometriosisLaparoscopic IdentificationMinimal and Mild DiseaseHistologic Confirmation
Buchweitz O et al., 2003·J Am Assoc Gynecol Laparosc
To evaluate the reliability of diagnosing minimal and mild endometriosis under routine conditions, and to determine to what extent disease activity is taken into account. Retrospective analysis (Canadian Task Force classification II-2). University teaching hospital. Laparoscopy. One hundred eighteen consecutive women with minimal and mild endometriosis undergoing routine surgery between 1994 and 1999. MAIN Analytic parameters were the total number of endometriotic lesions; intraoperative description of pigmented, nonpigmented, and nondefined lesions; and number of extirpated lesions and histologic detection rate. In 118 patients, 311 suspected endometriotic lesions were documented. Nonpigmented lesions were reported in only 27% of women. In 51% of surgical reports no importance was attached to disease morphology or activity. Only 1.2 biopsies/patient were taken. The histologic detection rate was 56%. In 49 patients the assumed intraoperative diagnosis was confirmed by histologic examination. Intraoperative description of endometriotic lesions is inadequate. Little attention is paid to the activity of the illness. There is room for improvement in the number of excisions and histologic detection, and an attempt should be made to find a way out of this diagnostic dilemma.
Reproductive EndocrinologyMicronutrient DeficienciesThyroid Hormone MetabolismTrace Element Deficiency
Several minerals and trace elements are essential for normal thyroid hormone metabolism, e.g., iodine, iron, selenium, and zinc. Coexisting deficiencies of these elements can impair thyroid function. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron supplementation improves the efficacy of iodine supplementation. Combined selenium and iodine deficiency leads to myxedematous cretinism. The normal thyroid gland retains high selenium concentrations even under conditions of inadequate selenium supply and expresses many of the known selenocysteine-containing proteins. Among these selenoproteins are the glutathione peroxidase, deiodinase, and thioredoxine reductase families of enzymes. Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage by excessive iodide exposure. In regions of combined severe iodine and selenium deficiency, normalization of iodine supply is mandatory before initiation of selenium supplementation in order to prevent hypothyroidism. Selenium deficiency and disturbed thyroid hormone economy may develop under conditions of special dietary regimens such as long-term total parenteral nutrition, phenylketonuria diet, cystic fibrosis, or may be the result of imbalanced nutrition in children, elderly people, or sick patients.
The incidence of Chlamydia trachomatis (Ct) infection and the possible correlation between couples presenting with first-trimester spontaneous abortions and active Ct infection was assessed. Additionally, the ability of Ct to infect zona-free hamster oocytes was explored by incubating the oocytes with spermatozoa from infected patients. A total of 961 women and 750 men consulting our reproductive medicine centre were screened for Ct using direct immunofluorescence. The general incidence of Ct infection was 9.4% in females (90 of 961) and 13.9% in males (104 of 750). In women with spontaneous abortions the incidence of Ct was 21.0% (14 of 66) compared with 8.9% (23 of 59) for women without spontaneous abortions and term pregnancies (chi-square, P < 0.05). When both partners of the couples were considered (one or both partners infected), the incidence rose to 68.8% (22 of 32) (chi-square, P < 0.001). In vitro studies using electron microscopy demonstrated the presence of Ct on the surface of and inside the oocyte. These results indicate a correlation between an active Ct infection and spontaneous abortion. Electron microscopy studies suggested the possibility of direct oocyte infection by Ct. Two models are proposed for the pathogenesis (i) direct zygote infection, and (ii) immune response to heat shock proteins expressed by the zygote and triggered by previous Ct infections.
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.
C-reactive protein (CRP) is the prototype acute-phase protein, which can increase up to 1000-fold after the onset of a stimulus. Aside from its disputed role as a marker of infection and/or inflammation in daily clinical practice, the protein has a wide variety of biological properties and functions. Due to its opsonizing abilities and its capability to activate human complement, CRP plays an important role in the innate host defense against different microorganisms, such as bacteria and fungi. The same opsonophagocyting properties can lead to clearance of host cell material, including nuclear constituents. Inflammation is one of the cornerstones in the etiology and pathogenesis of atherosclerosis, which led to worldwide attention being focused on CRP and its role in the process of atherosclerosis. This role may have a dual character. First, CRP levels reflect the 'burden' of inflammation within atherosclerotic lesions, thus reflecting the grade of vulnerability and instability of the plaques. For this reason, an increased level of the protein may be a prelude to rupture of the plaque and, thus, to occlusive arterial disease. Secondly, CRP may play an active role in the atherosclerotic process. CRP plays a role in the expression of different adhesion molecules on endothelial cells and the protein is able to activate human complement within the plaque. Furthermore, the recent discovery of local production of CRP and complement proteins within the plaque suggests an active role for the protein in the inflammatory cascade. Whatever the role for CRP in the atherosclerotic process, it has been proven that an elevated CRP level, with a cut-off point of approximately 3 mg/l, is associated with an increased risk of occlusive arterial disease, especially acute coronary syndromes.
InfertilityInsulin ResistanceInsulin Resistance and PregnancyFasting Insulin and Glucose
To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). Single center, case-controlled, prospective study. University-associated reproductive endocrinology clinical practice. PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.
Bone HealthAssessment GuidelinesScreening CriteriaOsteoporosis Screening
The purpose of this study was to evaluate the efficacy of the Edinburgh Postnatal Depression Scale versus routine clinical evaluation to detect postpartum depression among a low-income inner-city population and to evaluate risk factors associated with a positive score on the Edinburgh Postnatal Depression Scale. On the basis of the day of the month, all English-speaking patients who were seen for their postpartum visit were assigned either to routine clinical evaluation for postpartum depression or routine clinical evaluation plus the use of the 10-question Edinburgh Postnatal Depression Scale. During the 7-week study period, 72 women 35 women in the routine evaluation group and 37 women in the Edinburgh Postnatal Depression Scale group. Women who completed the Edinburgh Postnatal Depression Scale were significantly more likely than those in the routine evaluation group to be identified as 11 of 37 women (30%) versus 0 of 35 women (P <.001). A failed attempt at breast-feeding was associated with an increased risk of a score of > or =10 on the Edinburgh Postnatal Depression Scale (relative risk, 3.78; 95% CI, 1.03-13.89). The Edinburgh Postnatal Depression Scale appears to be a valuable and efficient tool for the identification of patients who are at risk for postpartum depression.
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, 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.
Chapron C et al., 2002·J Am Assoc Gynecol Laparosc
To determine whether routine clinical examination is sufficient for the diagnosis and establishing the location of deeply infiltrating endometriosis (DIE). Retrospective analysis (Canadian Task Force classification II-2). University-affiliated hospital. Patients. One hundred sixty women with histologically proved deeply infiltrating endometriosis. MAIN Speculum examination allowed endometriotic lesions to be viewed in only 14.4% (23) of patients, and a classic, painful, spheric nodule was palpated in only 43.1% (69). Results of routine clinical examination varied significantly with location of DIE. Whereas a nodule was found in 80.0% (24) of patients with vaginal endometriosis, this rate dropped to only 35.3% (6) and 33.3% (34) in those with DIE of the digestive tract and uterosacral ligaments, respectively (p <0.0001). High locations of DIE lesions at the level of uterosacral ligaments, bottom of the pouch of Douglas, and upper one-third of the posterior vaginal wall explain why results of routine clinical examination are so poor. The term "deep endometriosis infiltrating the rectovaginal septum" is generally incorrect in the true anatomic sense.
We examined the hypothesis that amniotic fluid (AF) infection and elevated cytokine concentrations may cause neonatal injury beyond that expected solely from prematurity. The effects of exposure to AF infection and elevated cytokine concentrations were measured in 151 infants born to afebrile women in preterm labor with intact membranes at less than or equal to 34 weeks' gestation. Amniotic fluid was collected by amniocentesis for culture and determination of tumor necrosis factor-alpha and interleukin-6. Cytokine concentrations, stratified by AF infection, were compared for three gestational age groups. We then examined the associations between a positive AF culture or elevated AF tumor necrosis factor-alpha concentration and adverse neonatal outcomes, adjusted for birth weight. Amniotic fluid from 45 (30%) of 151 pregnancies had microorganisms, an elevated tumor necrosis factor-alpha concentration, or both. Amniotic fluid cytokine concentrations were significantly higher among women in preterm labor at less than or equal to 30 weeks, compared with 31-34 weeks. Nine of 11 infants who died at less than or equal to 24 hours of age had AF infection or elevated AF tumor necrosis factor-alpha. For the 140 surviving infants, AF infection and/or an elevated AF tumor necrosis factor-alpha was associated with respiratory distress syndrome (adjusted odds ratio [OR] 1.7), grade 3-4 intraventricular hemorrhage (adjusted OR 2.2), necrotizing enterocolitis (adjusted OR 1.8), and multiple organ dysfunction (adjusted OR 3.0). Among infants born at less than or equal to 34 weeks to women who have intact membranes and are initially afebrile, those exposed to AF bacteria or cytokines have more adverse neonatal outcomes than unexposed infants of similar birth weight.
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 determine the influence of chorioamnionitis and neonatal sepsis on procalcitonin (PCT) levels in very-low-birth-weight (VLBW) infants within the first week of life. PCT serum levels were measured in cord blood 1 h after delivery and on day 3 and day 7 of life. Chorioamnionitis and neonatal sepsis within the first week were monitored. Chorioamnionitis was present in eight of 37 patients (21.6%). PCT on day 3 was increased in both the "No chorioamnionitis" (2.54 ng mL(-1), SEM 0.51) and "Chorioamnionitis" (6.96 ng mL(-1), SEM 2.93) groups of VLBW infants compared with the 1st hour values (0.45 and 0.58 ng mL(-1) SEM 0.07 and 0.11, respectively, P < 0.001) of the same patients. The postnatal gain was higher in the "Chorioamnionitis" group (P < 0.01). Neonatal sepsis was diagnosed (after exclusion) in 12 of 32 patients (37.5%). Mean values of maximum PCT in patients with and without sepsis were 8.41 ng mL(-1) (SEM 1.87) and 3.02 ng mL(-1) (SEM 1.38), respectively (P < 0.05). Sensitivity to sepsis of PCT, ratio of immature to total neutrophils (I : T), and C-reactive protein (CRP) were 75%, 50% and 25%, respectively. In the group of VLBW infants the PCT level within 72 h of delivery was markedly increased in patients with chorioamnionitis. T and CRP, PCT appears to be a more sensitive marker of neonatal sepsis.
EndometriosisNon-Surgical Diagnostic MethodsTransvaginal UltrasoundOvarian vs Non-Ovarian
To determine whether the surgical diagnosis of endometriosis can be predicted using symptoms, signs, and ultrasound findings. Prospective study (study sample); retrospective record review (test sample). Hospital of Desio (study sample) and Mangiagalli Hospital (test sample), Italy. PATIENT(S): Ninety women scheduled to undergo laparoscopy or laparotomy (study sample); 120 women who underwent laparoscopy (test sample). The study sample group was interviewed before surgery about infertility and dysmenorrhea, dyspareunia, and noncyclic pelvic pain and each member had a pelvic examination and a transvaginal ultrasound. At surgery, endometriosis was noted. For the test sample, the same information was abstracted from medical records after laparoscopy. MAIN OUTCOME MEASURE(S): The ability of symptoms, signs, and ultrasound to predict endometriosis at surgery. A classification tree was developed with the study sample and evaluated with the test sample. RESULT(S): Ovarian endometriosis, but not nonovarian endometriosis, could be reliably predicted with noninvasive tools. Ultrasound and examination best predicted ovarian endometriosis, correctly classifying 100% of cases with no false positive diagnoses in the study sample. Similar results were found in the test sample. CONCLUSION(S): Noninvasive tools may be used to identify women with ovarian, but not nonovarian endometriosis, with excellent agreement with surgical diagnosis.
Although shortened cervical length has been consistently associated with spontaneous preterm birth, it is not known when in gestation this risk factor becomes apparent. To determine whether sonographic cervical findings between 16 weeks' and 18 weeks 6 days' gestation predict spontaneous preterm birth and whether serial evaluations up to 23 weeks 6 days' gestation improve prediction in high-risk women. DESIGN, SETTING, Blinded observational study performed between March 1997 and November 1999 at 9 university-affiliated medical centers in the United States in 183 women with singleton gestations who previously had experienced a spontaneous birth before 32 weeks' gestation. Certified sonologists performed 590 endovaginal sonographic examinations at 2-week intervals. Cervical length was measured from the external os to the functional internal os along a closed endocervical canal. Funneling and dynamic cervical shortening were also recorded. Spontaneous preterm birth before 35 weeks' gestation, analyzed by selected cutoff values of cervical length. Forty-eight women (26%) experienced spontaneous preterm birth before 35 weeks' gestation. A cervical length of less than 25 mm at the initial sonographic examination was associated with a relative risk (RR) for spontaneous preterm birth of 3.3 (95% confidence interval [CI], 2.1-5.0; sensitivity = 19%; specificity = 98%; positive predictive value = 75%). After controlling for cervical length, neither funneling (P =.24) nor dynamic shortening (P =.054) were significant independent predictors of spontaneous preterm birth. However, using the shortest ever observed cervical length on serial evaluations, after any dynamic shortening, the RR of a cervical length of less than 25 mm for spontaneous preterm birth increased to 4.5 (95% CI, 2.7-7.6; sensitivity = 69%; specificity = 80%; positive predictive value = 55%). Compared with a single cervical measurement at 16 weeks' to 18 weeks 6 days' gestation, serial measurements at up to 23 weeks 6 days significantly improved the prediction of spontaneous preterm birth in a receiver operating characteristic curve analysis (P =.03). Cervical length assessed by endovaginal sonography between 16 weeks' and 18 weeks 6 days' gestation, augmented by serial evaluations, predicts spontaneous preterm birth before 35 weeks' gestation in high-risk women.
PCOSCardiovascular RiskInsulin Resistance and Cardiac FunctionDiastolic Dysfunction in PCOS
To assess cardiac flow parameters in patients with polycystic ovary syndrome (PCOS). A prospective case-control study. University-based hospital. PATIENT(S): Thirty consecutive patients with PCOS were enrolled. Thirty women with regular menstrual cycles served as the controls. INTERVENTION(S): Systolic and diastolic function parameters were assessed by standard two-dimensional and M-mode echocardiography. Insulin sensitivity was evaluated by a standard 75-g oral glucose tolerance test and area-under-curve insulin analysis. Serum hormones, lipid profile, homocysteine, vitamin B(12), folate, fibrinogen, uric acid, and plasminogen activator inhibitor-I concentrations were measured. MAIN OUTCOME MEASURE(S): Systolic and diastolic function parameters, insulin sensitivity and serum homocysteine levels. RESULT(S): The mean serum homocysteine and uric acid concentrations were significantly higher in the PCOS group. Patients with PCOS had significant hyperinsulinemia. All systolic function parameters were comparable between the two groups. However, patients with PCOS had significantly lower peak mitral flow velocity in early diastole and significantly lower ratio between the early and late peak mitral flow velocities and also had significantly longer isovolumic relaxation time, reflecting a trend for nonrestrictive-type diastolic dysfunction. The area-under-curve insulin correlated positively with peak mitral flow velocity in late diastole (r = 0.375). The mean cholesterol/high-density lipoprotein ratio correlated negatively with mean mitral flow velocity in early diastole (E) peak (r = -0.474). The mean fasting insulin level correlated negatively with mean E/A ratio (r = -0.387). CONCLUSION(S): Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular disease risk in patients with PCOS.
Fertility AwarenessBiomarker ComparisonUltrasound and Hormonal IndicesCervical Mucus and Urinary Hormones
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 transvaginal ultrasonography, cervical mucus, basal body temperature, urinary luteinising hormone, and ratio of urinary oestrogen to progesterone metabolites. Each of eight natural family planning clinics was to study 12 women for at least three cycles. One hundred and seven normally fertile and cycling women aged 18 to 45. Daily measurements of urinary luteinising hormone, follicle stimulating hormone, oestrone-3-glucuronide and pregnanediol-3alpha-glucuronide. Basal body temperature recording and cervical mucus checking. Transvaginal ultrasound examination of the ovaries. Delays between the expected day of ovulation according to the luteinising hormone peak or to ultrasound evidence and the expected days according to the other indices of ovulation. Ultrasonography was able to show evidence of ovulation in 283 out of 326 cycles. The average time lag between luteinising hormone peak and ultrasound evidence was less than one day (+0.46) but premature and late luteinising hormone-expected date of ovulation were observed in nearly 10% and 23% of cycles, respectively. Basal body temperature rise was observed in 98% of cycles. Cervical mucus peak symptom, rapid drop in the ratio of urinary metabolites, and luteinising hormone initial rise were all close to ultrasonographic evidence in more than 72% of cycles. For accuracy and practical reasons, the cervical mucus peak symptom, the ratio of urinary metabolites and luteinising hormone initial rise might be better indices of ovulation than the luteinising hormone peak.
To compare 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.
To compare the karyotype of babies conceived through ICSI with that of naturally conceived babies. Prospective controlled study. The Egyptian IVF-ET Center, Cairo, Egypt. PATIENT(S): Four hundred and thirty babies conceived through ICSI and 430 babies conceived naturally. INTERVENTION(S): ICSI and karyotyping. MAIN OUTCOME MEASURE(S): Abnormal karyotype. RESULT(S): Four hundred and thirty consecutive babies conceived through ICSI who were delivered in one hospital had 15 abnormal karyotypes (3.5%). Of the 15 babies, 7 were of female phenotype and 8 of male phenotype. Six babies had sex chromosome anomalies, 8 had autosomal anomalies, and 1 had combined sex chromosome and autosomal anomalies. A control group of 430 consecutive babies conceived naturally who were delivered in one hospital had no abnormal karyotype. The difference between the two groups was significant (P<.001). CONCLUSION(S): ICSI carries a small but significant increased risk of abnormal karyotyping to the offspring. This risk appears to be equally distributed between autosomal and sex chromosome anomalies.
General OB/GYNVaginal Medication DistributionMRI Pelvic AssessmentTopical Vaginal Therapies
To assess the use of magnetic resonance imaging (MRI) to determine the varying distribution of a vaginally placed gel over time and with different levels of patient activity. Prospectives interventional trial. University medical center. PATIENT(S): One nulliparous volunteer with normal menstrual cycles and no gynecologic disease who underwent seven MRI scans of the pelvis. INTERVENTION(S): Five mL of a commercially available topical spermicide was mixed with gadolinium-chelate magnetic resonance contrast material and introduced with a standard applicator. T1-weighted three-dimensional MRI was done to assess the distribution of the gel. MAIN OUTCOME MEASURE(S): Gel thickness and distribution. RESULT(S): The initial bolus of gel was delivered into the upper portion of the vagina, above the urogenital diaphragm. Thereafter, it spread into the vaginal fornices and "flattened" to cover the lateral aspects of the vagina. Without ambulation, the majority of spread was confined to the upper vagina. With ambulation and longer elapsed time, the gel spread further in the upper vagina and into the lower vagina, and significant vaginal surface coverage increased significantly. CONCLUSION(S): Magnetic resonance imaging can be used to monitor the spread of vaginally placed products and to evaluate coverage of topical drugs used for prevention and treatment, including those used for HIV prophylaxis.
Studies in animal models of spontaneous Hashimoto's autoimmune thyroiditis (HT) show that prophylactic treatment with levothyroxine (LT4) can reduce incidence and degree of lymphocytic infiltration in HT. The aim of the present study was to clarify whether there is a benefit of prophylactic treatment with LT4 in patients with euthyroid HT with respect to the progression of the autoimmune process. Twenty-one patients with euthyroid HT were checked for thyroid function (thyrotropin [TSH], free triiodothyronine [FT3], free thyroxine [FT4]), thyroid volume, antibodies (thyroglobulin [Tg-Ab], thyroid peroxidase [TPO-Ab]), and lymphocyte subsets. Peripheral (PBL) and thyroid-derived lymphocytes (TL) were analyzed by triple color flow cytometry. One-half of the patients with euthyroid HT were treated with LT4 for 1 year (n = 10). The other half (n = 11) were never treated with LT4. TL were obtained by fine-needle aspiration biopsy (FNAB). Thirteen healthy subjects (C) without medical history of thyroid disease served as controls concerning PBL, and patients with non-toxic nodular goiter (NG; n = 10) served as controls concerning TL. Thyroid-derived T-helper cells were found more frequently in euthyroid patients with HT compared to patients with NG (p < 0.01). After 1 year of therapy with LT4, TPO-Abs and B lymphocytes decreased significantly only in the treated group of euthyroid patients with HT (p < 0.05). In contrast, TPO-Abs levels did not change or even increased in untreated euthyroid patients with HT. Thyroid volume did not differ before and after therapy. Prophylactic treatment of euthyroid patients with HT reduced both serological and cellular markers of autoimmune thyroiditis. Therefore, prophylactic LT4 treatment might be useful to stop the progression or even manifestation of the disease. However, the long-term clinical benefit of prophylactic LT4 therapy in euthyroid patients with HT is yet to be established.
PregnancyInflammatory BiomarkersTNF-Alpha PredictionCytokine Levels in Pregnancy
To evaluate maternal serum tumor necrosis factor-alpha (TNF alpha) levels in patients with preterm labor without clinical signs of chorioamnionitis and to compare these with levels in nonlaboring controls. The study group consisted of 44 patients with a singleton pregnancy admitted to our department with the diagnosis of preterm labor between 26 and 36 weeks' gestation. The control group consisted of 25 healthy consecutive patients with a singleton pregnancy without preterm contractions who were seen for routine antenatal visits. Maternal serum TNF alpha was measured using a solid-phase, two-site chemiluminescent enzyme immunometric assay method, and levels were compared in patients with preterm labor and nonlaboring controls. The median maternal serum TNF alpha level for patients with preterm labor was 29.4 pg/mL (range, 12.3-173) as compared with 23 pg/mL (range, 11.9-62.7) in the control group (P = .031). Among 44 patients with preterm labor, 14 (32%) delivered within one week of admission. The median maternal serum TNF alpha level was significantly higher in patients who delivered within one week than in those who delivered after one week and controls (71.3 pg/mL [range, 28-173]) versus 22 pg/mL (range, 12.3-86) versus 23 pg/mL (range, 11.9-62.7) (P < .0001). TNF alpha was elevated in patients with preterm labor, suggesting a role for maternal serum TNF alpha in its initiation.
Josefsson A et al., 2001·Acta Obstet Gynecol Scand
Postnatal depression refers to a non-psychotic depressive episode that begins in or extends into the postpartum period. The aims of this study were to examine the prevalence of depressive symptoms in a pregnant and later postnatal population, to determine the natural course of these symptoms and whether there is an association between antenatal and postnatal depressive symptomatology. A longitudinal study with a total population of 1,558 consecutively registered pregnant women in the southeast region of Sweden. Presence of depressive symptoms was measured with the Edinburgh Postnatal Depression Scale on four occasions namely in gestational week 35-36, in the maternity ward, 6-8 weeks and 6 months postpartum. The prevalence of depressive symptoms during late pregnancy was 17%; in the maternity ward 18%; 6-8 weeks postnatally 13%; and 6 months postnatally, 13%. A correlation between antenatal and postnatal depressive symptoms was found (r=0.50, p<0.0001). Detection of women at risk for developing postnatal depressive symptoms can be done during late pregnancy. Antenatal care clinics constitute a natural and useful environment for recognition of women with depressive symptoms.
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.
The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived
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 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 luteoma, luteal cyst and hyperreactio luteinalis. Finally, ovarian insufficiency may occur too early.
To evaluate serial measurements of salivary estriol (E3) to detect increased risk of spontaneous preterm labor and preterm birth. A masked, prospective, multicenter trial of 956 women with singleton pregnancies was completed at eight United States medical centers. Saliva was collected weekly, beginning at the 22nd week of gestation until birth, and tested for unconjugated E3 by enzyme-linked immunosorbent assay. Women were separated into high-risk and low-risk groups using the Creasy scoring system. A single, positive (at or above 2.1 ng/mL) salivary E3 test predicted an increased risk of spontaneous preterm labor and delivery in the total population (relative risk [RR] 4.0, P <.005), in the low-risk population (RR 4.0, P < or =.05), and in the high-risk population (RR 3.4, P =.05). Two consecutive positive tests significantly increased the RR in all study groups, with a dramatic improvement in test specificity and positive predictive value but only a modest decrease in sensitivity. In women who presented with symptomatic preterm labor, salivary E3 identified 61% of those who delivered within 2 weeks, using a threshold of 1.4 ng/mL. Elevated salivary E3 is associated with increased risk of preterm birth in asymptomatic women and symptomatic women who present for evaluation of preterm labor.
To determine whether the degree of cervical lengthening after cerclage and whether serial follow-up measurements of cervical length after cerclage are predictive of pregnancy outcome. Eighty women whose primary physician determined that a prophylactic (n = 50) or urgent cerclage (n = 30) was indicated had transvaginal ultrasonographic evaluation before and after cerclage. Thereafter, most women had three additional transvaginal ultrasound examinations until 32 weeks' gestation. At each examination, the mean of three measurements was calculated. Statistical analyses were done by t test, analysis of variance, and logistic regression, with significance set at P <.05. The mean +/- standard deviation precerclage cervical length was 27.2 +/- 10.3 mm and after cerclage was 34.1 +/- 9.9 mm (n = 80, P <.001, paired t test). No significant association was found (r = -0.26) between the difference in cervical length (postcerclage - precerclage lengths) and pregnancy outcome. Patients with a prophylactic cerclage had a mean cervical length that was consistently longer in patients delivering at term compared with those who delivered preterm at 20 to 32 weeks' gestation. In the urgent cerclage group a significant difference in cervical length between those who delivered at term compared with preterm was evident only at 28 to 32 weeks. The increase in cervical length after cerclage is not predictive of term delivery. Serial cervical length measurements in the late second or early third trimester predict preterm birth but could provide earlier warning in patients with a prophylactic cerclage than in patients with urgent cerclage.
Reproductive EndocrinologyPeripheral Thyroid Hormone MetabolismLow T3 SyndromeThyroid Hormone Conversion
Peripheral metabolism of thyroid hormones is a critical component of the impact these hormones have on intracellular function. Thyroid hormones can be metabolized in peripheral tissue by deiodination, conjugation, deamination, and decarboxylation enzyme reactions. Therefore, alterations in these metabolic pathways might significantly impact the quantity of specific thyroid hormone metabolites influencing function at the cellular level. Available evidence also suggests that, under some circumstances, the activity of hepatic antioxidant enzyme systems and lipid peroxidation might influence the peripheral metabolism of thyroid hormones. Several syndromes, such as "euthyroid sick syndrome" and "low T3 syndrome," have been classified within the medical literature. The common feature of these disorders is a low level of circulating T3, with generally normal to slightly elevated blood T4 levels and either normal or slightly suppressed TSH levels. This pattern of altered thyroid hormone levels is generally agreed to be a result of impairment in extra-thyroidal peripheral metabolism. Hepatic and renal pathology, as well as catabolic states such as those induced subsequent to severe injury, illness, or trauma result in consistent shifts in the thyroid hormone profile, secondary to their impact on peripheral enzyme pathways. Lifestyle factors, such as stress, caloric restriction, and exercise, influence peripheral metabolism of thyroid hormones. Exposure to toxic metals, chemical poisons, and several drugs can also influence the peripheral fate of thyroid hormones. While the role of vitamins, minerals, and botanical extracts in thyroid hormone metabolism requires further elucidation, current evidence supports a role for selenium in the hepatic 5'-deiodination enzyme.
To estimate the community prevalence in Olmsted County, Minnesota of elevated scores on the Edinburgh Postnatal Depression Scale, a self-report screening tool for postpartum depression. At the 6-week postpartum visit, the Edinburgh Postnatal Depression Scale was administered to women who gave birth in Olmsted County between July 28, 1997 and March 28, 1998. Study sites included all ambulatory clinics that provide pregnancy care in the county, and women who missed postpartum visits were contacted by mail. A threshold of 12 or more points on the scale was selected for clinical use; data for scores of ten and above were also examined. Of the 909 Olmsted County women studied (response rate 83.2%), 11.4% (n = 104) had scores of 12 or greater, with a 95% confidence interval (CI) of 9.4%, 13.5%. The percentage of women with a positive screen increased to 19.8% (n = 180; 95% CI 17.2%, 22.4%) when scores of 10 or higher were included, as has been recommended for screening in primary care settings. Forty-eight or 5.3% of the subjects (95% CI 3.8%, 6.7%) indicated experiencing suicidal ideation during the previous week. More than 11% of women had elevated scores on the Edinburgh Postnatal Depression Scale, indicating a high likelihood of postpartum depression and the need for further assessment. The screening process required little extra time and was acceptable to the subjects and clinicians. Screening for postpartum depression is appropriate and feasible for clinical practice and increases the identification of women suffering from this serious, common, and highly treatable disorder.
PregnancyBiomarkers and PredictionIntra-amniotic InfectionInterleukin-6
To evaluate the potential role of amniotic fluid (AF) interleukin (IL)-6 as a predictor of preterm delivery and to consider possible explanations for the proportion of women with elevated AF IL-6 who deliver preterm yet lack microbiologically detectable intra-amniotic infection. We searched the English language human literature in MEDLINE, 1966 through September 1999, using the keywords "labor/infant," "premature," "cytokines/interleukin-6," and "AF." We also examined abstracts from the 1999 meetings of the Society for Maternal-Fetal Medicine and the Society for Epidemiologic Research. We identified other studies by reviewing the reference lists of published articles. The MEDLINE search yielded 55 citations. We focused on studies that reported on the association between AF IL-6 and preterm delivery. TABULATION, INTEGRATION, There is consensus in the literature that elevated AF IL-6 is a stronger predictor of preterm delivery than intra-amniotic infection detected by either microbiologic culture or polymerase chain reaction (PCR). Among women with elevated AF IL-6, PCR could detect a higher proportion of intra-amniotic infection than culture. A number of women with elevated AF IL-6 (33-70%) deliver preterm and do not have evidence of intra-amniotic infection by either culture or PCR. Possible explanations for this observation are considered. Elevated AF IL-6 is strongly associated with preterm delivery and merits future consideration in clinical settings to predict preterm delivery and guide patient care. Development of improved polymerase chain reaction-based clinical methods to detect intra-amniotic infection is necessary to better understand the relationship between elevated AF IL-6, intra-amniotic infection, and preterm delivery.
DiagnosticsHigh-Sensitivity CRP MethodsAssay Comparison and Standardization
C-reactive protein (CRP) can provide prognostic information about the risk of developing atherosclerotic complications in apparently healthy patients. This new clinical application requires quantification of CRP concentrations below those traditionally measured in the clinical laboratory. The Dade Behring BN II, the Abbott IMx, the Diagnostic Products Corporation IMMULITE, and the Beckman Coulter IMMAGE are four automated analyzers with high-sensitivity CRP (hs-CRP) methods. We evaluated these assays for precision, linearity, and comparability with samples from 322 apparently healthy blood donors. The imprecision (CV) of the BN II, IMx, IMMULITE, and IMMAGE methods was < or = 7.6%, < or = 12%, < or = 9.8%, and < or = 9.7% at 3.5 mg/L, respectively. The BN II, IMx, IMMULITE, and IMMAGE methods were linear down to < or = 0.30, < or = 0.32, < or = 0.85, and 2.26 mg/L, respectively. CRP concentrations demarcating each quartile in a healthy population were method dependent. The IMx method gave results comparable to the BN II method for values in the reference interval. The IMMULITE method had a positive intercept compared with the BN II method. The IMMAGE method demonstrated more scatter and a positive intercept compared with the BN II method, which may reflect the fact that it is a less sensitive assay. The four hs-CRP methods exhibited differences in results for a healthy population. Additional standardization efforts are required to ensure that hs-CRP results can be related to large-scale epidemiologic studies.
General OB/GYNDiagnosisManagementhCG and Progesterone
Ectopic pregnancy occurs at a rate of 19.7 cases per 1,000 pregnancies in North America and is a leading cause of maternal mortality in the first trimester. Greater awareness of risk factors and improved technology (biochemical markers and ultrasonography) allow ectopic pregnancy to be identified before the development of life-threatening events. The evaluation may include a combination of determination of urine and serum human chorionic gonadotropin (hCG) levels, serum progesterone levels, ultrasonography, culdocentesis and laparoscopy. Key to the diagnosis is determination of the presence or absence of an intrauterine gestational sac correlated with quantitative serum beta-subunit hCG (beta-hCG) levels. An ectopic pregnancy should be suspected if transvaginal ultrasonography shows no intrauterine gestational sac when the beta-hCG level is higher than 1,500 mlU per mL (1,500 IU per L). If the beta-hCG level plateaus or fails to double in 48 hours and the ultrasound examination fails to identify an intrauterine gestational sac, uterine curettage may determine the presence or absence of chorionic villi. Although past treatment consisted of an open laparotomy and salpingectomy, current laparoscopic techniques for unruptured ectopic pregnancy emphasize tubal preservation. Other treatment options include the use of methotrexate therapy for small, unruptured ectopic pregnancies in hemodynamically stable patients. Expectant management may have a role when beta-hCG levels are low and declining.
The present study was designed to evaluate the prognostic value of salpingoscopy in patients undergoing tubal laparoscopic surgery for infertility due to periadnexal adhesion or distal tubal occlusion. In addition, the clinical value of salpingoscopy was compared with a current classification system of adnexal adhesions and distal tubal occlusion. A total of 51 patients with either adnexal adhesions (24 patients) or hydrosalpinx (27 patients) were prospectively evaluated. Salpingoscopy was performed concomitantly with salpingo-ovariolysis or salpingoneostomy at the time of operative laparoscopy. There was no significant correlation between salpingoscopic classes and the classification system used for both the salpingo-ovariolysis and the salpingoneostomy groups of patients. The patients had a mean follow-up of 33 months. Patients with a normal tubal mucosa (salpingoscopic classes I and II) had a 71% cumulative term pregnancy rate in the salpingo-ovariolysis group and a 64% cumulative term pregnancy rate in the salpingoneostomy group. No intrauterine pregnancies were obtained in patients with intratubal damage (salpingoscopic classes III to V). There was a statistically significant correlation between the occurrence of a term pregnancy and the salpingoscopic classes, but not with the classification system used. These results suggest that patients with tubal infertility should be offered operative laparoscopy with salpingoscopy as the first step of treatment.
Prospective studies have shown that C-reactive protein (CRP) can be used to predict risk of future cardiovascular events. High-sensitivity methods for CRP (hs-CRP) measurement are needed for this purpose. We compared the clinical efficacy of an automated and commercially available latex-enhanced assay (Latex) for hs-CRP (Dade Behring) to a validated in-house ELISA, previously shown to predict future peripheral arterial disease (PAD) in asymptomatic populations. Using a prospective, nested, case-control design, we measured baseline hs-CRP concentrations in 144 apparently healthy men who subsequently developed symptomatic PAD and 144 age- and smoking habit-matched controls who remained free of vascular disease over the follow-up period of 60 months. The two hs-CRP assays correlated highly (r = 0.95; P <0.001), and all but two participants were classified into concordant quartiles or varied by only one quartile. The median hs-CRP of the case group was significantly higher than that of controls when measured by either the ELISA (1.34 vs 0.99 mg/L; P = 0.034) or the Latex method (1.80 vs 1.20 mg/L; P = 0.042). Furthermore, for both ELISA and the Latex method, the calculated relative risks of developing PAD increased significantly with each increasing quartile of hs-CRP. The calculated interquartile increase in relative risk of PAD was 31% (95% confidence interval, 5.2-62.2%; P = 0.01) for ELISA and 34% (95% confidence interval, 8.2-66.1%; P = 0.007) for the Latex method. Our findings indicate that the Latex method is equally as efficacious as the validated ELISA in classifying patients into cutoff points established by prospective studies for risk stratification for coronary and cerebrovascular disease.
To assess the value of laparoscopy in infertile women with normal hysterosalpingograms, with and without risk factors suggesting pelvic disease. We retrospectively reviewed 1,022 consecutive charts from a tertiary infertility practice. In 265 women, laparoscopies were performed after normal hysterosalpingograms. Laparoscopies were normal in 136 (51%) women, whereas 129 (49%) had one or more abnormal laparoscopic findings, including minimal or mild endometriosis (n = 85), moderate or severe endometriosis (n = 11), adnexal adhesions (n = 27), subserosal myomas (n = 17), ovarian neoplasms (n = 5), distal phimosis (n = 1) and salpingitis isthmica nodosa (n = 1). Only 7% of cases had findings that might require standard operative laparoscopy or laparotomy, although not all were causally related to infertility. A history of dysmenorrhea or dyspareunia increased the likelihood of detecting endometriosis from 41% to 64% and 69%, respectively. The presence of both symptoms increased the likelihood to 83%. In the presence of a normal hysterosalpingogram, laparoscopy identified other pelvic disease in about half of patients. Because most abnormalities were mild, this knowledge can be used to plan a micro-laparoscopic approach for many women, reserving traditional or operative laparoscopy for women with an abnormal hysterosalpingogram or extensive disease following micro-laparoscopy. Alternately, knowledge of the nature and severity of the expected laparoscopic findings might lead to bypassing laparoscopy in favor of assisted reproduction when the perceived benefit of surgical intervention is small.
To assess the efficacy and diagnostic value of GnRH agonist (GnRH-a) therapy in cases of hidden sciatic nerve endometriosis. Case report. Academic tertiary referral center for endometriosis treatment. PATIENT(S): Three patients with cyclic, catamenial sciatica associated with pelvic endometriosis who had electromyographic evidence of sciatic nerve damage but negative computed tomography and magnetic resonance imaging findings. INTERVENTION(S): Monthly administration of the GnRH-a leuprolide acetate plus daily transdermal E2 (25 microg). MAIN OUTCOME MEASURE(S): Relief of pain symptoms and improvement in motor function. RESULT(S): All three patients had clear decreases in pain and partial amelioration of claudication. CONCLUSION(S): Endometriosis of the sciatic nerve may be hard to diagnose with the use of current imaging techniques but may be proved by clinical response to GnRH analogue treatment and may be more frequent than previously thought.
PregnancyPrediction and ScreeningCervical CerclageCervical Length Measurement
We sought to determine the predictive accuracy for preterm delivery of transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation in high-risk patients and to determine whether cerclage prevents preterm delivery in patients with ultrasonographic cervical changes. Patients with asymptomatic singleton pregnancies at high risk for preterm delivery were followed prospectively from 14 weeks' to 23 weeks 6 days' gestation with transvaginal ultrasonography of the cervix. The subgroup of patients with either a cervical length of <25 mm or funneling of >25% or both was offered McDonald salvage cerclage, which was performed at the discretion of the patient and the obstetrician. The 2 groups (with and without cerclage) were compared for the primary outcome of preterm delivery at <35 weeks' gestation. One hundred sixty-eight women were followed, including 97 (58%) with >/=1 prior 14- to 34-week preterm deliveries. Of 63 (37. 5%) patients identified as having cervical changes, 23 (37%) had preterm delivery; of 105 patients with no cervical changes, 8 (8%) had preterm delivery (relative risk, 4.8; 95% confidence interval, 2. 3-10.1). The sensitivity, specificity, and positive and negative predictive values of either a short cervix of <25 mm or funneling of >25% or both were 74%, 70%, 37%, and 92%, respectively. Of 63 pregnancies in which there were cervical changes, 39 underwent cerclage and 24 did not. These 2 groups were similar for demographic characteristics, risk factors, and transvaginal ultrasonographic cervical length and funneling but dissimilar for gestational age at identification of cervical changes (18.3 vs 21.2 weeks' gestation in the groups with and without cerclage, respectively; P <.001). Multivariate logistic regression analysis after adjustment for gestational age at cervical changes showed no difference in the rate of preterm delivery between the groups with and without cerclage (odds ratio, 1.1; 95% confidence interval, 0.3-4.6). Stratified analysis of patients identified between 18 and 24 weeks revealed 22 pregnancies with cerclage and 22 pregnancies without cerclage, which was similar for all characteristics studied. The incidence of preterm delivery remained similar (27% vs 23%, respectively; P =.7), as did days from cervical changes to delivery (111 vs 96, respectively; P =.2). Transvaginal ultrasonography of the cervix between 14 and 24 weeks' gestation is a good predictor of preterm delivery in high-risk pregnancies. Cerclage may not prevent preterm delivery in patients identified to be at high risk for this outcome by transvaginal ultrasonography.
To assess the intratubal pressure (ITP) and patency status of the fallopian tubes before and after transcervical catheterization of the fallopian tubes (TCFT). Prospective procedural assessment. Pope Paul VI Institute for the Study of Human Reproduction. PATIENT(S): Two hundred thirty-four women with either primary or secondary infertility. INTERVENTION(S): Patients underwent selective hysterosalpingography and, in some cases, TCFT with measurement of the ITP before and after the procedure. MAIN OUTCOME MEASURE(S): The ITP before and after TCFT. RESULT(S): The mean (+/-SD) ITP in freely patent tubes was 0.53 +/- 0.06 atm, that in partially obstructed tubes was 1.23 +/- 0.52 atm, and that in completely obstructed tubes was 2.79 +/- 1.40 atm. After TCFT, the mean (+/-SD) ITP in partially obstructed tubes decreased to 0.64 +/- 0.31 atm and that in completely obstructed tubes decreased to 1.86 +/- 1.35 atm. The ITP was normalized in 76% of partially obstructed tubes and in 29.5% of completely obstructed tubes. In all cases of complete obstruction in which surgical correction was attempted, organic pathology was identified. CONCLUSION(S): The procedure described is a safe and easy means of obtaining reliable and significant information on the status of the proximal fallopian tube.
To test the association between cytokine levels in the amniotic fluid and (i) the vascular invasion phase of intrauterine infection, (ii) the occurrence of periventricular leukomalacia; to assess the correlation between C-reactive protein levels, a recognised biological marker of inflammation in maternal serum and cytokine levels in the amniotic fluid. Prospective clinical study. Fetal medicine unit and neonatal intensive care unit, Antoine Beclere Hospital, Clamart, France. Thirty-one pregnancies complicated by chorioamnionitis leading to birth before 32 weeks of gestation. Interleukin 1-beta, Interleukin 6 and TNF-alpha prospectively measured in the amniotic fluid. Histological examination of the placenta. Ultrasound examination and magnetic resonance imaging of the brains of the newborn infants performed within the first week of life. The occurrence of periventricular leukomalacia was assessed by transfontanellar ultrasound and magnetic resonance imaging. There was a significant positive correlation between the occurrence of histological chorioamnionitis, vascular extension of infection of the membranes, maternal inflammatory syndrome and neonatal sepsis. A strong association was found between maternal serum C-reactive protein concentrations and cytokine levels in the amniotic fluid. Interleukin-1beta was the best predictor of vascular extension of chorioamnionitis, and TNF-alpha was the best predictor of the development of severe early neonatal infection. There was no association between the amniotic fluid levels of cytokines and the development of periventricular leukomalacia. These data suggest that IL-1beta, IL-6 and TNF-alpha are produced in relation to intrauterine inflammation and infection, but cannot be directly implicated in the development of fetal cerebral white matter lesions.
InfertilityL-Arginine SupplementationTreatment StrategiesUterine and Follicular Blood Flow
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). During the ovarian stimulation regimen, the patients were submitted to hormonal (oestradiol and growth hormone), ultrasonographic (follicular number and diameter, endometrial thickness) and Doppler (uterine and perifollicular arteries) evaluations. Furthermore, the plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. All 34 patients completed the study. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate.
To determine the accuracy of amniotic fluid (AF) matrix metalloproteinase-9 measurements for diagnosing intra-amniotic infection in women with preterm labor. We performed amniocenteses in 44 women between 22 and 35 weeks' gestation who presented to our center with preterm labor and clinical suspicion of intra-amniotic infection. Each sample was analyzed by glucose measurement, Gram stain, and culture for aerobes, anaerobes, and mycoplasmas. We tested the AF for matrix metalloproteinase-9 using gelatin zymography and a commercial enzyme-linked immunosorbent assay (ELISA) system. We calculated accuracy and confidence intervals (CIs) for AF matrix metalloproteinase-9, glucose, and Gram stain for diagnosing intra-amniotic infection, using culture as the criterion standard. All patients who had matrix metalloproteinase-9 detectable by ELISA also demonstrated matrix metalloproteinase-9 by zymography. Six cases of intra-amniotic infection were confirmed by culture (prevalence 14%). The performance statistics of AF matrix metalloproteinase-9 for diagnosing sensitivity 83% (95% CI 53, 99), specificity 95% (95% CI 88, 99), positive predictive value 71% (95% CI 37, 99), and negative predictive value 97% (95% CI 92, 99). Two women had false-positive results; one had gram-negative rods on the AF Gram stain and developed clinical signs and symptoms of chorioamnionitis several hours after amniocentesis and the other had a purulent vaginal discharge and an AF glucose level less than 15 mg/dL. Both delivered within 24 hours of amniocentesis. Measuring matrix metalloproteinase-9 in the AF appeared to be reliable for diagnosing intra-amniotic infection. An elevated matrix metalloproteinase-9 concentration in the AF at a preterm gestational age may portend imminent delivery regardless of microbiologic confirmation of intra-amniotic infection.
PregnancyCerclagePreventionCervical Length Measurement
Open Access
To determine changes in length of incompetent cervices after cerclage, using transvaginal ultrasound. Patients were enrolled in a prospective, observational study under an Institutional Review Board-approved protocol. McDonald or Shirodkar sutures were placed according to physician preference. Pre- and postcerclage cervical lengths were measured within 72 hours of the procedure. At each examination, the first measurement was discarded, and a mean of the subsequent three measurements was calculated. Twenty-one Shirodkar and ten McDonald operations were done. The mean (+/- standard deviation) precerclage cervical length was 2.7+/-0.9 cm and the postcerclage cervical length was 3.6+/-0.9 cm (P<.001, paired t test). Prophylactic cerclage results in measurable increases in cervical length, which might contribute to the success of the procedure. Further study is needed to determine whether the degree of cervical lengthening after cerclage predicts term delivery.
PregnancyBiomarkersPremature Rupture of MembranesPeptide Markers
To determine whether adrenomedullin levels in amniotic fluid were associated with preterm labor. We measured immunoreactive adrenomedullin in amniotic fluid collected by amniocentesis from 36 women with clinical diagnosis of preterm labor or preterm premature rupture of membranes (PROM) and from 18 normal pregnant women. Amniotic fluid from cases of PROM and failure to respond to tocolysis were associated significantly with higher amniotic fluid adrenomedullin concentrations (177.0 +/- 22.5 pg/mL and 182.7 +/- 22.0 pg/mL, respectively, P < .01) than that from uncomplicated pregnancies (101.2 +/- 28.1 pg/mL) or preterm labor responsive to tocolysis (102.3 +/- 26.8 pg/mL). Amniotic fluid adrenomedullin is higher than normal in cases of PROM and preterm labor unresponsive to tocolysis, perhaps indicating enhanced synthesis from placenta or fetal membranes being stimulated by bacterial products.
To describe the anatomic and technical difficulties encountered with transvaginal ultrasound imaging of the cervix in a consecutive series of women at risk for preterm delivery. Three groups of women had cervical those with histories of preterm birth, those with incompetent cervices, and those admitted for preterm labor that did not progress. Standardized ultrasound examinations of the cervix involved measuring the length of the endocervical canal, funneling length, and internal os dilation with and without fundal pressure. Sixty consecutive women had transvaginal ultrasound examinations for assessment of the cervix. Forty-six had histories of preterm birth, five had incompetent cervices, and nine had arrested preterm labor. Six types of problems arose, which can be divided into anatomic or technical considerations, with an overall frequency of 27% (95% confidence interval 16%, 40%). Anatomic pitfalls that hampered identification of the internal os included an undeveloped lower uterine segment (n = 5), a focal myometrial contraction (n = 1), rapid and spontaneous cervical change (n = 1), and an endocervical polyp (n = 1). Technical pitfalls included incorrect interpretation of internal os dilation because of vaginal probe orientation (n = 7) and artificial lengthening of the endocervical canal because of distortion of the cervix by the transducer (n = 1). We caution those who perform cervical length examinations to be wary of falsely reassuring findings due to potential anatomic and technical pitfalls.
To study the prevalence of polycystic ovaries (PCO) in women of reproductive age. A total of 189 healthy volunteers aged 20-45 years were examined. The subjects were divided into < or =35 and > or =36 years. Transvaginal ultrasonography was performed and blood samples were collected on cycle day 1-6. The prevalence of PCO in the entire study population was 14.2% (27/189). In the age group of < or =35 years the prevalence was 21.6% (19/88) and in the age group of > or =36 years 7.8% (8/101). Compared to women with normal ovaries, those with PCO had significantly higher serum testosterone (T) concentrations. Women with PCO tended to have lower serum FSH concentrations and higher LH/FSH ratios than controls. Women with PCO had significantly more irregular cycles (44% vs. 19%, p=0.001) and problems in conceiving (25.9% vs. 9.2%, p=0.01) than women with normal ovaries. The findings demonstrate that the prevalence of PCO in healthy women varies with age, being more common among women aged < or =35 years than in those aged > or =36 years. Although the hormonal parameters and clinical findings among women with PCO mimicked those of PCOS, it remains unclear if these women will later develop full-blown syndrome.
Our goal was to study the effect of therapeutic McDonald cerclage on cervical length with the use of transvaginal ultrasonography. Cervical length was measured serially in singleton pregnancies in which there were doubts regarding cervical competence. When shortening of the cervix was substantial before 27 weeks' gestation a McDonald cerclage was applied. Wilcoxon signed rank test was used, and 1-tailed P <.05 was considered significant. In the 34 pregnancies studied, the mean cervical length measured at a mean gestational age of 14 weeks had decreased significantly (P <.0001) from 42 mm (95% confidence interval 38-47) to 21 mm (95% confidence interval 19-23) at a mean gestational age of 20 weeks 5 days, when a cerclage was applied. After the cerclage the mean cervical length increased significantly (P <.0001) to 34 mm (95% confidence interval 30-38) at a mean gestational age of 22 weeks 1 day (95% confidence interval 21 weeks 1 day-23 weeks 2 days). Therapeutic McDonald cerclage results in a longer cervical length as measured by transvaginal ultrasonography.
General OB/GYNCesarean Scar DefectSonohysterographyPostmenstrual Spotting
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.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Detection
The purpose of our study was to analyze the efficacy of serum C-reactive protein (CRP), white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) serial evaluations in the prediction of chorioamnionitis in cases of premature rupture of membranes (PROM). A group of 80 patients with PROM before 35 weeks' gestation were evaluated prospectively and managed expectantly. We applied the expectant management with the permanent use of tocolysis, antibiotics, steroids, amnioinfusions of artificial amniotic fluid and intravaginal chemotherapeutics. Patients were monitored with frequent vital signs, fetal heart rate evaluation and everyday CRP, WBC and ESR. All afterbirths were examined to establish the presence of histologic chorioamnionitis (gold standard of intrauterine infection). S: 59 (73.7%) patients had significant chorioamnionitis on histopathology and only 15 of them had clinical chorioamnionitis. Serum CRP serial determinations (definition 1) > 1.2 mg/dl; 2) > 2.0 mg/dl; 3) > 1.2 mg/dl and increasing in two consecutive days) were found the most reliable with a sensitivity 1) 91.5%; 2) 85%; 3) 88%, specificity 57%; 76%; 86%, positive predictive value 86%; 90%; 94.5%, negative predictive value 70.5%; 64%; 72% and accuracy 82.5%; 82.5%; 87.5% respectively. The efficacy of WBC (abnormal > 12500/mm3; > 15000/mm3; > 12500/mm3 and increasing in two consecutive days) and ESR (abnormal > 60 mm/h; > 60 mm/h and increasing in two consecutive days) serial evaluations was significantly lower. Moreover, in cases of chorioamnionitis CRP increased above the upper limit of normal 3 days earlier than WBC or ESR. S: CRP was found the most reliable indicator of histologic chorioamnionitis and indicated the presence of intrauterine infection earlier than WBC or ESR.
PCOSUltrasound MorphologyOvarian Stromal ChangesTransvaginal Ultrasonography in PCOS
To investigate the relationship between the ovarian stromal area and clinical hormonal characteristics in women with polycystic ovary syndrome (PCOS). Twenty-eight women with PCOS (group 1) and 26 healthy women (group 2) participated in this study. For measuring the ovarian stromal area, transvaginal ultrasonography was performed on all women during the early follicular phase of the menstrual cycle. Venous blood was sampled from the women to determine serum follicle stimulating hormone, luteinizing hormone (LH), estradiol, androstenedione, free testosterone (FT), total testosterone (TT), 17 alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate, and fasting insulin and glucose levels. Two-tailed t and Pearson correlation tests were used for statistical analysis. Women with PCOS were heavier, and their serum FT, TT and LH levels were significantly higher than in the normals (P < .001, P < .012 and P < .001, respectively). The ovarian stromal area measured by transvaginal ultrasonography was also significantly larger than in the normals (P < .001). Only basal serum insulin levels seemed to correlate positively with the ovarian stromal area in women with PCOS (r = .43 P = .09). Although transvaginal ultrasonography has played an important role in the evaluation of women with PCOS, we could not demonstrate a relationship between the ovarian stromal area and hormonal characteristics of PCOS. Therefore, transvaginal ultrasonography and hormonal parameters must be used as complementary diagnostic methods in women with PCOS.
Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled i.v. glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18-40 yr; body mass index, >26 kg/m2) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S(I)) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S(I) and a fasting I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). I was more strongly correlated with S(I) than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S(I) as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, I ratio I ratio was significantly predictive of S(I) in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a I ratio of less than 4.5 as abnormal (using an S(I) value below the 10th percentile of our control population as evidence for insulin resistance), I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis I ratio was the single best screening measure for detecting insulin resistance. I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.
PostpartumAnxiety and DepressionMood DisordersEdinburgh Postnatal Depression Scale
A community-based sample of 107 women completed the Beck Anxiety Inventory, Beck Depression Inventory, State-Trait Anxiety Inventory, and Edinburgh Postnatal Depression Scale at 14 weeks postpartum and at 30 weeks postpartum. The point prevalence of anxiety was 8.7% at 14 weeks and 16.8% at 30 weeks postpartum. The point prevalence of depression was 23.3% at 14 weeks and 18.7% at 30 weeks postpartum. The incidence of anxiety during this time period was 10.28%, and the incidence of depression was 7.48%, indicating high incidences of both postpartum anxiety and depression later in the postpartum period. The Edinburgh Postnatal Depression Scale was found to have a strong correlation with the State Anxiety Scale of the State-Trait Anxiety Inventory (r = .73 at 14 weeks, r = .82 at 30 weeks), suggesting that the Edinburgh Postnatal Depression Scale may be a good screening instrument for anxiety as well as depression.
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.
PregnancyPrediction BiomarkersFetal FibronectinDiagnostic Test Accuracy
To assess the cervicovaginal fetal fibronectin test to predict preterm delivery. We searched MEDLINE, Current Contents, Index Medicus, and proceedings of meetings for studies published between 1991 and June 1997. Inclusion criteria were prospective cohort study; test performed between 20 and 36 weeks' gestation; fetal fibronectin measured by a previously described assay, with a cutoff level set at 50 ng/mL; test results not disclosed to women or physicians; and fewer than 20% of study participants excluded from the analysis. TABULATION, INTEGRATION, Twenty-nine relevant studies were stratified according to the prevalence of preterm delivery, the number of tests performed, and delivery before 34, 35, or 37 weeks. Sensitivities, specificities, and likelihood ratios were calculated in each study. The summary estimates of the likelihood ratio for tests yielding positive results or tests yielding negative results along with their 95% confidence intervals (CIs) were computed in each stratum according to a random-effects model. All summary likelihood ratios for a test yielding positive results indicated a significant association with preterm delivery. The strongest association was found between a single test with positive results and delivery before 37 weeks in a low-risk population (likelihood ratio 7.5; 95% CI 4.6, 12.3). This association also was found in high-risk women (likelihood ratio 3.5; 95% CI 2.6, 4.6). In high-risk women, a test yielding negative results was associated with a reduction in risk of preterm delivery (likelihood ratio 0.4; 95% CI 0.3, 0.5). Fetal fibronectin in cervicovaginal secretions is associated with preterm delivery in both high-risk and low-risk women.
To examine the occurrence of polycystic ovaries (PCO) in women with gestational diabetes mellitus (GDM). This was a retrospective comparative study of ultrasonographic findings of ovaries in 31 women with GDM and 30 healthy controls matched according to maternal age and body mass index (BMI). Women who presented evidence of impaired glucose tolerance during pregnancy were excluded from the control group. Transvaginal ultrasonographic examination was performed during the follicular phase of the menstrual cycle, after breast-feeding had been discontinued. Polycystic ovary was a more frequent finding among women 14 women with GDM (44%) and two controls exhibited PCO. No differences were found in BMI before pregnancy or in the weight gain during pregnancy between the groups. No difference was observed in the mean birth weight of the infants between the study groups. Polycystic ovaries were a common finding among women with GDM. The data suggest that women with PCO are at risk for developing GDM and should be screened accordingly.
PostpartumDepression Risk FactorsPostpartum Depression PredictionPredictive Scales for PPD
Depressed new mothers usually do not seek and therefore do not receive any psychiatric help. In order to assess predictive signs of postpartum depression (PPD), an unselected sample of 570 women were seen by midwives during their pregnancy, using a questionnaire elaborated by ourselves and Derogatis' Hopkins Symptom Checklist. Three months after delivery each new mother was examined again by the same midwife using Cox' Edinburgh Postnatal Depression Scale. The medical files were also examined. Of the new mothers, 58 (10.2%) suffered from PPD. Most significant factors were socio-professional difficulties, multiparity, deleterious life events, depressive mood prior to delivery, early mother-child separation and negative birth experience. The coping abilities of the depressed mother were decreased and her vulnerability to new stress factors increased. It is possible to detect women at risk for PPD already during pregnancy. We therefore elaborated a very simple, short predictive scale which is in the process of validation. Protective factors still have to be studied. Knowledge of these factors should help all caregivers to recognize, during pregnancy, women at risk for PPD, in order to initiate preventive and/or therapeutic measures.
Reproductive EndocrinologyStress-Related DisordersPsychosomatic EtiologyCRF Stimulation and Dexamethasone Suppression
Although numerous organic conditions may cause chronic pelvic pain (CPP), diagnostic laparoscopy reveals a normal pelvis in many patients with CPP. However, psychological studies yield a high frequency of psychopathology and increased prevalences of chronic stress and traumatic life events, ie, sexual and physical abuse, in women with CPP, suggesting a relationship between posttraumatic stress disorder (PTSD) and CPP. As chronic stress and PTSD have been associated with specific alterations of the hypothalamic-pituitary-adrenal (HPA) axis, we explored stress history, psychopathology and HPA axis alterations in women with CPP. We recruited 16 patients with CPP and 14 painfree, infertile controls from a general hospital where diagnostic laparoscopy was performed. Psychological assessment included standardized interviews on clinical symptoms, abuse experiences and major life events as well as psychometric testing for PTSD-like symptoms and depression. Endocrinological evaluation involved determinations of diurnal salivary cortisol levels and hormonal responses to a corticotropin-releasing factor (CRF) stimulation test (100 microg human CRF) and a low-dose dexamethasone suppression test (0.5 mg). We observed increased prevalences of abuse experiences and PTSD in women with CPP as well as a higher total number of major life events, whereas the mean extent of depression was within the normal range. With respect to endocrine measures, women with CPP demonstrated normal to low diurnal salivary cortisol levels, normal plasma-adrenocorticotropin (ACTH), but reduced salivary cortisol levels in the CRF stimulation test, and an enhanced suppression of salivary cortisol by dexamethasone. Women with CPP demonstrate HPA axis alterations, that partly parallel and partly contrast neuroendocrine correlates of PTSD, but show marked similarity to findings in patients with other stress-related bodily disorders. These findings suggest that a lack of protective properties of cortisol may be of relevance for the development of bodily disorders in chronically stressed or traumatized individuals.
EndometriosisUreteral InvolvementSurgical and Medical ManagementUreteroscopy
Intrinsic ureteral endometriosis is rare. Early detection and treatment is extremely important to preserve renal function. A 37-year-old woman with right flank pain was diagnosed with a polypoid lesion at excretory urogram. The polyp was removed under ureteroscopy and was found to be endometriosis. Subsequent exploratory laparotomy and ureterolysis failed to document other foci of endometriosis. Resection of the ureter was not needed. She received medroxyprogesterone for 6 months, and a ureteral stent was left in place for 3 months postoperatively. Excretory urogram showed no obstruction 6 months postoperatively. This appears to be the first reported case of ureteral endometriosis documented initially at ureteroscopy. Prompt treatment may relieve symptoms and preserve renal function. Resection of the ureter may be avoided in some patients.
Houston JG et al., 1998·Cardiovasc Intervent Radiol
To evaluate the technical success and outcome of fallopian tube recanalization (FTR) in salpingitis isthmica nodosa (SIN). SIN is a well-recognized pathological condition affecting the proximal fallopian tube and is associated with infertility and ectopic pregnancy. We reviewed the presentations, films, and case records of all patients attending for FTR for infertility from 1990 to 1994. Technical success and total, intrauterine, and ectopic pregnancy rates at follow-up were determined. SIN was observed in 22 of 349 (6%) patients. FTR was attempted in 34 tubes in these 22 patients. Technical success was achieved in 23 of 34 (68%) tubes affected by SIN. In 5 of the 11 failed recanalizations, failure was due to distal obstruction. At least one tube was patent on selective postprocedural salpingography in 17 of 22 (77%) patients. There were no recorded perforations or complications. At follow-up (mean 14 months), total, intrauterine, and ectopic pregnancy rates were 23%, 18%, and 4.5%, respectively. FTR in SIN is technically successful and, compared with previously reported results in unselected infertility patients, is associated with only a slightly less favorable intrauterine pregnancy rate and a comparable ectopic pregnancy rate. The findings of SIN at FTR should not discourage attempted fluoroscopic transcervical recanalization.
EndometriosisTransrectal UltrasonographyUltrasound for Deep EndometriosisRectovaginal Septum
To evaluate the validity of transrectal ultrasonography in the assessment of rectovaginal endometriosis. We compared the findings of transrectal ultrasonographic examination performed before surgery with the operative and pathologic findings in 140 women who underwent laparoscopy or laparotomy for suspected endometriosis. The ultrasonographer was asked to investigate whether any deep endometriotic lesions were present in the rectovaginal septum and to define the lateral extension on the basis of involvement of the uterosacral ligaments. In addition, infiltration of the rectal and vaginal walls was evaluated. Thirty-four women had endometriosis infiltrating the rectovaginal septum confirmed by combined operative and pathologic findings. Ultrasonography showed a sensitivity and specificity of 97% and 96%, respectively, in the diagnosis of the presence of rectovaginal endometriosis. The sonographer identified infiltration of the rectal and vaginal walls correctly in all cases in whom it was present, but also reported rectal infiltration in three cases not confirmed by the surgeon and pathologist. The sensitivity and specificity in the diagnosis of uterosacral ligament infiltration were 80% and 97%, respectively. If our preliminary results are confirmed by a larger series, transrectal ultrasonography will be considered a valid diagnostic tool in the evaluation of rectovaginal endometriosis.
This study was undertaken to determine the relationship between fetal fibronectin, short cervix, bacterial vaginosis, other traditional risk factors, and spontaneous preterm birth. From 1992 through 1994, 2929 women were screened at the gestational age 22 to 24 weeks. The odds ratios for spontaneous preterm birth were highest for fetal fibronectin, followed by a short cervix and history of preterm birth. These factors, as well as bacterial vaginosis, were more strongly associated with early than with late spontaneous preterm birth. Bacterial vaginosis was more common--and a stronger predictor of spontaneous preterm birth--in Black women, while body mass index less than 19.8 was a stronger predictor in non-Black women. This analysis suggests a pathway leading from Black race through bacterial vaginosis and fetal fibronectin to spontaneous preterm birth. Prior preterm birth is associated with spontaneous preterm birth through a short cervix. Fetal fibronectin and a short cervix are stronger predictors of spontaneous preterm birth than traditional risk factors. Bacterial vaginosis was found more often in Black than in non-Black women and accounted for 40% of the attributable risk for spontaneous preterm birth at less than 32 weeks.
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.
PregnancyhCG Structure and MetabolismhCG Measurement in Trophoblastic DiseaseGestational Trophoblastic Disease
To examine the structure and metabolism of human chorionic gonadotropin (hCG) and the effect of molecular heterogeneity on the immunodiagnosis and monitoring of gestational trophoblastic disease. A review of the current medical literature concerning measurement of hCG and hCG-related molecules. hCG molecules in gestational trophoblastic disease are more heterogeneous or degraded in serum and urine samples than in normal pregnancy. Appropriate measurement and monitoring of hCG levels in gestational trophoblastic disease require an understanding of hCG structure and metabolism.
PregnancyBiomarkersCytokine MeasurementPremature Rupture of Membranes
To determine whether serum interleukin-6 concentrations predict impending preterm delivery. Blood samples were collected from 130 gravidas at 22-34 weeks' gestation. The study group consisted of 89 women evaluated for preterm contractions or premature rupture of membranes, and these women were compared with 41 outpatient controls without evidence of labor or infection, chosen by clinicians at the time of routine prenatal visits. Serum interleukin-6 concentrations were measured using a specific enzyme-linked immunosorbent assay kit. Analyses were by the Mann-Whitney U and the Kruskal-Wallis tests. All 41 control subjects had serum interleukin-6 concentrations less than 8 pg/mL. Sixteen of the 89 study patients had serum interleukin-6 concentrations greater than or equal to 8 pg/mL and 73 had values less than 8 pg/mL. When the serum interleukin-6 concentration was at least 8 pg/mL, the median interval from collection to delivery was significantly shorter than that among study and control subjects with serum interleukin-6 less than 8 pg/mL (5.5 versus 240 and 1801 hours, respectively; P < .001). The median gestational age at delivery was significantly lower when the serum interleukin-6 concentration was at least 8 pg/mL, compared with study and control subjects with serum interleukin-6 concentrations less than 8 pg/mL (29.6 versus 33.4 and 39.0 weeks, respectively; P < .001). In patients with preterm contractions, the interval from collection to delivery was significantly shorter when the serum interleukin-6 concentration was at least 8 pg/mL than when it was less than 8 pg/mL (3 versus 600 hours, P < .001). Similarly, the median gestational age at delivery was significantly lower when serum interleukin-6 was at least 8 pg/mL (29.0 versus 36.1 weeks, P < .001). Maternal serum interleukin-6 concentrations appear to be elevated in women destined to deliver prematurely. Measurement of this cytokine may prove useful in treating patients at high risk for preterm delivery.
PregnancyInfection and Inflammation BiomarkersInterleukin-6 and Neopterin in PregnancyImmunological Mechanisms
Oleszczuk J et al., 1997·Eur J Obstet Gynecol Reprod Biol
We estimated the levels of interleukin 6 (IL-6) and neopterin, in serum of twelve nonpregnant (group A) and 28 pregnant women between 28-36 weeks of pregnancy. Group B consisted of eight patients with uncomplicated pregnancy, group C consisted of thirteen pregnant women with clinical signs of preterm labour and without laboratory markers of infection and group D consisted of seven pregnant women with signs of preterm labour and with laboratory markers of infection. The levels of IL-6 and neopterin were significantly higher in group D compared to groups A, B and C (p < 0.05). Similarly, the level of C-reactive protein (CRP) and total white blood cell count (the laboratory markers of infection) were significantly higher in group D than in groups A, B and C. Total white blood cell count was significantly lower in group A than in group B and D (p < 0.05). There were no significant differences in values of IL-6, neopterin and CRP between groups A, B and C (p > 0.05). In all groups, significant correlations were found between IL-6 and neopterin as well as total white blood cell count and CRP. Our results suggest that IL-6 and neopterin may be the markers of preterm labour caused by infection. On the other hand, cell-mediated immune response may be involved in the mechanisms of preterm labour.
This paper presents demographic data about use of NFP in Europe and the factors which have been identified as influencing that very low use level. Experience with a new ovulation detection device in clinical trials and observations of its over-the-counter promotions is discussed in the context of what is already known about how to maximize uptake of contraception in main-stream service provision. Some suggestions are offered as to appropriate means of encouraging women who are using artificial methods or no method to understand enough about their natural fertile cycle to consider NFP as an acceptable option.
To develop and evaluate a questionnaire used antepartum to screen for postpartum depression. Demographic and clinical data, based on previously identified variables, were obtained from 106 second-trimester gravidas (sample I) by interview, self-administered questionnaire and medical record review. The Beck Depression Inventory (BDI) was administered at 1, 6 and 12 weeks postpartum (PP). Statistical analysis, including stepwise linear regression with maximum r-squared improvement, identified a subset of the 24 most predictive variables. This antepartum questionnaire (APQ) was validated retrospectively in the original sample and prospectively in a second group of 99 women (sample II). In both sample populations the APQ had acceptable sensitivity (80-82%) and specificity (78-82%). The incidence of postpartum depressive symptoms (PPDS) rose from 10% to 17% by six weeks without an appreciable decline at 12 weeks (15%). The percentage of women showing more than mild depressive symptoms increased with PP time from 30% at 1 week to 47% at 12. The APQ is now available for screening and evaluating early therapeutic intervention in PPDS.
PregnancyPremature Rupture of MembranesInterleukin-8Chorioamnionitis
Interleukin-8 (IL-8), a 72 amino acid peptide secreted by cells of the immune system and of the amnion, chorion and decidua, was measured in women in late pregnancy. IL-8 was detected in the urine of 91 of 104 women with premature rupture of the fetal membranes, with values exceeding 1000 ng/L in cases of severe intra-amniotic infection. Women with urinary tract infections were excluded. The routine measurement of IL-8 in urine, together with C-reactive protein in serum, thus provides a low risk and technically simple approach to the assessment of intra-amniotic infection.
PCOSUltrasound vs Endocrine CriteriaTransvaginal UltrasoundNormogonadotropic Oligomenorrhea
To investigate the predictive value of polycystic ovaries for endocrine signs of polycystic ovary syndrome (PCOS). Controlled descriptive study. Academic tertiary care fertility clinic. PATIENT(S): Normogonadotropic (FSH levels between 1 and 10 mIU/mL conversion factor to SI unit, 1.0) oligomenorrheic or amenorrheic women visiting our fertility clinic and a control group of regularly cycling, healthy, normal weight volunteers recruited by advertisement. INTERVENTION(S): Single blood samples and transvaginal sonography were performed. MAIN OUTCOME MEASURE(S): Serum levels of FSH, LH, androstenedione (A), and T and ovarian volume, ovarian stroma density, and follicle number. RESULT(S): In control women, the 95th percentile was calculated for ovarian volume, follicle number, and stroma count as well as endocrine parameters. The use of these upper limits of normal in the study group resulted in 217 (66%) patients with polycystic ovaries on ultrasound (defined as increased mean ovarian volume and/or mean follicle number per ovary), whereas only 120 (36%) patients exhibited elevated serum androgens (increased A and/or T concentrations) and 155 (47%) showed elevated LH levels. Sensitivity and specificity of single or combined sonographic parameters for prediction of elevated serum LH or androgen concentrations were limited. CONCLUSION(S): In the study group of normogonadotropic oligomenorrhea or amenorrheic infertile women, we set strict cutoff levels for various criteria used in the literature for defining PCOS. Groups defined by sonographic or endocrine PCOS criteria did overlap, but sonographic parameters had limited predictive value for abnormal hormone serum levels.
To evaluate the luteal phase in women with rigorously defined unexplained infertility. Prospective study. National Center for Infertility Research at Michigan. PATIENT(S): Evaluation of 1,885 women with infertility identified 12 women who met the rigorously defined criteria [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.
InfertilityDiagnostic Testing PatternsReproductive EndocrinologyClinical Practice Variation
To determine how board-certified reproductive endocrinologists vary in their approach to the clinical tests performed on the infertile couple. A cross-sectional study to assess differences in the approach to evaluating the infertile couple. A population-based national survey. PARTICIPANT(S): United States board-certified reproductive endocrinologists. MAIN OUTCOME MEASURE(S): The frequency of clinical tests and evaluation procedures by physician age, sex, size and setting of practice, institutional affiliation, and geographic location. RESULT(S): The overall response rate was 84%. Although the majority of practitioners routinely order a semen analysis (99.9%), an assessment of ovulation (98%), a hysterosalpingogram, (HSG; 96%), laparoscopy (89%), and a postcoital test (PCT, 79%), there was less agreement regarding hormonal testing (range, 22% [LH] to 66% [PRL]), use of pelvic ultrasounds (55%), hysteroscopy (53%), cervical cultures (range, 24% to 54%), and antisperm antibody testing (24%). Compared with male colleagues, female physicians order two to three times more cervical cultures and endometrial biopsies. Serum hormonal testing was two to three times more commonly ordered by younger (< 40 years) compared with older physicians, and physicians in private practice twice as frequently ordered hormonal testing, cervical cultures, PCTs, and antisperm antibody studies compared with their academic-affiliated colleagues. Western U.S. physicians order hormonal tests and cervical cultures 50% less often than their midwest and eastern counterparts. CONCLUSION(S): Trained specialists rely heavily on five "traditional" semen analysis, an assessment of ovulation, HSG, laparoscopy, and PCT. With regard to additional modes of testing, there is marked variability by physician sex, age, type of practice, and geographic location.
Reproductive EndocrinologyLuteal Phase Defect DiagnosisTransvaginal Color DopplerCorpus Luteum Function
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.
InfertilityHysterosalpingographyRadiation Exposure SafetySelective Salpingography and Catheterization
To evaluate the risk of radiation exposure to infertility patients during a gynecoradiologic procedure. Retrospective clinical study. Medical school-affiliated infertility center. PATIENT(S): Three hundred thirty-two consecutive infertility patients undergoing a gynecoradiologic procedure. INTERVENTION(S): Patients underwent a gynecoradiologic procedure as part of their infertility workup and the fluoroscopic exposure time was analyzed. MAIN OUTCOME MEASURE(S): The fluoroscopic exposure (rad time) during gynecoradiologic procedures, including hysterosalpingogram (HSG), selective salpingography, tubal catheterization, and others. RESULT(S): The rad time (mean +/- SD) was 63 +/- 54 seconds for normal HSG (n = 94, range 17 to 404 seconds), 100 +/- 61 seconds for abnormal HSG (n = 53, range 28 to 272 seconds), 111 +/- 57 seconds for unilateral selective salpingography (n = 36, range 31 to 324 seconds), 142 +/- 74 seconds for bilateral selective salpingography (n = 87, range 40 to 430 seconds), 176 +/- 77 seconds for unilateral tubal catheterization (n = 27, range 70 to 342 seconds), and 239 +/- 82 seconds for bilateral tubal catheterization (n = 30, range 110 to 381 seconds). Five patients had other procedures, such as lysis of intrauterine adhesions (n = 2) and resection of an uterine septum (n = 3), for which the rad time was in a range of 180 to 300 seconds. CONCLUSION(S): The radiation exposure of patients during a gynecoradiologic procedure, using previously described standard techniques, is well within established margins of safety.
To study the effects of clomiphene citrate (CC) on the endometrium by ultrasound and to reveal the echogenic difference between the control cycle and the CC cycle. Retrospective study of patients before and during a CC treatment. Department of Obstetrics and Gynecology, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. PATIENT(S): Seventy-nine infertile women who had a spontaneous ovulation and a normal luteal function. INTERVENTION(S): Patients received 50 mg/d CC between days 5 and 9 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Endometrial thickness, echogenic pattern of the endometrium, serum E2 content, and E2 and P receptor contents in the endometrium. RESULT(S): Endometrial thickness was significantly thinner during the CC cycle (7.6 +/- 1.4 mm, mean +/- SD, n = 79) than during the control cycle (8.5 +/- 1.7 mm, n = 79) on late proliferative days, but there was no significant difference on midsecretory days (10.8 +/- 2.2 mm during the CC cycle, n = 79; 11.2 +/- 2.2 mm during the control cycle, n = 79). The echogenic patterns, however, were different between the two cycles on midsecretory days. Moreover, the incidence in which patients showed a grade 3 endometrium on midsecretory days was significantly higher during the conceived CC cycle compared with the not-conceived CC cycle. Serum E2 levels were significantly higher, but E2 receptor contents in the endometrium were significantly lower during the CC cycle (67 +/- 46 fmol/mg, n = 13) compared with the control cycle (123 +/- 89 fmol/mg, n = 15) on late proliferative days. CONCLUSION(S): Clomiphene citrate affected the echogenic pattern of the endometrium, and most of the endometrium showed a grade 3 pattern on midsecretory days during the conceived CC cycle. Under the CC treatment, the comfortable endometrium for embryos might be different from the control cycle.
PregnancyBiomarkersPremature Rupture of MembranesC-Reactive Protein
C-reactive protein (CRP) levels were evaluated during spontaneous labour, in imminent premature parturition (IPP) and after preterm rupture of oocyst membranes (PROM). Increasing CRP level during spontaneous labour was found in 16.6% parturients. Elevated CRP level in patients with IPP makes it impossible to predict premature labour. In parturients with PROM, increase in CRP level makes further infection predictable only in a few cases.
Fishman A et al., 1996·Eur J Obstet Gynecol Reprod Biol
Malignant transformation to endometriosis is a well documented phenomenon that occurs most commonly in the ovaries with cancer arising in extra-ovarian endometriosis being a rare event. A retrospective clinical-pathological evaluation of eleven cases with malignant tumors arising in endometriosis was performed to evaluate the prognostic impact of various factors. Nuclear DNA content (ploidy) was assessed through flow cytometric study. Ovarian origin was identified in eight cases and three were associated with extra-ovarian endometriosis. Histologic type was endometrioid carcinoma in ten patients. The eleventh case had high grade endometrial stromal sarcoma. All tumors were diploid with no relation to stage, grade, or clinical outcome. The S-phase fraction (SPF) was analyzed in nine patients and no correlation could be demonstrated with any histologic parameters or clinical outcome. The DNA content seems to have no association with the classical prognostic parameters in these cases.
PregnancyDepression ScreeningBeck Depression InventorySensitivity and Specificity
To determine the test characteristics of a self-report questionnaire, the Beck Depression Inventory, when used as a screening test for depression in a population of ambulatory pregnant women. One hundred five pregnant women completed the Beck Depression Inventory and underwent a structured interview using the National Institute of Mental Health Diagnostic Interview Schedule-version III. Current depression was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-III-R. A receiver operating characteristic curve was constructed for the Beck Depression Inventory score as a predictor of current depression. A table of sensitivities, specificities, predictive values, and likelihood ratios was created for various cutoff values. For the 105 women enrolled, the median Beck Depression Inventory score was 8.0. Twelve women (11%) were diagnosed with current depression and had a median Beck Depression Inventory score of 25.5, compared with those without current depression, who had a median score of 8.0 (P = .001). The area under the receiver operating characteristic curve was 0.9940. Using a cutoff range of greater than 16, the sensitivity of the Beck Depression Inventory to detect current depression was 0.83, the specificity was 0.89, the positive predictive value was 0.50, and the negative predictive value was 0.98. The Beck Depression Inventory can serve as a rapid screening test for depression during pregnancy. A higher cutoff value is required for pregnant women than is customarily used outside of pregnancy.
Involvement of the gastrointestinal tract by gynecologic disease processes-endometriosis, gynecologic neoplasms, inflammatory processes, and complications from radiation therapy or surgery for gynecologic tumors-may mimic primary gastrointestinal carcinoma on radiologic images. Endometriosis most often involves the anterior wall of the rectosigmoid colon, adjacent to the pouch of Douglas, and typically produces extrinsic mass effect on the serosa, with the overlying mucosa left intact. Direct extension of ovarian cancer to the colon through the subperitoneal space produces mass effect with serosal spiculation, tethering, and fixation; annular constriction; or partial or complete obstruction. Intraperitoneal seeding of ovarian carcinoma most frequently involves the colon and is seen as extrinsic masses, often with serosal spiculation and tethering. Cervical carcinoma, which most commonly spreads by direct invasion of the pelvic side wall and adjacent structures, produces serosal spiculation and circumferential narrowing. Benign ovarian or uterine tumors are purely extrinsic and have a smooth interface with the colonic wall. Tubo-ovarian abscesses are difficult to differentiate from cystic ovarian neoplasms or endometriomas. Radiation colitis causes narrowing of the rectum with intact mucosa and can be differentiated from recurrent tumor, unlike radiation-induced injury of the small bowel, which may be difficult to distinguish. Surgical adhesions produce a discrete transition point between dilated bowel proximally and nondilated distal bowel. Familiarity with the varied patterns of gastrointestinal tract involvement is important for accurate interpretation of imaging studies.
Our purpose was to determine whether perioperative transvaginal ultrasonographic evaluation of the incompetent cervix treated with emergency cerclage is predictive of pregnancy outcome. Twenty-nine women who underwent emergency cerclage at 16 to 26 weeks of gestation had transvaginal ultrasonographic evaluation of the cervix within 48 hours before and after surgery and at least three times thereafter until 28 weeks of gestation. The following (1) funnel width, (2) funnel length, (3) endocervical canal length, (4) the distance between the internal and external os, (5) upper cervix (length of closed endocervical canal above the cervical cerclage), (6) lower cervix (endocervical canal length below suture), and (7) cervical index (1+ Funnel length/Endocervical canal length). Values are reported as the median in millimeters, and statistical analysis was performed by use of the Mann-Whitney U test, Wilcoxon signed-rank test, Spearman rank correlation, 2 x 2 contingency tables, and multiple regression analysis with significance set at p < 0.05. Cerclage procedures resulted in significant improvement in postoperative median measurements of funnel width (15 vs 4.0 mm, p < 0.0001), funnel length (29 vs 3 mm, p < 0.0001), and endocervical canal length (2 vs 27 mm, p < 0.0001). There was a significant relationship between preoperative funnel width (r = -0.51, p = 0.007), postoperative endocervical canal length (r = 0.39, p = 0.04), length of the lower cervix (r = 0.39, p = 0.038), and the cervical index (r = -0.39, p = 0.038). An upper cervical length < 10 mm was a good predictor of delivery before 36 weeks of gestation, sensitivity 85.7% (12/14), specificity 66.7% (10/15), positive predictive value 70.6% (12/17), negative predictive value 83% (10/12), and Fisher's exact p = 0.008. Postoperatively all patients had upper cervical lengths < 10 mm by 28 weeks of gestation. Preoperative digital assessments of cervical dilatation before surgery did not correlate with gestational age at birth (r = -0.031, p = 0.36). In cases of cervical incompetence treated with emergency cerclage, perioperative transvaginal ultrasonographic assessment of the cervix reveals that the procedure results in improved ultrasonographic status of the cervix and that the ultrasonographic cervical findings before and after surgery correlate with pregnancy outcome.
PregnancyScreening and PreventionCervical Length ScreeningOutpatient Tocolysis Management
To characterize the continuum between normal and preterm labor to prevent spontaneous preterm birth and low birth weight. Between August 1, 1992, and November 30, 1993, obstetric patients from a large managed care medical group were assigned in rotation to five private practice offices for pregnancy care. In the study office (374 births), a systematic approach of visit-by-visit screening, patient education, selective office evaluation of cervical change by transvaginal ultrasound examination, outpatient modification of activity, and graded oral or subcutaneous tocolysis was used; inpatient tocolysis was used only when outpatient management failed. In the comparison offices (1391 births), transvaginal ultrasound was not used and conventional methods were used at the discretion of the attending physicians. Birth weights below 1500 g (P = .008; odds ratio [OR] 0.08, 95% confidence interval [CI] 0.05-1.32), 2000 g (P = .21; OR 0.21, 95% CI 0.05-0.88), and 2500 g (P = .008; OR 0.44, 95% CI 0.23-0.83) occurred significantly less often in the study group than in the comparison group. The difference in spontaneous preterm births under 2500 g was also significant (P < .001; OR 0.08, 95% CI 0.01-0.58). By emphasizing transvaginal ultrasound and graded outpatient tocolysis, the diagnosis and management of preterm prelabor was associated with a reduction in the rate of spontaneous preterm birth and low birth weight infants.
General OB/GYNChronic Pelvic PainACOG RecommendationsPelvic Pain Assessment
Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists, 1996·Int J Gynaecol Obstet
Although treating patients with chronic pelvic pain may pose a challenge, such patients can often be treated successfully. Effective modalities are available to lessen the impact of the pain and offer the reasonable expectation of return to normal function.
To evaluate the presence of fetal fibronectin in the cervix and vagina as a screening test for spontaneous preterm birth. Two thousand nine hundred twenty-nine women at ten centers were routinely screened every 2 weeks from 22-24 to 30 weeks for cervical and vaginal fetal fibronectin. A positive test was defined as a value equal to or greater than 50 ng/mL. The relation between a positive test at four gestational ages and spontaneous preterm birth at various intervals after the test was determined. In each testing period, 3-4% of the fetal fibronectin tests were positive. The correlation between cervical and vaginal fetal fibronectin at the same visit was always approximately 0.7 (P < .001), and that between cervical or vaginal fetal fibronectin in consecutive visits was between 0.17 and 0.25 (P < .001). The sensitivity of fetal fibronectin at 22-24 weeks to predict spontaneous preterm birth at less than 28 weeks was 0.63, and the relative risk for a positive versus negative test was 59. The specificity was always 96-98%, whereas the positive predictive value rose from 13% to 36% as the upper limit of the definition of preterm birth was increased from less than 28 to less than 37 weeks. The relative risk for spontaneous preterm birth after a positive fetal fibronectin test compared with a negative fetal fibronectin test varied substantially by testing period and by the definition of spontaneous preterm birth, but always remained greater than 4 and statistically significant. A positive cervical or vaginal fetal fibronectin test at 22-24 weeks predicted more than half of the spontaneous preterm births at less than 28 weeks (sensitivity 0.63). As the definition of spontaneous preterm birth was extended to include later gestational ages or when the fetal fibronectin test was performed later in pregnancy, the level of association between a positive fetal fibronectin test and spontaneous preterm birth, while remaining highly significant, tended to decrease. Although fetal fibronectin is an excellent test for predicting spontaneous preterm birth, we present no evidence that the use of this test will result in a reduction in spontaneous preterm birth.
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 role of the cervix in the pathogenesis of premature delivery is controversial. In a prospective, multicenter study of pregnant women, we used vaginal ultrasonography to measure the length of the cervix; we also documented the incidence of spontaneous delivery before 35 weeks' gestation. At 10 university-affiliated prenatal clinics, we performed vaginal ultrasonography at approximately 24 and 28 weeks of gestation in women with singleton pregnancies. We then assessed the relation between the length of the cervix and the risk of spontaneous preterm delivery. We examined 2915 women at approximately 24 weeks of gestation and 2531 of these women again at approximately 28 weeks. Spontaneous preterm delivery (at less than 35 weeks) occurred in 126 of the women (4.3 percent) examined at 24 weeks. The length of the cervix was normally distributed at 24 and 28 weeks (mean [+/- SD], 35.2 +/- 8.3 mm and 33.7 +/- 8.5 mm, respectively). The relative risk of preterm delivery increased as the length of the cervix decreased. When women with shorter cervixes at 24 weeks were compared with women with values above the 75th percentile, the relative risks of preterm delivery among the women with shorter 1.98 for cervical lengths at or below the 75th percentile (40 mm), 2.35 for lengths at or below the 50th percentile (35 mm), 3.79 for lengths at or below the 25th percentile (30 mm), 6.19 for lengths at or below the 10th percentile (26 mm), 9.49 for lengths at or below the 5th percentile (22 mm), and 13.99 for lengths at or below the 1st percentile (13 mm) (P < 0.001 for values at or below the 50th percentile; P = 0.008 for values at or below the 75th percentile). For the lengths measured at 28 weeks, the corresponding relative risks were 2.80, 3.52, 5.39, 9.57, 13.88, and 24.94 (P < 0.001 for values at or below the 50th percentile; P = 0.003 for values at the 75th percentile). The risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy.
To compare the diagnostic and prognostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and temperature with that of amniotic fluid (AF) WBC in preterm labor. One hundred two women with preterm labor and intact membranes were studied. Maternal blood was collected to measure C-reactive protein concentration and WBC, and maternal temperature was also measured. Amniotic fluid obtained by amniocentesis was cultured and WBC determined. Receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis. Patients with acute histologic chorioamnionitis had significantly higher median C-reactive protein concentration, WBC, temperature, and AF WBC than patients without this lesion (P < .05). Receiver operating characteristic curve and survival analysis demonstrated that an elevated C-reactive protein, WBC, or AF WBC was strongly associated with the likelihood of histologic chorioamnionitis, shorter interval to delivery, clinical chorioamnionitis, and neonatal morbidity (P < .05 for each). Of all the tests, AF WBC was the best independent predictor of a positive AF culture (odds ratio [OR] 16.8), interval to delivery (hazard ratio 5.7), clinical chorioamnionitis (OR 15.2), neonatal sepsis (OR 16.8), and significant neonatal complications (OR 7.4), after other confounding variables were adjusted (P < .05 for each). An elevated C-reactive protein, WBC, or AF WBC identified patients with intrauterine infection and adverse perinatal outcomes. Amniotic fluid WBC was a better independent predictor of these outcomes than C-reactive protein, WBC, or temperature.
The aim of this study was to investigate the correlation between the cytokine levels in the amniotic fluid (AF) and the histological stage of chorioamnionitis (CAM) in premature labor. AF of 6 cases (7 samples of AF were obtained as one was a twin pregnancy) in whom CAM was diagnosed histologically, and 12 cases without CAM were included in this study. Amniotic fluid was obtained within 24 hours prior to delivery. Cytokine levels (IL-2, -4, -6, TNF-alpha, IFN-gamma) in AF were measured by an ELISA method. Levels of IL-2 and -6 in the CAM-positive group (mean +/-S.E., 52.9 +/- 83.9 pg/ml, and 20,537.9 +/- 8853.7 pg/ml, respectively) were higher than those in the CAM-negative group (i.e. undetectable, and 65.6 +/- 27.5, respectively) with a statistical significance of p < 0.05, p < 0.001, respectively. There was a positive linear relationship between IL-6 levels of AF and the placental histological inflammatory stages of Blanc in the CAM-positive group. From these results it would appear that the IL-6 level in AF is the most sensitive test in the detection of extraamniotic infection or intraamniotic infection in preterm labor with intact membranes and also indicates the severity infection.
Contraception/ComparisonVenous ThromboembolismGenetic Risk FactorsFactor V Leiden and Contraception
Recent concern about the safety of combined oral contraceptives (OCs) with third-generation progestagens prompted an examination of data from a population-based case-control study (Leiden Thrombophilia Study). We compared the risk of deep-vein thrombosis (DVT) during use of the newest OCs, containing a third-generation progestagen, with the risk of "older" products. We also investigated the influence of family history of thrombosis, previous pregnancy, age, and the thrombogenic factor V Leiden mutation. We selected 126 women with DVT and 159 controls aged 15-49 (mean age 34.9) and premenopausal and found, as compared with non-users, the highest age-adjusted relative risks to be that for an OC containing desogestrel and 30 micrograms ethinyloestradiol (relative risk [RR] 8.7, 95% CI 3.9-19.3). We found lower relative risks for all other types of OC, ranging from 2.2 to 3.8. In a direct comparison, users of the desogestrel-containing oral contraceptive had a 2.5-fold higher risk (95% CI 1.2-5.2) than users of all other OC types combined. The relative risk for the desogestrel-containing OC was similar among women with and without a family history--ie, preferential prescription because of family history cannot explain our findings. Nor could the excess risk be explained by previous pregnancy, and it was highest in the youngest age categories, where we would expect most new users. The age-adjusted RR for the desogestrel-containing contraceptive was 9.2 (3.9-21.4) among non-carriers of the factor V Leiden mutation and 6.0 (1.9-19.0) among carriers of the mutation. This latter risk is superimposed on the 8-fold increased risk of venous thrombosis for carriers of the factor V Leiden mutation. The risk of carriers using the desogestrel-containing OC as compared with noncarrier non-users will therefore be increased almost 50-fold. Use of low-dose OCs with a third-generation progestagen carries a higher risk of DVT than the previous generation of OCs. The absolute risk of DVT associated with these OCs seems to be especially high among carriers of the factor V Leiden mutation and among women with a family history of thrombosis. However, the higher risk associated with OC with a third-generation progestagen compared with previous generations was also present in women without factor V Leiden and with no family history.
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.
SurgerySalpingoneostomy and Salpingo-ovariolysisSalpingoscopic AssessmentSalpingoscopy Prognostic Value
To compare the prognostic value of salpingoscopy with a current classification system of adnexal adhesions and distal tubal occlusion in patients with tubal infertility undergoing reconstructive tubal surgery. Prospective clinical study. Department of Obstetrics and Gynecology of the Catholic University, a tertiary care University Center in Rome, Italy. Fifty-five infertile patients with either adnexal adhesions (29 patients) or hydrosalpinx (26 patients) undergoing reconstructive tubal surgery. Salpingoscopy performed concomitantly to salpingo-ovariolysis or salpingoneostomy at the time of either operative laparoscopy or laparotomy using microsurgical techniques. Salpingoscopic findings were compared with a current classification system of adnexal adhesions and distal tubal occlusion. The patients were followed for a mean follow-up of 49 months; the pregnancy rates achieved were correlated with the salpingoscopic findings and the classification system used. There was a significant correlation between the salpingoscopic grade and the occurrence of a term pregnancy for both the salpingo-ovariolysis and salpingoneostomy groups of patients. There was no significant correlation between the classification system used and the occurrence of a term pregnancy for both groups of patients. Salpingoscopy plays an important role in selecting the patients who may benefit the most from reconstructive tubal surgery.
DiagnosticsDoppler Assessment of Corpus LuteumNoninvasive DiagnosisBlood Flow Assessment
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.
InfertilityClomiphene Citrate EffectsEndometrial Thickness and Echo PatternClomiphene Impact
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.
PregnancyUltrasound AssessmentFirst Trimester ViabilityGestational Sac and CRL Dynamics
To compile, for the first time, serial ultrasonographic findings during the first trimester of pregnancy in women with a history of primary recurrent spontaneous abortion so as to define the dynamics of early normal and abnormal gestations in this category of gravidas. Transvaginal ultrasonograms were obtained weekly from 5 to 12 weeks' gestational age in 40 women, 10 recurrent spontaneous aborters and primiparas (controls), with both successful and failed gestations. Embryonic heart motion was detected in 40-50% of successful pregnancies during the fifth week of gestation and in the balance by the sixth week, while heart motion was detected in no more than 50% of pregnancies that later failed. Of the failed pregnancies, all were evident by the eighth week of gestation, including those with previously documented viability. The gestational sac size and crown-rump length were smaller than expected in both failed groups, with the sac size difference evident as early as week 5 and the crown-rump length difference apparent by week 7. Appropriate timing of the initial ultrasonogram in recurrent aborters (i.e., 8 weeks' gestational age) can identify, by means of heart motion and gestational sac features, all pregnancies that will ultimately fail.
General OB/GYNEpidemiologyPredictive Risk FactorsThyroid Disease
The original Whickham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the incidence and natural history of thyroid disease in this cohort. DESIGN, Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, in addition to death certificates, two-thirds had information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91% were tested for clinical, biochemical and immunological evidence of thyroid dysfunction. Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean incidence (with 95% confidence intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism in women was 0.8/1000 survivors/year (0.5-1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an increase with age in hypothyroidism but no age relation in hyperthyroidism. The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially. The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors identified at first survey. The odds ratios (with 95% confidence intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A logit model indicated that increasing values of serum TSH above 2mU/l at first survey increased the probability of developing hypothyroidism which was further increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism in women. This historical cohort study has provided incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease identified twenty years earlier.
InfertilityDiagnostic AssessmentAccuracy and LimitationsTubal Patency Testing
To determine whether the diagnostic accuracy and prognostic value of hysterosalpingography (HSG) could be improved if routine spot films were replaced by an on-line recorded gynecoradiologic study.
Medical school-affiliated private infertility center.
In 1992, a review of 152 infertile women with infertility who demonstrated a normal HSG, by standard criteria of spot film evaluation, in 117 (77%). They were further investigated by gynecoradiologic study if the HSG revealed asymmetrical tubal filling, an increased perfusion pressure, and/or evidence for abnormal tubal spill. In 1993, 47 women with normal HSG by spot film criteria underwent bilateral selective salpingography and were subdivided into those with normal (group I, n = 23) and abnormal (group II, n = 24) tubal perfusion pressures. Patients in both study groups then were treated for their infertility independently of pressure perfusion measurements.
Clinical pregnancy rates (PRs) over the ensuing 6 to 10 months. Among 117 women with apparently normal spot film HSG, 64 (55%) demonstrated asymmetrical tubal filling, 32 (27%) demonstrated abnormal spillage into the peritoneal cavity, and 55 (47%) demonstrated abnormally elevated injection pressures. Among 98 women who underwent bilateral selective salpingography, 43 (44%) demonstrated bilaterally normal tubal perfusion pressures and 55 (56%) showed an abnormally elevated pressure in at least one oviduct. Of 47 women that were followed prospectively in 1993, patients with normal perfusion pressure (group I) demonstrated a significantly higher PR than women with elevated tubal pressure (group II) from 2 months and on after the procedure. Routine spot film HSG is of limited value in assessing tubal status beyond the determination of tubal patency. Especially with regard to fertility potential, HSG should be replaced by gynecoradiologic study.
To evaluate catalase activity as a rapid predictor of microbial invasion of amniotic fluid (AF). The study population consisted of 74 patients before 36 weeks' gestation with preterm labor or premature rupture of membranes (PROM). Subjects were excluded if there was evidence of clinical chorioamnionitis or fetal distress at admission. Amniocentesis was done within 24 hours of admission, and the AF was cultured for aerobic and anaerobic bacteria and for Mycoplasma species. All AF samples were Gram stained, and slides were examined by microbiology technologists. Amniotic fluid catalase activity was measured immediately after amniocentesis using a commercially available kit. The sensitivity of the Gram stain and catalase activity were compared using McNemar exact test. Amniotic fluid cultures were positive in 12 of 37 (32%) patients presenting with preterm labor and in 21 of 37 (56%) patients with PROM. Catalase activity was significantly more sensitive than Gram stain in detecting positive AF cultures in cases of PROM (P < .001) and preterm labor (P < .04). Catalase activity is a simple, rapid test that is useful in identifying subclinical intra-amniotic infection in patients with preterm labor or PROM.
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. 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. PR ratio may be important to become pregnant.
In this study we evaluated different markers of infection and their relationship to preterm delivery. Forty-four consecutive women with singleton pregnancies in uncomplicated preterm labor were investigated. C-reactive protein (CRP) in peripheral maternal blood, amniotic fluid cytokines, amniotic fluid leukocyte count, and amniotic fluid culture were performed in all patients. Thirty-six patients responded to standard tocolytic therapy and delivered after 34 weeks' gestation. In eight patients treatment failed and they delivered before 34 weeks' gestation. Two of these eight patients had a positive amniotic fluid culture for Ureaplasma urealyticum. The positive culture was accompanied by an elevated neutrophil count in the amniotic fluid. Elevated amniotic fluid levels of tumor necrosis factor (TNF) (more than 23 pg/mL), interleukin-6 (IL-6) (more than 2292 pg/mL) and interleukin-8 (more than 164 pg/mL) correlated with early preterm delivery. CRP levels in serum had a low sensitivity (38%) but a high specificity (94%) in predicting preterm delivery. This study indicates that preterm labor can be initiated by infection. Markers of infection obtained by amniocentesis have a better sensitivity and positive predictive value than noninvasive markers. Elevated IL-6 (more than 2292 pg/mL) seems to be the best predictor for preterm delivery, with a sensitivity of 75% and a specificity of 97%.
We describe the epidemiologic characteristics of conception, including subclinical early pregnancy loss, in a population of healthy women volunteers who had heterogeneous fertility experiences, and we describe the conception experience of women within this group who had evidence of impaired fertility. This was a prospective observational study of a cohort of women employed in two semiconductor manufacturing facilities. A total of 148 volunteers completed interviews and daily diaries and collected daily urine specimens for an average of 7 months. Conception, including subclinical losses and clinical pregnancies, was determined with a highly sensitive and specific assay for urinary human chorionic gonadotropin, and ovulation was determined with assays of urinary ovarian steroid hormones. There were 679 menstrual cycles at risk for pregnancy contributed by 124 (84%) of the 148 women. Women with evidence of subfertility before or during the study period had a rate of early pregnancy loss of 70% compared with 21% in women without fertility problems (relative risk 2.6, 95% confidence interval 1.8 to 3.8). The risk of pregnancy loss associated with subfertility increased with age and remained the same in women treated with clomiphene citrate. These results suggest that subfertile women have increased subclinical pregnancy losses regardless of fertility treatment and that the association between reduced fertility and advancing age may be related, in part, to early subclinical pregnancy loss.
InfertilityClomiphene Citrate Side EffectsVisual DisturbanceFertility Drug Complications
To identify a distinctive constellation of persistent visual abnormalities secondary to treatment with clomiphene citrate. Description of the clinical findings in three patients with visual disturbance secondary to clomiphene treatment. A neuro-ophthalmology referral center. Three women aged 32 to 36 years treated for infertility with clomiphene for 4 to 15 months. All three patients experienced prolonged afterimages (palinopsia), shimmering of the peripheral field, and photophobia while undergoing treatment with clomiphene. The results of the neuro-ophthalmologic examination and electrophysiologic studies were normal in all three patients. Unlike previously reported cases, visual symptoms did not resolve on cessation of treatment. Patients remain symptomatic from 2 to 7 years after discontinuing treatment with the medication. Treatment with clomiphene can cause prolonged visual disturbance. Patients who develop such symptoms should be advised that continued administration may cause irreversible changes. Women with characteristic visual symptoms should be questioned about past use of clomiphene.
To investigate the role of transcervical tubal catheterization in diagnosis and treatment of proximal tubal obstruction associated with salpingitis isthmica nodosa. Retrospective case study. University hospital and outpatient radiology practice. Fifty-two women with proximal tubal obstruction associated with salpingitis isthmica nodosa. Selective salpingography and catheter recanalization using fluoroscopic guidance. The number of tubes visualized to the fimbria as a percentage of the tubes with proximal tubal obstruction on the initial hysterosalpingogram was determined as a measure of diagnostic efficacy. To evaluate the treatment potential of catheter recanalization, the patients were grouped according to tubal status at the conclusion of the procedure and subsequent pregnancies were evaluated. Forty-seven of 65 tubes (72%) with proximal tubal obstruction were recanalized successfully. Among the 19 women who were able to conceive only via a recanalized salpingitis isthmica nodosa tube, there were 6 live births (32%) and two tubal pregnancies (10%). Selective salpingography allows complete tubal diagnosis in almost three fourths of patients with proximal tubal obstruction and salpingitis isthmica nodosa. The radiographic diagnosis of salpingitis isthmica nodosa may be pressure dependent. Intrauterine pregnancies occur via recanalized salpingitis isthmica nodosa tubes, therefore catheter recanalization may be attempted before tubal microsurgery or IVF in patients with proximal tubal obstruction and associated salpingitis isthmica nodosa.
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 "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.
To document the abnormal findings at hysteroscopy and laparoscopy in patients with chromic pelvic pain. Prospective evaluation at surgery of women treated consecutively between January 1, 1991, and December 30, 1992. A private practice. One hundred forty-one women with pelvic pain (average age 35 yrs). Laparoscopy was performed in all patients, and hysteroscopy in all but one, who had had a hysterectomy. Endometrial and endocervical biopsies were performed. MAIN In 42 (30%) of 140 patients with a primary diagnosis of chronic pelvic pain hysteroscopic evaluation with endometrial and endocervical biopsies revealed an abnormality. Findings at hysteroscopy included leiomyomas in 25 patients (18%), intrauterine polyps in 9 (6.4%), and cervical stenosis in 4 (2.9%). Three women (2.1%) had intrauterine scarring and one (0.7%) had a bicornuate uterus. Endometrial biopsies showed adenomatous hyperplasia with atypia, and cystic hyperplasia in one patient each. Endocervical biopsies revealed cervical dysplasia in four women (2. 89%). An abnormal finding was documented on laparoscopic examination in all 141 patients. These included endometriosis in 113 patients (80%), adhesions in 67 (48%), leiomyomas in 59 (42%), and enlarged globular uterus in 34 (24%). In addition, appendiceal abnormalities were present in three women (2.1%) and hernia in two (1.4%). Hysteroscopic abnormalities were found in 30% and laparoscopic abnormalities in 100% of patients who had a primary diagnosis of chronic pelvic pain.
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.
Insufficient breast milk is the most common reason for premature termination of breast-feeding. The causes of lactation insufficiency are usually multifactorial; in a small percentage of cases it is due to primary lactation failure of unknown origin. The aim of this study was to investigate whether lactation insufficiency of unknown origin could be caused by serum lactogens that had reduced biological activity.
Women with lactation insufficiency of unknown origin and normal lactating controls were subjected to a standardized breast-feeding test for assessment of milk production. Thirty minutes later, serum samples were obtained for determination of total lactogen bioactivity, using an in-vitro bioassay, and levels of prolactin (PRL) and growth hormone (GH) using radioimmunoassay (RIA). Twelve lactating mothers with a clinical diagnosis of lactation insufficiency of unknown origin were compared with 12 matched mothers with normal lactation. The Nb2 lymphoma cell bioassay was used to measure total lactogen bioactivity in sera. Conventional RIA kits were used to estimate serum PRL and GH concentrations. Mean milk yield on standardized test feed was 21.6 ml for patients and 146.5 ml for controls. In both patient and control groups the total serum lactogen bioactivity ranged from about 150 to 5000 mIU/l, while the serum RIA (PRL+GH) levels ranged from about 350 to over 7000 mIU/l. There was no evidence of lactogens with reduced bioactivity in the patients' sera. Lactation insufficiency in the women studied cannot be explained by serum lactogens that possess unusually low bioactivity.
Menstrual CycleMineral DeficiencyEtiologyTrace Element Assessment
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.
Reproductive EndocrinologyDiagnostic AccuracySensitivity and SpecificityLuteal Phase Defect Detection
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 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 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).
To characterize ampullary endosalpingeal findings in women with occlusive or nonocclusive salpingitis isthmica nodosa. Prospective case study. Obstetrics and Gynecology Department of a University Hospital. Twenty women (38 tubes) with occlusive or nonocclusive salpingitis isthmica nodosa were studied. Salpingoscopy was performed during diagnostic laparoscopy in 20 women (38 tubes) with hysterosalpingographic evidence of salpingitis isthmica nodosa. Salpingoscopic findings were recorded and the patients were managed accordingly. Of the 38 tubes 10 appeared radiographically and laparoscopically normal. Two tubes were occluded distally. Of the 26 tubes with occlusive or nonocclusive salpingitis isthmica nodosa, 5 (19.2%) showed varying degrees of endosalpingeal abnormality. Patients with abnormal salpingoscopy were regarded as having bipolar tubal disease and were referred for assisted conception. The remaining patients were scheduled for microsurgical tubal reconstruction. One in five patients with proximal tubal disease may have ampullary endosalpingeal damage of varying degrees. However, the significance of this finding in relation to subsequent management strategies and fertility outcome is yet to be characterized.
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.
To evaluate further the safety and efficacy of selective ostial salpingography combined with transcervical wire recanalization for the diagnosis and treatment of proximal tubal obstruction. Prospective study. Division of Reproductive Endocrinology and Department of Radiology at Harbor-University of California Los Angeles (UCLA) Medical Center, a tertiary care academic institution. Twenty-eight infertile patients diagnosed with proximal tubal obstruction by hysterosalpingogram (HSG) or by chromopertubation at laparoscopy (total of 46 obstructed tubes). After antibiotic prophylaxis and IV analgesia a conventional HSG was performed. If proximal tubal obstruction was confirmed, selective salpingography was done under fluoroscopic guidance. If proximal tubal obstruction was still present, wire recanalization using a new prototype cannula was then performed. If recanalization was successful, contrast media was injected to confirm tubal patency. Proximal tubal patency, complete tubal patency, pregnancies. Eleven of 46 tubes (23.9%) were patent by HSG. Ostial salpingography of the remaining 35 tubes revealed 6 patent tubes (13%). Nine of the 29 obstructed tubes (31%) had successful wire recanalization, and 8 of these were patent distally. There were 4 intrauterine pregnancies (IUPs) and 1 ectopic pregnancy after recanalization and 2 IUPs after ostial salpingography. Selective salpingography should be considered at the time of an HSG showing proximal tubal obstruction. If indicated, wire recanalization can also be attempted. Selective ostial salpingography combined with wire recanalization is a safe and effective procedure for the diagnosis and treatment of PTO.
PregnancyInfection ScreeningPuerperal EndometritisC-Reactive Protein in Pregnancy
Silent intrauterine infection as cause of preterm labour should be recognised early by measuring C-reactive protein (CRP) levels in the maternal serum. Ensuing antibiotic therapy may not only cause gestational prolongation, but also has a positive effect on pathology during the puerperal period. Consequently, we examined the rate of infectious puerperal complications of 181 patients who suffered from so-called idiopathic preterm labour. 84 patients showed normal CRP-levels at the onset of tocolysis (< 5 mg/l); an elevated level was found in 97 patients (> 5 mg/l). Patients with elevated CRP-levels and supplemented antibiotic therapy during pregnancy (n = 51) showed significantly fewer symptoms of postpartal endometritis than women with similarly elevated CRP-levels but without antibiotics (n = 46). This effect was not produced when preterm labour was associated with normal CRP-levels. Patients with premature contractions and elevated CRP-values at the onset of tocolysis seem to benefit from the antibiotic therapy during pregnancy because they show reduced infectious complications throughout the puerperal period.
NaProTECHNOLOGYOvulation MonitoringUltrasoundClassification Systems
The sperm function of fertile men (control), infertility patients (experimental), and men with varicocele were compared. The bioassays used were the follicular fluid-induced acrosome reaction, the binding to the zona pellucida, and the penetration of zona-free hamster oocytes. The percentage (mean +/- SEM) of reacted spermatozoa was 35 +/- 3 in the control, 22 +/- 1 in the experimental, and 22 +/- 3 in the varicocele. The minimum value of acrosome reaction in control men was 20%. The mean number of zona-bound spermatozoa was 250 +/- 30 in the control, 160 +/- 28 in the experimental, and 196 +/- 44 in the varicocele. The minimum number of zona bound spermatozoa in control men was 50. The mean number of hamster oocytes penetrated was 50 +/- 8 in the control, 19 +/- 3% in the experimental, and 10 +/- 3 in the varicocele. The minimum number of oocytes penetrated in control men was 6%. In the experimental group, 22 men had a normal sperm function, 58 had 1 or 2 bioassays below the minimum (relative dysfunction), and 10 had all bioassay below the minimum (abnormal sperm function). The results of these bioassays could help to reclassify the infertile men in several subgroups.
PregnancyCervical Length AssessmentTransvaginal Cervical MeasurementPrediction and Risk Stratification
To establish a nomogram for the length of the uterocervical canal and to determine whether this can be used to predict preterm delivery. Cervical length was measured by transvaginal ultrasonography in 32 women (21 primigravid, 11 multigravid) with threatened preterm delivery, and in 177 normal singleton pregnancies between 18-37 weeks' gestation. Regression analysis was used to create the nomogram. Student t test was used to compare the groups. A linear relationship was found between cervical length and gestational age (r = -0.4, P < .001). Comparison of cervical length on admission in the patients with threatened preterm delivery showed that 11 preterm deliveries occurred in women who had a mean cervical length of 23.2 mm (range 17-29), whereas 21 term deliveries occurred in women with a mean cervical length of 31.7 mm (range 21-42). The difference was significant (P < .001). A cervical length of less than 20 mm on admission had a positive predictive value of 100%. These patients had preterm delivery despite tocolytic therapy during hospitalization. The risk of preterm delivery is high in women whose cervical length on admission is less than 30 mm, and strict management is required for those with a cervical length of less than 20 mm.
To examine and discuss the pathology, diagnosis, incidence, and patient profile of salpingitis isthmica nodosa and to question its natural history, propose management strategies, and identify areas of promising research. Over 50 studies were reviewed, evaluated, and compared to offer the clinician a foundation on which to generate treatment plans. Salpingitis isthmica nodosa is diagnosed by the pathological presence of isthmic diverticula and may be suggested by characteristic changes on hysterosalpingogram. Its incidence in healthy, fertile women ranges from 0.6% to 11%, but it is significantly more common in the setting of ectopic pregnancy and infertility. There are no studies, retrospective or prospective, that clearly dictate appropriate therapy. Given its progressive nature and probable deleterious effects on fertility, we propose that microtubal surgery be the definitive treatment for qualified women who have salpingitis isthmica nodosa.
The purpose of this study was to determine the relationship between C-reactive protein (CRP) levels and intraamniotic infection in 48 women presenting with preterm labor and intact membranes. Blood samples for CRP tests were obtained immediately before the performance of transabdominal amniocentesis. The prevalence of amniotic fluid cultures positive for organisms was 14.6%. In 16 women (33.3%) positive CRP levels were obtained. There were no significant differences in the prematurity rate or the prevalence of microbial invasion of the amniotic cavity between women with positive CRP levels and women with negative levels. The sensitivity, specificity, and positive and negative predictive values for the detection of amniotic infection were 71.5%, 73.2%, 31.3% and 93.8%, respectively. Based on these results, we suggest that in women with preterm labor and negative CRP levels, routine amniocentesis may not be essential to the initial workup.
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.
PregnancyInflammatory BiomarkersInfection DiagnosisC-Reactive Protein in Pregnancy
To evaluate clinical, microbiologic, and histologic findings associated with elevated C-reactive protein levels among women in preterm labor or with preterm premature rupture of the membranes (PROM). Obstetric data, serum C-reactive protein levels, and amniotic fluid (AF) and chorioamniotic membrane cultures and histology were obtained on 203 women presenting between 22-34 weeks' gestation in preterm labor or with PROM. Women with C-reactive protein greater than 1.5 mg/dL were more likely to deliver within 7 days of enrollment (54 of 68, 79%) than were women with normal C-reactive protein levels (45 of 135, 33%) (P < .001). The median C-reactive protein levels and association with rapid delivery did not differ between women with intact versus ruptured membranes. Elevated C-reactive protein levels were associated with a positive AF culture among women in preterm labor with intact membranes. To control for confounding by a long interval to delivery, only the group delivering within 7 days was considered for evaluation of C-reactive protein levels and placental and infant outcome. Among women delivering within 7 days, elevated C-reactive protein was associated with the development of clinical chorioamnionitis and with infant death before hospital discharge, but not with a positive membrane culture or histologic chorioamnionitis. Elevated C-reactive protein appears to be associated with AF infection, delivery within 7 days of admission, and infant death among women delivering preterm, but not with membrane infection or inflammation. Elevated C-reactive protein may be helpful in determining the need for AF culture and in targeting studies of antibiotic therapy among women in preterm labor or with preterm PROM.
Mårtensson O et al., 1993·Acta Obstet Gynecol Scand
In 25 women with primary or secondary infertility, primary hysterosalpingography (HSG) or laparoscopy with chromopertubation indicated 33 proximal and 2 distal tubal obstructions. Four salpingectomies had been performed earlier. All patients were considered for transcervical catheter salpingoplasty (TCSP) to reconstruct tubal patency. Secondary examination with repeat HSG or selective osteal salpingography confirmed 26 proximal and 3 distal tubal occlusions while 17 tubes were patent. Selective osteal salpingography was performed successfully in 32 of 33 (97%) tubes. Sixteen of 26 (61.5%) proximally occluded tubes were successfully recanalized by coaxial catheter and guidewire technique while two of three distally occluded tubes were reopened by forceful flushing of contrast medium. So far, one ectopic and five intrauterine pregnancies were achieved in ten patients with observation time more than four months. Three patients have had normal deliveries. The favorable results, lack of complications and low costs seem to justify the recommendation to use selective salpingography and fallopian tube recanalization as the first intervention in patients with obstruction of the proximal fallopian tube.
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.
InfertilityClomiphene Citrate Side EffectsClomiphene EffectsDrug-Induced Changes
To analyze the effects of clomiphene citrate (CC) on cervical mucus (CM) and endometrial morphology independently of hormonal changes encountered when CC is administered for ovulation induction. Volunteers whose ovarian functions were temporarily suppressed (n = 18) by a long-acting GnRH agonist and 6 women of similar age suffering from premature ovarian failure (POF) received E2 and P. Half of the women also received CC (50 mg/d, days 2 to 6). Tertiary University Institution, Hôpital A. Béclère. PATIENTS, Eighteen volunteers suffering from infertility not related to a uterine cause and 6 women of similar age suffering from POF. Plasma gonadotropins, E2, and P were measured at baseline to confirm that the ovaries were inactive and twice weekly during physiological E2 and P replacement. Cervical mucus was analyzed on day 14 and scored from 0 to 15. Endometrial biopsies were obtained on replacement days 20 and 24 for conventional histology and immunocytochemistry analysis of estrogen receptors and progesterone receptors (PR). Premature ovarian failure women whose results have been previously published served as controls for day 20 biopsies. Cervical mucus scored lower in women who received CC (5.5 +/- 3.2) than in controls (13.6 +/- 4.7, mean +/- SEM). On day 20, endometrial findings were similar in women treated with CC and in controls. On day 24, specimens showed a significant delay in endometrial maturation in women treated with CC. On day 24, only staining for PR selectively persisted in endometrial stroma, and no difference was observed between women who received CC and controls. Our results indicate that CC significantly alters CM quality and late luteal phase endometrial morphology despite physiological levels of plasma E2 and P. Hence, clinicians should monitor E2 levels when using CC, and caution should be exerted when supraphysiological levels of E2 are not present to counterbalance the effects of CC on the CM and the endometrium.
Serum progesterone (P) levels were determined at the time of routine prenatal registration (227 patients) or upon presentation for evaluation of vaginal bleeding and/or abdominopelvic cramping/pain (135 patients). P associated with a normal intrauterine gestation was 24.63 +/- 4.19 (SD) ng/mL as compared with 6.29 +/- 2.43 ng/mL and 6.02 +/- 2.39 ng/mL for spontaneous abortions and ectopic gestations, respectively. Further, P differed between asymptomatic (11.92 +/- 9.61 ng/mL) and symptomatic patients (4.81 +/- 3.92 ng/mL) who were subsequently shown to have an abnormal gestation. By establishing a P cutoff point of < or = 14.2 ng/mL and < or = 10.5 ng/mL in asymptomatic and symptomatic patients, respectively, 100% screening sensitivity was reached, and therefore no abnormal gestations would escape detection in our study population. P was either in the normal or abnormal range as early as four weeks' estimated gestational age and persisted as such through the luteal-to-placental shift and up to the time of pregnancy loss or 12 weeks' estimated gestational age. Although there was no significant correlation between P and chorionic gonadotropin levels and pregnancy outcome, the binding constant for native chorionic gonadotropin was 15-52 times lower in 12 of 41 cases of spontaneous abortion but not ectopic gestation, suggesting a possible molecular basis for suboptimal P production. P is therefore an excellent adjunctive marker for prediction of early pregnancy outcome, and in some cases qualitative abnormalities in chorionic gonadotropin may dictate its production.
To investigate the correlation between opacification and perfusion pressures during hysterosalpingography (HSG) and selective salpingography under the assumption that the latter may add to the diagnostic capabilities of the procedures. Perfusion pressures were uniformly evaluated by standardizing injection volume per time interval of contrast medium and the delivery system. Pressures were measured in a closed system through a digital manometer and recorded on tracing paper. Fully ambulatory gynecoradiology suite at academically affiliated infertility center. Thirty infertility patients. Hysterosalpingography and selective salpingography for diagnostic purposes. Correlation between opacification patterns and perfusion pressures. The evaluation of perfusion pressures during HSG is unreliable because they may be affected by uterine factors and will only reflect the oviduct of least resistance. In contrast, perfusion pressures during selective salpingography are reflective of only the investigated tube. They appear to lie within a functionally normal range of up to 350 mm Hg. Tubes by opacification judged as normal exhibited a pressure range of 429 +/- 376 mm Hg, which was significantly lower than that of abnormally appearing oviducts (957 +/- 445 mm Hg; P = 0.001). The concomitant performance of perfusion pressure studies during selective salpingography further enhances the diagnostic capability of selective salpingography over HSG in the diagnostic evaluation of fallopian tubes.
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.
Menstrual CycleHormonal PathophysiologyFemale Androgen ExcessAndrogen Assessment in PMS
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.
There are no absolute objective diagnostic criteria for cervical incompetence. Abdominal and endovaginal ultrasonographic assessment of endocervical length, both of which have been associated with technical problems, have been used to establish the diagnosis. Cervical cerclage may be useful in preventing silent cervical dilatation; however, no prospective trials with and without cerclage have been performed when endocervical shortening has been demonstrated by ultrasonography.
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.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Prediction
Physicians compared clinical history, examination, and laboratory data on 10 pregnant women at various gestational ages with intact membranes till labor began (controls) with data on 25 pregnant women also at various gestational ages who experienced premature rupture of membranes (PROM) (cases) to determine the value of C-reactive protein (CRP) in maternal and cord blood as a predictor of chorioamnionitis in women with PROM. 32% of cases had clinical chorioamnionitis and 44% histopathological chorioamnionitis. The maternal serum level of CRP in cases with and without chorioamnionitis at delivery was statistically higher than that of the controls (45.82 CRP mg/L and 9.71 CRP mg/L vs. 6.6 CRP mg/l; P.05). Further the CRP level in cord blood of cases with chorioamnionitis also stood much higher than that of the controls (p.001). In addition, the total leukocytic count (TLC) for cases with chorioamnionitis at delivery was much higher than it was for the control group at delivery (12,510 TLC/cubic mm vs. 18,231 TLC/cubic mm; p.05). A significant difference also existed between the temperature of the cases with chorioamnionitis and that of the controls (37.11 degrees Celsius vs. 63.97 degrees Celsius; p.05). Sensitivity and specificity tests showed that CRP 24 mg/L was the most reliable predictor of chorioamnionitis (100% and 93.3% respectively) followed by TLC (77.8% and 92.8% respectively) then temperature (55.6% and 78.6% respectively). Thus CRP can be used to predict premature delivery and simultaneously reduces unnecessary premature delivery of many PROM cases which occur due to fear of developing infections in both the mother and the fetus.
To assess the deleterious effect of clomiphene citrate (CC) on the development of the endometrium and its improvement by the addition of ethinyl estradiol (E2). Infertility-treated patients, monitored for induction of ovulation or timing of insemination (control group). We studied four groups of women during an ovulatory cycle with various treatment schedules. Group 1: untreated patients; group 2: patients treated by CC; group 3: patients treated by CC + ethinyl E2; group 4: patients treated by human menopausal gonadotropin. Follow-up of the patients was done by vaginal ultrasonography and measurements of blood E2. In the group treated by CC, both endometrial thickness and uterine volume growth during the follicular phase were lower as compared with untreated controls and menotropin-treated patients. The addition of ethinyl E2 to these patients reversed this deleterious effect of CC without interfering with ovulation. Ethinyl E2 may reverse the deleterious effect of CC on endometrial development during the follicular phase.
In order to clarify the relationship between endometrial histology and progesterone (P4), plasma P4 and estradiol levels in the luteal phase were measured in 126 cases of unexplained infertility. Endometrial biopsies were performed in the midluteal period of menstrual cycles. Forty-three of the 126 cases showed retarded endometrium. Of these 43 cases, 23 exhibited three different types of abnormal P4 secretion. Type A showed low P4 levels throughout the luteal period. Type B showed low P4 levels only in the early luteal period. Type C showed normal P4 levels in the early luteal period followed by a prompt decline. These findings indicated that P4 determination during the early, mid- and late luteal phases is necessary to assess P4 secretion. However, 20 of the 43 cases had normal P4 levels through the entire luteal phase, demonstrating an insufficient response of the endometrium to P4. Consequently, histological examination of the endometrium is required to investigate the luteal phase defect.
A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of 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.
Excised tubal segments from 94 infertile women with tubal obstruction, with a mean infertility duration of 5.3 years, and 40 women with ectopic tubal pregnancy were studied histopathologically to evaluate the association with salpingitis isthmica nodosa (SIN). The mean age of the 94 infertile women with tubal obstruction was 24.5 years. Hysterosalpingographies and laparoscopy were performed on all of them. Only the women with ectopic pregnancies we performed salpingectomy on were included in the present study. The incidence of SIN in women with tubal obstruction was 7.4%, in women with ectopic tubal pregnancy 10%, and in the control group the incidence was 0.2%. In 60% of the cases, SIN was present in both of the tubes. Based on this study, we conclude that SIN is significantly associated with infertility and ectopic tubal pregnancy.
Fifty-one consecutive twin pregnancies studied prospectively were compared with 153 consecutive control twin gestations that were concurrently delivered, but chosen retrospectively. Study patients were managed by a protocol that used weekly ultrasound surveillance combined with clinical assessment. Control subjects were not managed by protocol or ultrasound surveillance. Seven of 51 study patients (13.7%) were diagnosed as having cervical incompetency before 30 weeks' gestation (range 18-28 weeks, mean 24). In comparison, 14 of 153 controls (9.2%) delivered before 30 weeks' gestation (range 18-29 weeks, mean 25). The mean cervical length, dilatation, and membrane herniation (funneling) at diagnosis were 1.9, 2.2, and 3.6 cm, respectively, for patients with cervical incompetency. There was a significant difference in perinatal mortality. All study twins survived, whereas nine control subjects delivered at a mean gestational age of 22.7 weeks, with a loss of 17 infants. Life table analysis demonstrated that a significantly greater proportion of controls delivered very low birth weight, premature twins. The use of ultrasound and clinical criteria to select patients for cerclage placement helped prevent birth of the youngest and smallest twins and significantly decreased perinatal mortality in the study group. Routine cerclage placement is not recommended for twin gestations, but multifetal gestations may benefit from ultrasound surveillance for cervical incompetency.
To determine possible etiologies of unsuccessful fluoroscopically guided tubal canalization, we studied the histology of tubal segments in cases of failed canalization for proximal tubal obstruction. Factors contributing to cases of unsuccessful fluoroscopically guided tubal canalization remain unclear. Prospective. Reproductive Endocrinology Clinic. Twenty-seven cornual and/or isthmic tubal segments from 15 patients who underwent proximal tubal surgery after fluoroscopically guided tubal canalization were studied. Specimens were prepared with hemotoxylin-eosin and Masson trichrome stains. Histologic examination of excised cornual and isthmic tubal segments revealed abnormalities in 93% of specimens. Obliterative fibrosis (61%), chronic salpingitis (57%), and salpingitis isthmica nodosa (42%) were the most commonly found histologic tubal abnormalities. One case of complete tubal occlusion and tubal schistosomiasis was also detected. These data suggest that cases of failed fluoroscopically guided tubal canalization may be secondary to severe intrinsic tubal disease and tubal occlusion and not to the technique. Fluoroscopically guided tubal canalization may provide a means of differentiating a functional obstruction amenable to conservative management from true occlusion requiring management by microsurgical techniques or in vitro fertilization.
To test a sonoscopic technique developed for transvaginal catheterization and recanalization of the fallopian tube. In a feasibility study, catheterization was performed with the use of laparoscopic control. Patients with bilateral proximal tubal obstruction underwent fallopian tube recanalization under ultrasonic observation. This study represents patients evaluated for primary or secondary infertility at Humboldt University Hospital. PATIENTS, Proximal tubal obstruction had been diagnosed on previous hysterosalpingogram and with laparoscopy. None. Tubal patency was assessed by hydrotubation under ultrasonic observation. Transvaginal catheterization was successful in 31 (91.2%) of the 34 tubes. In 19 patients with proximal tubal obstruction, patency of both or at least one tube was achieved in 16 (84.2%) women. Five (31.6%) of 16 patients successfully recanalized were found to have an intrauterine pregnancy at a 6-month follow-up interval. This catheterization technique should be investigated for possible use in diagnostic schedule early in the evaluation of the infertile patient. Also, the transvaginal recanalization of proximally obstructed tubes calls into question the application of microsurgical treatment of a selected group of patients.
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)
At an interdisciplinary workshop on home monitoring of uterine activity, participants reviewed the basis of this technology and its use in the identification of women at high risk of preterm delivery and in the prevention of preterm birth. Although the guard-ring devices in current use appear capable of detecting uterine activity, they do not clearly distinguish between Braxton Hicks contractions and the contractions of early labor. There was agreement that women destined for preterm delivery have more uterine activity on average than do other women of comparable gestational age but that there is substantial overlap between the two groups. Thus it is uncertain whether this difference can be used effectively for screening purposes. Conferees agreed that there is considerable evidence that twice-daily monitoring of very-high-risk women, in conjunction with daily nursing support and high-quality obstetric care, may prevent preterm births. Available evidence does not clearly distinguish the contribution of tocodynamometry from that of nursing support. A number of areas were identified in which further research is needed.
Evaluation of selective salpingography for diagnosis and treatment of tubal injection failure during hysterosalpingography (HSG). Prospective study. Obstetrics and Gynecology Department, University of Genoa (Italy)--tertiary care. One hundred eighty infertile women with unilateral or bilateral proximal tubal injection failure during HSG were submitted to the procedure. Under fluoroscopy, a 4.5-F nylon catheter (3-F tip) was inserted into the ostium with or without the aid of a J-shaped, coaxial, angiographic guide wire, and 2 to 3 mL of contrast medium were injected. The procedure lasts 20 to 30 sec/tube. Of 155 tubal ostia, 145 (94.2%) were catheterized. Of the 146 catheterized tubes, 110 (75%) were rendered patent. Of the others, 21 (14.3%) presented hydrosalpinx or distal obstructions, and isthmic obstruction was present in 5 (3.4%). Patency of at least one tube was achieved in 82 (81.2%) of the 101 catheterized women; 8 conceived spontaneously and 11 after gamete intrafallopian transfer to the recanalized tube. During HSG, selective salpinography can be performed when proximal injection failure is observed to determine its cause or to restore patency.
Maternal serum C-reactive protein (CRP) has been studied extensively as an adjunct in the diagnosis of subclinical infection among pregnant women with preterm labor or preterm rupture of membranes. However, before the utility of CRP can be studied in pregnancies with these complications, the effects of normal pregnancy and labor on maternal serum CRP levels must be established. We determined CRP levels serially from 22 weeks' gestation until delivery in healthy pregnant women without antepartum complications. Median CRP values for women not in labor ranged from 0.7-0.9 mg/dL, depending on gestational age; 95% of the values were 1.5 mg/dL or lower. No consistent change in CRP levels with gestational age was found among serially sampled women not in labor. The median CRP value for women in labor at term was 1.3 mg/dL, and 32% of values were over 1.5 mg/dL. Median CRP values in normal pregnancies appear to be higher than standardized values for nonpregnant individuals, and CRP values are further elevated in labor. Understanding the physiology and temporal course of the increase in CRP in normal pregnancy and labor may help to clarify the appropriate use of CRP in complicated pregnancies.
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 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.
Obstruction of the uterine (proximal) end of the fallopian tube is noted on up to 20% of hysterosalpingograms and has a variety of underlying causes. Definitive diagnosis and treatment in the past have required laparoscopy or laparotomy with tubal resection. Selective salpingography and fallopian tube recanalization with fluoroscopically guided catheters has emerged as an improved method both for diagnosis and treatment in these patients. Technical success rates for overcoming the obstruction and visualizing distal tubal anatomy range from 76% to 95%. Pregnancy rates after the procedure vary depending on the patient populations studied; however, early results indicate a greater than 50% intrauterine pregnancy rate by 1 year. The rate of ectopic pregnancy is approximately 10% and that of early tubal reocclusion is less than 30%. Selective salpingography and fallopian tube recanalization is recommended as the first intervention in patients with obstruction of the proximal fallopian tube.
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.
Transcervical fallopian tube catheterization (TFTC) was performed in 22 infertile patients with bilateral fallopian tube obstruction and a mean duration of infertility of 3.3 years. A high prevalence of previous ectopic pregnancy (n = 8, 36%), tubal ligation and/or reconstruction (n = 5, 23%), spontaneous or therapeutic abortion (n = 6, 27%), and previous intrauterine device use (n = 14, 64%) was noted. The authors successfully catheterized 40 (98%) of 41 tubes without serious complication and visualized the distal tube in 36 (88%) of 41 tubes. Free spill in at least one tube was seen in 17 (77%) of 22 patients. Nineteen patients had a history of previous laparoscopy or laparotomy for tubal disease, in 16 of whom laparoscopic results were available for review. Retrospectively, in 15 (94%) of 16 patients all clinically relevant abnormalities would have been detected by means of TFTC alone. Five patients conceived, three with intrauterine and two with ectopic pregnancies. Patients with intrauterine pregnancies had normal-appearing tubes after TFTC, while those with ectopic pregnancies had residual tubal abnormalities after recanalization. TFTC is a safe, accurate diagnostic procedure that provides more information than hysterosalpingography and, in most cases, as much or more information about the fallopian tubes than laparoscopy.
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)
Reproductive EndocrinologyCorpus Luteum DynamicsLaparoscopy and UltrasoundDiagnosis
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.
PregnancyDetection and MonitoringHome Uterine Activity MonitoringTocodynamometry
The relative contribution of uterine activity obtained by home monitoring with a guard ring tocodynamometer compared with seven specific signs and symptoms reported during patient/nurse contact as an aid in detecting preterm labor has not been studied. In this prospective, multicenter study, patients at risk for developing early labor who were randomized to receive home uterine activity monitoring and perinatal nursing support were assessed. The initiator of provider contact (uterine activity detected on routine transmission, patient-perceived signs and symptoms of preterm labor during perinatal nurse contact, or both) resulting in a diagnosis of preterm labor was recorded. Contraction data were then analyzed for an association with preterm labor. There was a strong association of increased uterine activity (four or more contractions per hour) on a repeat monitoring strip with preterm labor (P less than .001). Among patients diagnosed with preterm labor, 31% had increased uterine activity detected on a routine transmission without patient-reported signs and symptoms, compared with 24% who were diagnosed as the result of patient-reported symptoms without increased uterine activity. Daily objective uterine activity data alone have greater incremental value over and above other signs and symptoms as an aid to the physician in diagnosing preterm labor.
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.
Menstrual CycleLength Determination MethodsQuantitative AnalysisBBT Validation Against LH Peak
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 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.
Fertility AwarenessOvulation Prediction AccuracyLH Surge vs Cervical MucusComparative Validation
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.
PregnancySigns and SymptomsPatient Education and AwarenessPreterm Labor Symptom Recognition
Patient and staff education concerning the subtle signs and symptoms that precede a clinical diagnosis of preterm labor have not been well established. Therefore we interviewed 100 patients for the presence or absence of various symptoms and signs during the 7 days preceding diagnosis of preterm labor. An additional 100 patients without preterm labor matched for gestation were chosen at random as control subjects. A history of increased uterine contractions, menstrual cramps, constant backache, constant pelvic pressure, increased amount and consistency and color change of vaginal discharge, and increased frequency of urination were present with a statistically significant higher frequency in patients with preterm labor compared with controls. Twenty-nine percent of patients did not report any uterine contractions and only half described them as painful. Fewer than 50% of the women reported contractions as frequently as every 10 minutes or more.
InfertilityDiagnosis and TreatmentTransvaginal Catheter DilatationSelective Salpingography
Selective salpingography and transvaginal catheter dilatation were performed in 157 women with infertility to diagnose, localize, and classify obstructive diseases of the fallopian tubes and to correct obstruction of the proximal (uterine-end) tube. In 61 (39%) of the patients, the selective salpingograms showed patent tubes despite the fact that two previous hysterosalpingograms showed obstruction of the proximal (uterine-end) tube. Transvaginal catheter dilatation successfully recanalized the proximal portion of the tubes in 79 (82%) of 96 patients with obstructed tubes. In 18 of 25 with successful transvaginal catheter dilatation and 6-month follow-up salpingography, the tubes remained patent. Coexisting disease of the distal (ovarian-end) tubes was diagnosed in 29 (18%) of the patients. Pregnancy was achieved in 11 of the 157 patients (six in whom obstructions were corrected by transvaginal catheter dilatation and five in whom selective salpingograms showed patent tubes). There were no complications due to the procedure. The excellent diagnostic and therapeutic yield, lack of complications, and low cost justify the use of these percutaneous techniques to investigate female infertility and to treat obstruction of the uterine end of the fallopian tube.
PregnancyInfection DetectionC-Reactive Protein ChorioamnionitisChorioamnionitis Prediction
The purpose of this study was to critically review published studies regarding sensitivity, specificity, and positive and negative predictive values of antenatal tests to diagnose chorioamnionitis or fetal-neonatal sepsis in preterm premature rupture of the membranes. A Medline Data-Base computer program search from 1980 to 1988 identified 39 studies, 23 of which were accepted after independent review with preset criteria. An ideal test to predict chorioamnionitis or neonatal sepsis was not found. The low success rate for amniocentesis and the need for repeat taps preclude the acceptance of tests on the basis of amniotic fluid. Single, small studies, the precision of which has never been tested, show good indices for repeatedly increased serum levels of C-reactive protein (greater than 20 mg/L), a high level of C-reactive protein greater than 40 mg/L, or a day-to-day coefficient of variation for C-reactive protein of greater than 30% in the prediction of histologic or clinical chorioamnionitis. Ultrasonographic observation of fetal activity, if published study results are confirmed, may be of value to predict amniotic fluid bacterial colonization.
Proximal tubal obstruction, either unilateral or bilateral, is a frequent finding on hysterosalpingogram (HSG). Approximately two-thirds of the fallopian tubes resected for proximal tubal obstruction reveal an absence of luminal occlusion. The distinction between true pathologic occlusion and either spasm or plugging is crucial in determining therapy. We combined hysteroscopic cannulation of the proximal fallopian tube with laparoscopy in 11 patients with proximal tubal obstruction diagnosed by HSG and confirmed at laparoscopy. Hysteroscopic cannulation was able to be performed in 72% of the fallopian tubes attempted, and there was a postcannulation patency rate by HSG of 73%. Six of the 11 patients became pregnant after tubal cannulation and adjunctive distal tubal surgery. Hysteroscopic cannulation of the fallopian tube is a safe diagnostic procedure that can be used to identify those patients with true proximal occlusion, and may also serve as a therapeutic procedure in some of these patients.
PregnancyPremature Rupture of MembranesC-Reactive Protein in PregnancyChorioamnionitis Diagnosis
The usefulness of maternal C-reactive protein (CRP) measurements in the diagnosis of chorioamnionitis and puerperal and neonatal infectious morbidity was studied among 147 patients with preterm rupture of the membranes (PROM). Thirty-three patients developed chorioamnionitis, 10 patients developed puerperal endometritis, and 21 newborn infants developed neonatal infections. There was no difference in the highest antepartum CRP between patients with or without chorioamnionitis. The overall test performance for CRP was poor suggesting that elevated antepartum CRP may be misleading in the diagnosis of chorioamnionitis. However, use of serial CRP measurements increases the test performance. The high negative predictive value suggests that CRP is useful in predicting the absence of chorioamnionitis.
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 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.
InfertilityOvarian Function EvaluationSalivary ProgesteroneLuteal Phase Insufficiency
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.
Menstrual CycleLuteal Phase Defect EtiologyNormal Follicular DevelopmentLuteal Phase Dating
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 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 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)
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%.
Endovaginal and transabdominal sonography (EVS and TAS, respectively) are effective methods for monitoring ovarian follicular development. Our study evaluates both modalities by subjective comparisons and objective correlations with serum estradiol levels. In 21 of 41 studies, TVS showed more follicles over 1 cm than did TAS. The same number was seen by both in 17 studies and more by TAS in only 3 studies. Margins of the follicles were sharply defined in 37 of 41 EVS studies (90%) but only in 18 of 41 TAS studies (41%). In each of the 4 cases in which follicles were not sharply defined by EVS the ovaries were located high in the pelvis. In 29 sonographic studies, there were corresponding estradiol levels. The number and size of dominant follicles correlated well with estradiol levels (r = .9074) for EVS but less so (r = .3816) for TAS. EVS has several advantages when monitoring follicular development.
General OB/GYNToxicologyAbdominal Radiograph Findings
We report a patient with fatal acute arsenic poisoning presenting as vomiting and diarrhea with the finding of intra-abdominal radiopacities on radiographs. These represent the classic features of acute arsenic toxicity and are detailed here as a reminder to others facing a similar puzzling patient with this potentially treatable poisoning.
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.
InfertilityClomiphene CitrateLuteal Phase AssessmentDiagnosis and Treatment
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 4%, disagreement of more than 2 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.
General OB/GYNInflammatory MarkersC-Reactive ProteinInfectious Morbidity
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. (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.
InfertilityDiagnostic EvaluationLuteal Phase ProfilesLuteal Phase Dating
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.
InfertilityDiagnostic CriteriaAccuracy and ReproducibilityReference Standards
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.
PregnancyInfection BiomarkersTocolysis OutcomesC-Reactive Protein in Pregnancy
Tocolytics were administered in 66 consecutive women in uncomplicated preterm labour with intact fetal membranes (53 singleton and 13 twin pregnancies). C-reactive protein (CRP), a marker of infection, was determined daily and used retrospectively to investigate the role of subclinical infection in preterm labour and to predict the efficacy of tocolysis and the development of a clinical perinatal infection. CRP was also determined in 66 women in uncomplicated labour at term (53 singleton and 13 twin pregnancies). The placenta was examined for histological evidence of infection in all patients who were delivered before 36 weeks (n = 21) and in all women in the control group (n = 66). Elevated CRP levels were more often found in patients who were refractory to tocolysis, suggesting an underlying infectious morbidity. Placental infection was found in 62% of the preterm delivery group and in 12% of the control group. There was an association between elevated CRP levels and histological evidence of placental infection. However, confounding factors such as urinary tract infections limit the usefulness of the CRP test. Because CRP cannot predict clinical perinatal infection accurately, its clinical relevance is very limited.
InfertilityClomiphene Citrate Side EffectsAnti-Estrogen EffectsEndometrial Thickness Monitoring
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.
Menstrual CycleEndometrial DatingUltrasound vs Hormonal MethodsProgesterone and Estradiol Secretion
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.
Traditional therapies for abnormal cervical mucus, other than timed intrauterine insemination, are noteworthy for being ineffectual. Patients (n = 27) with documented abnormal Insler scores in repetitive cycles and failure to conceive with traditional treatments were screened with conjugated equine estrogens (CEE) for estrogen responsiveness of the cervix. Only 5 patients were found unresponsive. Seventeen patients with CEE-responsive cervices then were treated with human gonadotropins (hMG), initially 1 ampule days 5 to 11. If the mucus failed to improve, the hMG was increased to standard doses. Eight patients responded to 1 ampule hMG with improved mucus and conception. The remainder required 2 ampules hMG. In patient cycles with corrected cervical mucus, the viable fecundibility (fv) was 0.35. This is significantly higher than predicted for this population (fv = 0.09; P less than 0.01). In all, 14 of 17 patients conceived viable pregnancies during hMG treatment. It is concluded that graduated hMG is efficacious in treating patients with abnormal cervical mucus responsive to CEE. It is preferable to either in vitro fertilization or gamete intrafallopian transfer, based on both cost and efficacy for most patients.
PregnancyMenstrual Dating AccuracyUltrasound vs Menstrual DatingPostterm Pregnancy Diagnosis
Despite recognition that estimation of gestational age (GA) based on maternal recollection of the last normal menstrual period (LNMP) is fraught with error, it is not generally appreciated that the magnitude and direction of this error vary as a function of the LNMP estimate. Early second-trimester (16 to 18 weeks) ultrasound determinations of the fetal biparietal diameter were used as the "gold standard" to test the validity of LNMP-based GA estimates in 11,045 women. The large majority of deliveries occurring at or near term showed LNMP estimates that were valid within plus or minus seven days of the ultrasound estimate. As the LNMP GA deviated progressively toward earlier or later GAs, however, the discrepancies became quite marked, especially for postterm dates. The positive predictive values of the LNMP GA estimates decreased dramatically from term (.949) to preterm (.775) to postterm (.119) deliveries. These systematic errors in menstrual GA estimates have profound implications for unnecessary induction, dysfunctional labor and cesarean section, and resultant neonatal and maternal morbidity.
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.
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.
To assess uterine activity before labor in patients delivering preterm, at term, and postterm, the maximum spontaneous contraction frequency per 10-minute window during the initial portion of antepartum fetal heart rate monitoring was analyzed. Patients with multiple gestation, third trimester bleeding, polyhydramnios, or premature rupture of membranes and those already diagnosed with preterm labor were eliminated from the study. Of the 2446 remaining patients (7247 antepartum fetal heart rate tests) who went into spontaneous labor, 237 did so before 37 completed weeks of gestation, 1077 entered labor at term (38 to 42 completed weeks), and 1132 did so after 42 weeks. There was a significant increase in maximum uterine activity per 10-minute window from 30 to 44 weeks of gestation (average 4.7% per week; r = 0.97, p less than 0.0001). When compared with patients delivering spontaneously at term, average maximum uterine activity per 10-minute window was greatest in the preterm labor group (p less than 0.05) and least in the postterm labor group (p less than 0.05). These differences were present for several weeks preceding the onset of spontaneous labor. All three groups showed a surge of uterine activity during the 3 days before the onset of spontaneous labor.
Evidence from our laboratory with the use of cultured (primary and passaged) cells has extended our initial observation that human uterine fibroid is an extrapituitary source of prolactin. Fibroid prolactin antigen in conditioned medium reacted specifically in radioimmunoassay for human pituitary prolactin. Control experiments demonstrated that the radioimmunoassay results were not spurious due to degradation of tracer 125I-labeled prolactin. Immunoparallel dilution curves indicated antigenic relatedness of pituitary and fibroid prolactin. In a calibrated Sephadex G-100 column, fibroid prolactin eluted in the same region (20.3 to 20.9 kd) as purified pituitary prolactin. Glycosylated prolactin, detected by concanavalin A affinity column chromatography, appeared to constitute only a small percentage of fibroid prolactin made in culture. The ratio of fibroid prolactin bioactivity (lactogen Nb2 lymphoma bioassay) to antigen (radioimmunoassay) was 0.77. These data indicate that human uterine fibroid tissue produces a molecule similar to or, perhaps, identical with pituitary prolactin.
Samples of semen and cervical mucus were provided by 18 couples. Cervical mucus was obtained for each day possible and stored at 4 degrees C until all the samples were collected. Flat capillary tubes were loaded with the mucous samples and spermatozoa from the husband's semen sample were allowed to migrate through the cervical mucus (3 cm column) into culture medium. The spermatozoa recovered after migration through cervical mucus were assayed in vitro with zona-free hamster oocytes. Control experiments were carried out using spermatozoa from the same semen sample but prepared by the swimming-up technique. Altogether, 557 eggs in the control group and 1236 eggs in the experimental group were analysed, and the results demonstrated that the % of sperm penetration, the mean number of sperm decondensations per penetrated egg and the mean number of spermatozoa adhering per egg all had higher values (P less than 0.05) for the control samples than for the experimental samples. We suggest that cervical mucus modifies human spermatozoa, as measured by their interaction with zona-free hamster oocytes.
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.
General OB/GYNInfection MarkersC-Reactive ProteinDiagnosis and Management
This study was designed to derive the predictive value of C-reactive protein (CRP) in peripheral venous serum of patients admitted to hospital with suspected premature rupture of the membranes (PROM). CRP was assayed by each of 4 separate methods and the results have been compared for accuracy and practical value with respect to clinical outcome and the histopathology of the placenta. Of the 4 techniques used only the latex test had characteristics suitable for a diagnostic screen. While the results were only semiquantitative, when comparisons were made to other techniques no significant change in clinical diagnosis would have been made. The results have confirmed that chorioamnionitis and preterm labour are often associated, but in some instances the extent of inflammatory infiltration was greater than might have been expected from the short time interval between documented membrane rupture and delivery. Thus it may be speculated that some cases of PROM are secondary to, rather than causative of, infection. Finally it is suggested that a controlled therapeutic trial of active intervention in those cases of PROM with elevated CRP in the absence of other clinical parameters suggestive of intrauterine infection should be undertaken.
Chaaban M et al., 1988·J Gynecol Obstet Biol Reprod (Paris)
We have retrospectively studied the changes in the level of C-reactive protein (CRP) and of white blood cells in 82 patients who had premature rupture of the membranes between the 20th and the 36th week of pregnancy in order to estimate the possibility of prenatal screening for amnion infections in early rupture of the membranes. The level of CRP was shown to be quickly and significantly raised in cases of clinical or histological chorioamnionitis, whereas the change in maternal leucocytes alters little and later. The level of CRP can be worked out as an early biological marker which is sensitive and cheap in the clinical supervision of cases with early rupture of the membranes.
PregnancyPremature Rupture of MembranesC-Reactive ProteinChorioamnionitis
In a prospective blind study 380 daily serum samples from 55 women with preterm premature rupture of the membranes were analysed for C-reactive protein (CRP). Although the last CRP before delivery was higher in patients with histological chorioamnionitis (P = 0.007), considerable overlap between infected and non-infected pregnancies occurred, precluding the use of CRP as a diagnostic test if published normal levels were used. When upper limits were set at 30, 35, or 40 mg/l, the last CRP before delivery proved 90, 95 and 100% specific and 88, 92 and 100% positively predictive of infection in singleton pregnancies. Such high specificities are needed to prevent inappropriate intervention based on false positive results. We therefore propose upper limits for single estimations of 30, 35, or 40 mg/l depending on the relative risks of preterm delivery versus infection at various gestational ages. In addition, consecutive values greater than 20 mg/l appeared highly predictive of infection.
Endometriosis presents a large variety of color manifestations, most nonblack, and many easily missed unless meticulous inspection is used to identify small or nonhemorrhagic lesions. An evolution in appearance with age may occur, with resultant spurious effects on conclusions regarding the natural history of the disease. This study confirms and expands the concept of nonhemorrhagic appearances presented by Jansen and Russell.
AndrologyPenetration AssayDiagnostic TestingSperm Function Tests
The human sperm-hamster egg penetration assay (SPA) has been used to evaluate male fertility under in vivo conditions. The test is not only unstandardized, but agreement does not exist as to the lower limits of normal penetration rates. Therefore, it is not surprising that there is considerable doubt as to whether any correlation exists between SPA results and the behavior of sperm in an in vitro laboratory situation. We investigated this question by examining the SPA results and the subsequent fertilization and cleavage rates in the in vitro fertilization program at Pennsylvania Hospital. The sperm from men whose SPA results were 11% or more fertilized 86% of the morphologically normal and mature human oocytes to which they were exposed. Men whose SPA scores ranged from 1% through 10% fertilized 65% of human oocytes, and men whose sperm failed to penetrate hamster eggs still were able to fertilize 41% of the human oocytes. The differences between these groups are statistically significant. This information can be of practical prognostic value during in vitro fertilization cycles in which the number of mature oocytes seen ultrasonographically appears to be at a minimum.
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 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)
Fertility AwarenessUrinary Hormone AssaysNatural Family PlanningHome-Based Immunoassays
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.
From 1979 to 1985, 18 patients who were found to have proximal tubal obstruction by hysterosalpingography and laparoscopic chromopertubation underwent resection of the obstructed tubal segment and reimplantation or microanastomosis. Resected tubal segments were studied histologically, and in 11 of the 18 cases no tubal occlusion could be demonstrated. A variety of histologic abnormalities were noted, however, including six cases in which the tubal lumen contained an amorphous material of unknown etiology, often appearing to form a cast of the tube. Such "plugs," which the authors believe to be previously unreported, have no clearly established clinical significance at present. However, if they cause tubal occlusion, this would explain several previously published findings, and would also have implications for therapy.
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.
A technique of translaparoscopic salpingoscopy is utilized to evaluate the ampullary segment of the Fallopian tube in patients suffering from infertility. Comparison of this technique with hysterosalpingography in a series of 32 patients with hydrosalpinges demonstrates its superiority in the evaluation of the tubal mucosa. This new diagnostic approach allows a more accurate selection of patients for either microsurgical repair, in-vitro fertilization (IVF) or gamete intra-Fallopian transfer (GIFT).
PregnancyPremature Rupture of MembranesInflammatory BiomarkersC-Reactive Protein in Pregnancy
The value of maternal C-reactive protein (CRP) levels as predictors of fetal and maternal infective morbidity and fetal mortality was assessed prospectively over a 6-month period in all cases of premature rupture of the fetal membranes or suspected premature labour. Statistical analysis of results showed that CRP at a level of 1.32 mg/dl is a sensitive marker of infective morbidity in mother and neonate. Furthermore, there was a significant association between raised CRP levels and low-birth-weight babies, suggesting that intra-uterine infection is a major cause of prematurity in the study population.
The development of a 10-item self-report scale (EPDS) to screen for Postnatal Depression in the community is described. After extensive pilot interviews a validation study was carried out on 84 mothers using the Research Diagnostic Criteria for depressive illness obtained from Goldberg's Standardised Psychiatric Interview. The EPDS was found to have satisfactory sensitivity and specificity, and was also sensitive to change in the severity of depression over time. The scale can be completed in about 5 minutes and has a simple method of scoring. The use of the EPDS in the secondary prevention of Postnatal Depression is discussed.
Fertility AwarenessBiological IndicatorsSymptothermal MethodHormonal and Clinical Markers
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.
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.
InfertilityLuteinized Unruptured Follicle SyndromeLimitations of Traditional MethodsLUF Syndrome
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.
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.
C-reactive protein has been used to identify patients at high risk for infectious morbidity with preterm labor or preterm rupture of membranes. In this article we report on 104 patients with preterm labor symptoms (n = 45) or preterm rupture of the membranes (n = 59) and serial evaluations of C-reactive protein measured by latex agglutination and laser nephelometry. The simple, inexpensive latex method appears comparable to the laser method in predicting infectious morbidity and can be used clinically. Elevated C-reactive protein values before delivery predict infectious morbidity in only 8% to 29% of patients, and up to 18% of patients with serious infections may be misdiagnosed as having normal C-reactive protein values before delivery.
InfertilityCervical Mucus DeficiencyEstrogen Receptor AssessmentEndocervical Gland Function
Endocervical gland estrogen receptor (ER) deficiency has been proposed as a possible cause for the poor cervical mucus (CM) in some infertile women with cervical factor. Cytosol ERs were measured in endocervical tissue obtained by biopsy within 3 days of ovulation (determined by the endogenous luteinizing hormone [LH] surge) in five infertile women with persistent poor preovulatory CM (group 1) and in endocervical tissue obtained in the late follicular phase in eight ovulatory women with excellent CM (group 2). ER concentrations were measured in Fmol/mg protein by the dextran-coated charcoal separation method (New England Nuclear Kit, Boston, MA). CM score evaluation and measurement of serum estradiol (E2) and progesterone (P) levels were performed concomitantly. Serum E2 levels of 123.4 +/- 29.3 pg/ml (mean +/- standard error of the mean [SEM]) in group 1 were comparable to E2 levels of 123.3 +/- 15.0 pg/ml in group 2. Serum P concentrations of 0.9 +/- 0.27 ng/ml in group 1 were comparable to 0.79 +/- 0.29 in group 2. A CM score of 4.6 +/- 0.69 in group 1 was significantly lower than 11.6 +/- 0.53 in group 2 (P less than 0.01). The cytosol ER was negative in four of five women in group 1, whereas in group 2, ER was positive in six, borderline in one, and negative in one subject. This study suggests that cytosol ER may be deficient in some women with cervical factor.
Effective tocolytic therapy depends on the ability to make an early diagnosis of preterm labor. This study was designed to assess whether daily ambulatory home monitoring of uterine activity could facilitate early diagnosis of preterm labor. Of 76 patients at high risk for preterm labor who used daily ambulatory tocodynamometry, approximately half developed preterm labor. Evaluation when the diagnosis of preterm labor was first established has shown that in 8% of the patients the cervix was dilated more than 2 cm, shortened to less than 0.5 cm in 23%, and the fetal membranes were intact in all subjects. The same evaluation in 76 nonrandom contemporary controls matched for risk factors, maternal age, and parity has shown that more than 50% had a cervix dilated more than 2 cm, 38% had a cervix shorter than 0.5 cm, and 24% had rupture of the fetal membranes. Ultimately, 88% of the monitored patients and 59% of controls delivered at term. Comparisons between these groups indicate that intermittent home tocodynamometry may indeed be useful in making the early diagnosis of preterm labor.
InfertilityFollicular Development AbnormalitiesFollicular Growth AssessmentLH Surge Abnormalities
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%).
The absorption, metabolism, and clearance of progesterone (P) from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg at 9:00 A.M. and 200 mg at 9:00 P.M. for 5 consecutive days. Mean peak plasma concentrations of P were observed 2 hours after ingestion of both the 100 and 200 mg doses and were 22.7 and 47.7 nmol/l, respectively. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment; those of 17-hydroxyprogesterone were least raised. Increases in the plasma levels of 20 alpha-dihydroprogesterone were more sustained than those of P, and the plasma concentrations remained elevated at approximately 20 nmol/l for at least 12 hours after P administration. We conclude that administration of oral P 100 mg in the morning and 200 mg at night increases the circulating concentrations of P and the biologically active metabolite 20 alpha-dihydroprogesterone, and that the duration of these increases is sufficient to evoke progestational responses in responsive end-organs.
Cervical examination between 26 and 30 weeks' gestation is described as a method for identifying women at risk for delivery before 34 weeks. Blinded cervical examinations were performed in 185 consecutive women, and 15 (8%) were found to have cervixes dilated 2 or 3 cm. The incidence of delivery before 34 weeks' gestation was 27% in such women compared with 2% in those whose cervixes were undilated or 1 cm. Other factors linked to cervical dilatation included parity and prior preterm delivery. However, parous women with cervical dilatation remained at increased risk for delivery before 34 weeks' gestation. We conclude that early third-trimester cervical examination may be an important adjunct in identifying women at risk for preterm delivery.
Polycystic ovaries were defined with ultrasound imaging in a series of 173 women who presented to a gynaecological endocrine clinic with anovulation or hirsutism. Polycystic ovaries were found in 26% of women with amenorrhoea, 87% with oligomenorrhoea, and 92% with idiopathic hirsutism--that is, hirsutism but with regular menstrual cycles. Fewer than half the anovulatory patients with polycystic ovaries were hirsute, but in 93% of cases there was at least one endocrine abnormality to support the diagnosis of polycystic ovaries--that is, raised serum concentrations of luteinising hormone, follicle stimulating hormone ratio, or raised serum concentrations of testosterone or androstenedione. This study shows that polycystic ovaries, as defined by pelvic ultrasound, are very common in anovulatory women (57% of cases) and are not necessarily associated with hirsutism or a raised serum luteinising hormone concentration. Most women with hirsutism and regular menses have polycystic ovaries so that the term "idiopathic" hirsutism no longer seems appropriate.
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 …
PregnancyMonitoring and PreventionTocolysis ManagementAmbulatory Tocodynamometry
A study to evaluate whether ambulatory tocodynamometry at home could enhance the management of oral tocolysis was performed. On discharge from the hospital, after completing parenteral tocolysis, 60 patients received a lightweight tocodynamometer, designed for storage and transmission of uterine activity data. Sixty additional contemporary patients, who were matched for maternal age, parity, and risk factors, served as a control group. In addition to instructions regarding self-detection of recurrent preterm labor, monitored patients recorded uterine activity for greater than or equal to 200 min/day and then transmitted the data to the study center. Tocolytic dosage was adjusted to maintain mean uterine contraction frequency of less than 4/hr. Persistent uterine contractions of greater than or equal to 4/hr lead to in-hospital evaluation for recurrent preterm labor. The results indicate that the monitored group had a lower incidence of preterm births mostly because of a decrease in the proportion of patients with failed tocolysis. It is suggested that surveillance of uterine activity at home during oral treatment for preterm labor may be instrumental in improving perinatal outcome in high-risk patients.
PregnancyCervical Incompetence DiagnosisCervical Length MeasurementPrevention of Preterm Delivery
To evaluate the feasibility of the use of serial ultrasound measurements of cervical length, membrane protrusion, and dilatation to discriminate between the competent and the incompetent cervix, 107 at-risk patients and 30 control subjects were examined prospectively. Patients were divided into five groups based on treatment and method of diagnosis. Epidemiologic, ultrasound, and outcome data were analyzed. Means and standard deviations for ultrasound measurements were established. Highly significant differences between all prediagnostic and postdiagnostic-pretreatment measurements were found (p less than 0.001). Highly significant differences were also found between all postdiagnostic-pretreatment and postdiagnostic-posttreatment measurements (p less than 0.001). No significant differences between prediagnostic and postdiagnostic-posttreatment measurements were noted. The incidence of preterm delivery was significantly higher among untreated diagnosed patients (p less than 0.01). By combined clinical and ultrasound criteria 51 patients (47.7%) were identified as not having cervical incompetency. Fifty-six patients (52.3%) were diagnosed.
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.
PregnancyCervical Ripening PredictionCervical AssessmentScreening and Prevention
A group of 8303 women was studied to determine the timing of cervical ripening. It was confirmed that these signs of cervical change can be observed several weeks before preterm births. The precocious signs of external ripening can be recognized during a vaginal examination and may be useful in predicting preterm labor.
General OB/GYNDiagnostic ImagingCervical AssessmentCervical Insufficiency
Artifacts interfering with sonographic imaging of the uterine cervix in pregnancy are described. Increasing the amount of fluid in the urinary bladder closes the cervix and alters the configuration of the lower uterine segment, while increased intra-uterine pressure results in reciprocal changes. Angulation of the transducer and manual pressure thereon distort sonographic findings. It is concluded that, contrary to recent reports in the literature, sonography cannot reliably demonstrate changes in cervical compliance during pregnancy. Vaginal examination remains the ultimate diagnostic modality for the diagnosis of the incompetent cervix, while sonography may be used as an adjunct only.
Menstrual CycleCervical MucusClinical OutcomesProfessional Training
The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tocolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful.
DiagnosticsLuteal Phase AssessmentDiagnostic MethodsEndometrial Dating
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.
Progesterone (P) has not been administered orally because of reportedly poor bioavailability and a rapid clearance rate. Unfortunately, the synthetic derivatives, although orally active, have a number of disadvantages and fail to mimic natural P completely. To investigate the bioavailability and short-term toxicity of oral micronized P, a standardized dose of 200 mg of micronized P was administered to nine healthy postmenopausal women and one male subject. Serial determinations of serum P concentrations demonstrated rapid absorption of P. Peak concentrations of P rose from a negligible baseline level to 17.0 +/- 4.9 ng/ml at an average of 2.8 +/- 0.35 hours after administration. The peak concentrations of P were equivalent to those observed in the midluteal phase in normal control cycles (14.1 +/- 2.7 ng/ml). All subjects exhibited significant elevation of P over baseline levels that persisted for at least 6 hours after the single oral dose and returned to initial levels by 24 hours. There was no significant change in estradiol, follicle-stimulating hormone, luteinizing hormone, cortisol, aldosterone, lipids, or hepatic enzymes during the 24-hour study interval.
General OB/GYNVitamin B6 ToxicityPyridoxine-Induced Sensory Neuropathy
We describe 16 patients with neuropathy associated with pyridoxine abuse. The clinical picture of a pure sensory central-peripheral distal axonopathy was consistent. Pyridoxine dose was 0.2 to 5 g/d, and duration of consumption before symptoms was inversely proportional to the daily intake. In all patients with adequate follow-up, improvement followed discontinuation of pyridoxine. The ready availability of up to 1-gram tablets makes it likely that this neuropathy will continue to be seen.
A system capable of ambulatory home monitoring of uterine activity and data transmission was evaluated in a group of pregnant patients. The evaluation 1) Is the information as reliable as that obtained by the current stationary monitors; 2) Does the information obtained by the tested system relate to that obtained by direct intrauterine pressure measurements; and 3) Is the system simple enough to be used by the unsupervised gravida at home? The results indicate that the tested system can provide reliable information about uterine activity in ambulatory patients. A good correlation between the intensity of contractions and the recording of uterine activity by this system could be demonstrated, particularly in the presence of mild to moderate contractions. The tested monitor proved to be simple to use even in the untrained gravida. Additional studies to determine the role of ambulatory home monitoring of uterine activity in patients with cervical cerclage, placenta previa, and preterm labor will need to be performed to establish its role in current obstetric practice.
In a consecutive series of 167 patients reaching the stage of embryo transfer after in vitro fertilization and embryo transfer, 19 clinical pregnancies ensued. The serum progesterone (P) levels were significantly greater on the first and second (P less than 0.01) and third (P less than 0.05) postaspiration days for those who conceived. Higher circulating levels of P were achieved on days 1, 2, and 3 (P less than 0.05) by the daily injection of P, 50 mg in oil, given for 5 consecutive days, beginning immediately after follicle aspiration. Both pregnancy and nonpregnancy cycles demonstrated high circulating P levels, but the study implies that relatively higher levels are required for conception, and such levels can be achieved by the use of intramuscular P.
InfertilityOvulatory DysfunctionCombined Ultrasound and Hormonal MonitoringLuteinized Unruptured Follicle
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.
InfertilityDiagnosis and AssessmentEndometrial Biopsy HistologyProgesterone Insufficiency
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 plasma concentrations of medroxyprogesterone acetate (MPA) in 14 women administered the progestagen for threatened abortion during the first 6 weeks of pregnancy were measured by specific radioimmunoassay. Treatment (52 nmol orally every 6 h) was continued to 18 weeks of gestation. The mean plasma concentration of MPA rose rapidly during day 1 of treatment to 14.1 +/- 1.84 nmol/l. It reached 21.5 +/- 2.3 nmol/l by 7 days and subsequently stabilized at around 26.8 +/- 5.0 nmol/l by the end of week 2. Urinary steroid profiles were determined by gas-liquid chromatography and mass spectrometry for six of the MPA-treated women and compared with those of six untreated women of similar gestational age. No differences were detected between the two groups of women, suggesting that the administration of MPA during pregnancy did not alter qualitatively or quantitatively the metabolism and excretion into urine of progesterone and oestrogens.
Fertility AwarenessMethod ComparisonUltrasound vs BiomarkersDonor Insemination Timing
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.
Eighteen women with cervical ectropion and 12 women with ectropion and vaginal discharge were treated by cryosurgery. Evaluation of the cervical mucus characteristics by cervical score and in vitro penetration test was performed before treatment and 2 months later. In the group with ectropion only (group A) the total cervical score was 5.7 +/- 0.4 and 11.9 +/- 0.06 (P less than 0.001) (mean +/- standard error) before treatment and 2 months later, respectively. In the group with ectropion and vaginal discharge (group B) the total cervical score before and after cryosurgery was 3.8 +/- 0.4 and 11.8 +/- 0.1 (P less than 0.001), respectively. In vitro penetration tests in group A before and after treatment were 0.72 +/- 0.1 and 2.9 +/- 0.08 (P less than 0.001), respectively. In group B, in vitro penetration tests before and after cryosurgery were 0.25 +/- 0.1 and 2.8 +/- 0.1 (P less than 0.001), respectively. It appears that cryosurgery improves the cervical mucus characteristics. It is recommended that infertile patients with hostile cervical mucus and ectropion will be treated by cryosurgery.
An in vitro bioassay for lactogenic hormones, based on the specific mitogenic effects of lactogens on cultured Nb2 node rat lymphoma cells, was used to measure the levels of lactogens in whole serum and in fractionated serum samples from three patients with prolactin (PRL) secreting pituitary adenomas. Under basal conditions, after pituitary stimulation, and following treatment with bromocriptine which greatly decreased the serum PRL levels, the bioassay (BA) results closely paralleled fluctuations in the sum of radioimmunoassay (RIA) estimates of serum PRL and growth hormone concentrations. The extreme sensitivity (10 pg/ml) of the BA facilitated measurement of PRL in fractions obtained after Sephadex G-100 chromatography of only 0.1 to 0.3 ml of sera from both untreated and bromocriptine-treated prolactinoma patients. In both types of samples, similar heterogenous patterns of bioactive PRL were observed, although most of the recovered activity appeared to be due to monomeric PRL. BA and RIA of fractions obtained after DEAE cellulose chromatography of sera from untreated prolactinoma patients revealed two PRL peaks, the first one containing 75% of the activity. Therapy with bromocriptine led to a reduction in the total serum PRL activity and, in particular, in the activity of the second peak.
Fertility AwarenessUltrastructureScanning Electron MicroscopyCervical Mucus Changes
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.
Fertility AwarenessCanalization PhenomenonFerning and Channel FormationMonitoring Methods
Cervical mucus forms channels when dried under a coverslip. The 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.
Thirty-seven consecutive patients with singleton pregnancies in "uncomplicated" preterm labor with intact membranes suitable for tocolysis were evaluated for evidence of silent chorioamnionitis by means of maternal serum C-reactive protein and amniotic fluid white blood cell count, Gram stain, and cultures. Abnormalities in these markers of infection were found to be significantly more common in cases that were refractory to tocolysis. These cases also showed both pathologic evidence of chorioamnionitis and a significantly greater neonatal early infectious morbidity. We conclude that silent chorioamnionitis is a significant cause of "uncomplicated" preterm labor refractory to conventional methods of tocolysis.
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%.
Twenty-eight patients with type I diabetes mellitus, legally blind as a result of proliferative retinopathy, were recruited into a program designed to teach and evaluate tactile methods for self-monitoring of blood glucose (SMBG). Vision ranged from "blind" to "able to read large print." Techniques with wipe-off strips (Chemstrip bG or BM Test BG, Boehringer-Mannheim, Canada Ltd., Dorval, Quebec, Canada) use the opposite hand as a guide, operation of timing devices by touch, and special methods for labeling and storing strips. Methods with wash-off strips (Dextrostix, Ames Division, Miles Laboratories, Rexdale, Ontario, Canada) employ the fingers as a guide in directing the wash water. The accuracy of tactile methods was documented. Clinical parameters of glucose control improved in patients with adequate data after 6 mo of tactile SMBG. Glycosylated hemoglobin in 17 patients decreased from 11.3 +/- 2.1% to 9.4 +/- 1.5% (P = 0.005). Patients experienced significantly fewer reactions and low blood sugar readings as well as lowering of mean blood glucose values from 158 +/- 56 to 141 +/- 51 (P = 0.025).
PregnancyTocolysis OutcomesInfection BiomarkersC-Reactive Protein Pregnancy
Subclinical intrauterine infection is an important cause of preterm labor, specifically where tocolysis has failed. Fifty patients in preterm labor with singleton pregnancies were studied prospectively to determine whether the presence or absence of C-reactive protein, a nonspecific marker for infection, would correlate with success or failure of tocolysis. Of the 50 patients, tocolysis failed in 11 of 15 women with a positive C-reactive protein determination. Tocolysis succeeded in 33 of 35 cases where C-reactive protein was negative (P less than .0005). Urinary tract infection occurred in 40% of the study patients, but was not a confounding factor in the interpretation of C-reactive protein.
InfertilityUltrasound-Guided TherapyFollicular Development AssessmentProgesterone Supplementation
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.
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 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 forming group III 'dysharmonic luteal phases (DLP)'. 6 women had advanced EB 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 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.
The principal function of muscular tissue is contraction. This is also true for the uterus this function begins with sexual maturation. During pregnancy special conditions are brought about by the increasing distention of the uterine cavity. For clinical practice, external tocography is of importance for the recognition of uterine motility Data in the literature on the normal frequency of contractions during pregnancy vary greatly and caused us to study this topic. Moreover, most cases of prematurity independent of other causes suppose a prematurely increased uterine motility. In order to register this activity a portable recording apparatus was developed. We studied in particular the question for how long and how often uterine contractions should be recorded. A one hour daily recording was found to be sufficient. In order to gain information on the average number of contractions it suffices to record during one week. In 26 healthy primiparous and 28 multiparous women the number of contractions from the 25th to 41st gestation week was recorded. A notable finding was the frequency peak about the 32nd week. The number of pregnancy contractions as a sole parameter for the recognition of impending premature delivery is not sufficient. However, the information may be important when taking in conjunction with the previous history and the state of the cervix. We considered tocolysis indicated when as a weekly average there are more than two contractions per hour with beginning cervical dilation or more than three contractions per hour regardless of cervical findings.(ABSTRACT TRUNCATED AT 250 WORDS)
Fourteen women experiencing early pregnancy failure have been studied during the time of conception and at frequent intervals until spontaneous abortion occurred. Serial measurements of serum estradiol, progesterone, 17 alpha-hydroxyprogesterone, prolactin, human placental lactogen (hPL), and human chorionic gonadotropin (hCG) were determined; regular sonar scanning allowed the time of fetal death to be determined to within 7 days in six patients and a diagnosis of blighted ovum to be made in the remainder. In all patients serum progesterone and estradiol concentrations were within the normal range up to 7 weeks but appeared to decrease from about 8 weeks' gestation whether or not a living fetus was present. The placenta continued to produce hCG and hPL but, despite the continuing presence of hCG, the levels of 17 alpha-hydroxyprogesterone declined to concentrations below those associated with normal pregnancy. These data suggest that the placenta may require a particular stimulus to take over production of progesterone and estradiol.
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.
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.
PregnancyPremature Rupture of MembranesChorioamnionitis PredictionC-Reactive Protein in Pregnancy
A group of 52 patients with premature rupture of the membranes (PROM) before 34 weeks' gestation were evaluated prospectively and managed expectantly. Of 42 patients who were delivered of their infants, 26 (61.9%) had significant chorioamnionitis on histopathology, and 18 had positive microbial cultures at delivery. However, only seven patients (16.7%) developed clinical signs of chorioamnionitis. There were no maternal deaths or perinatal deaths attributable to sepsis. Only two infants (less than 5%) had positive blood cultures. All patients were assessed daily for the development of chorioamnionitis. Amniocenteses were not routinely performed. White blood cell counts, band neutrophil counts, and erythrocyte sedimentation rate determinations were found to be unreliable. C-reactive protein determinations were found most reliable with a high sensitivity and specificity. Elevated C-reactive protein levels correlated better with pathologic confirmation of chorioamnionitis than with the clinical febrile morbidity. Clinical implications for the management of PROM are discussed.
General OB/GYNVitamin ToxicitySupplement-Induced Neuropathy
We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption. Four were severely disabled; all improved after withdrawal. Weakness was not a feature of this condition, and the central nervous system was clinically spared. Although consumption of large doses of pyridoxine has gained wide public acceptance, this report indicates that it can cause sensory neuropathy or neuronopathy syndromes and that safe guidelines should be established for the use of this widely abused vitamin.
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.
DiagnosticsCervical MucusProtocolProfessional Training
Urinary testosterone and androstanediol were measured by gas chromatography in four groups 22 healthy women (control group), 21 healthy women with a family history of breast cancer (familiality group), 39 patients with breast lumps which consisted of ductal or lobular hyperplasia (hyperplasia group) and 18 patients with infiltrating breast carcinoma (carcinoma group). On the basis of normal values found in our laboratory, steroid levels were above normal in 4.5% of the controls, 4.7% of the familiality group, 38.5% of the hyperplasia group (P less than 0.01 vs controls) and 61.1% of the carcinoma group (P less than 0.001 vs control group). The mean testosterone level in the carcinoma group (11.3 +/- 6.78 S.D.) and the mean androstanediol level in the hyperplasia group (47.25 +/- 31.0 S.D.) were significantly higher than those of the control group (testosterone 6.25 +/- 3.48 S.D., androstanediol 32.55 +/- 20.0 S.D.). No significant difference was found in mean testosterone or androstanediol levels between the control group and the familiality group (testerone 5.41 +/- 3.6 S.D., androstanediol 29.38 +/- 15.89 S.D.). We conclude that increased excretion of androgenic steroids is a hormonal abnormality common to breast cancer patients and to patients with breast epithelial hyperplasia, but not to subjects with a family history of carcinoma of the breast.
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.
Sixty-nine infertile women with a midluteal serum progesterone level of 4 to 14 ng/ml were treated with a graduated dosage schedule of clomiphene citrate until the progesterone level on day 21 was greater than 20 ng/ml. Thirty-one pregnancies occurred, 58% during the first adequate treatment cycle and 19% during the second cycle. The abortion rate was 23%. After 6 adequate treatment cycles, laparoscopic evaluation was performed on 28 of 39 patients who did not conceive. Pathology was noted in 57%. Seven of 17 patients with intraperitoneal causes of infertility conceived after alternative therapy. The corrected pregnancy rate was 60%. Results of this study suggest that low luteal phase progesterone levels may compromise fertility and that clomiphene citrate enhances pregnancy rates.
Many studies have been published on luteal phase deficiency, and the emphasis in most of them is on progesterone deficiency. In this study 144 patients (455 cycles) with infertility were studied. The patients were divided into four groups. Group 1 consisted of patients with high estradiol and high progesterone levels in the midluteal phase. Group 2 consisted of patients with high estradiol and low progesterone levels. Group 3 consisted of patients with low estradiol and low progesterone levels. Group 4 consisted of patients with low estradiol and high progesterone levels. As expected, patients in groups 2 and 3 showed a low conception rate with outphased endometrial biopsy. However, group 4, in spite of the normal progesterone levels, had a low conception rate with an outphased endometrium. We conclude that estradiol deficiency during the luteal phase is a major factor in infertility, and replacement therapy with progesterone alone in these patients may not improve fertility.
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.
InfertilityOvulatory DysfunctionFollicular MonitoringEstradiol and Progesterone
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.
Fifty-eight psychoses beginning within two weeks of childbirth are compared with 52 episodes of nonpuerperal psychotic illness occurring in young women. A clinical approach based on the use of multiple information sources and integrated assessment was used. Statistically significant differences between the two groups of patients were found in 52 of 214 psychopathological variables. Postpartum patients had more manic symptoms and "confusion," while nonpuerperal patients had more schizophrenic symptoms. The Research Diagnostic Criteria (RDC) showed an excess of schizoaffective (manic) puerperal patients and schizoaffective (depressed) or schizophrenic nonpuerperal patients. Only five of 58 puerperal episodes met RDC for schizophrenia. The relative lack of schizophrenic symptoms in the puerperal group was confirmed by self-ratings. The results are interpreted as supporting a link between puerperal psychosis and manic-depressive disease.
DiagnosticsOvarian Ultrasound MonitoringFollicular Development TrackingSonographic Methods
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 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.
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 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 either ovulation delay or a slow increase in temperature (longer than 2 days). Plasma steroid concentrations also demonstrated a perturbation 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.
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.
PregnancyPremature Rupture of MembranesC-Reactive ProteinChorioamnionitis Prediction
The management of patients with premature rupture of membranes (PROM) poses one of the most serious dilemmas in obstetrics since PROM significantly increases the likelihood of prematurity and serious perinatal infection. Early infection is not reliably predicted nor detected by standard laboratory parameters. Serum C-reactive protein (CRP) levels were assayed along with white blood cell count, differential, and temperature course in patients with PROM and controls. Elevated CRP very accurately divided patients with evidence of infectious morbidity from those without such evidence (p < 0.001). In 109 patients there were 11 false negatives and no false positives. In 14 of 20 patients followed with serial comparisons who developed morbidity, CRP became elevated at least 12 hours prior to any other parameter measured. Changes in the other six patients were concurrent. The results suggest that CRP may be a reliable, early predictor of infectious morbidity and thus may be of benefit in the selective management of patients with PROM.
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.
Cytogenetic analysis of 1000 spontaneous abortions showed 463 to have an abnormal chromosome constitution. The proportion of chromosome abnormalities varied with the gestational age of the abortus and the type of tissue cultured but was not significantly different among the five racial groups represented in the study population. It was suggested that differences in the rate of chromosome abnormalities among cytogenetic studies of spontaneous abortions were the result of methodological differences in sample selection rather than real biological variation among study populations. The only factor found to be unequivocally associated with the aetiology of chromosome abnormalities in spontaneous abortions was increasing maternal age in trisomies.
Purpose Endometriosis is a benign estrogen-responsive disease which shares some characteristics with malignant tumors such as invasion and unrestrained growth. In this respect, the epidermal growth factor receptor family (EGFR or erbB-1 and erbB-2 to -4) is known to play an important role in tumor biology. The 1) to investigate the expression patterns of the four erbB receptors, 2) to ascertain if there was a correlation between the EGFR family expression and the expression of the estrogen receptor α (ERα). 48 peritoneal and 12 ovarian human endometriotic lesions were analyzed by immunohistochemistry. The confirmation of the immunohistochemical findings was made by Western blot analysis. Using the Mann-Whitney-U test, statistical analysis was performed. Results In peritoneal and ovarian endometriosis, all members of the EGFR family and ERα are detectable in stromal and epithelial cells, but the expression is different within the tissues. Only in ovarian endometriosis was a statistical association observed between EGF receptor and ERα expression (p<0.017). Conclusions The differential expression of the erbB receptors suggest that the erbB family might play an important role in the pathogenesis of endometriosis. A significant association between EGF receptor expression and the ERα expression was only found in ovarian endometriosis.
InfertilityLuteal Phase DefectProgesterone MeasurementLuteal Phase Dating
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.
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.
PregnancyHormonal MonitoringProgesterone and hCG in Early PregnancyPredictive Hormone Markers
Progesterone and human chorionic gonadotrophin (HCG) in serum and pregnandiol in urine were measured in 64 patients admitted to hospital because of threatened abortion. Blood samples were taken and urine specimens collected at regular intervals during admission and after discharge during the rest of the pregnancy. A reference range was worked out for each hormone based on the hormone values obtained from the pregnancies proceeding to term. The predictive significance of values within and below the reference range was determined, for the initial sample and for serial samples. An association between hormone levels and outcome of pregnancy was observed but it is concluded that both single and serial determinations of progesterone and pregnandiol and serial determinations of HCG are unsatisfactory for the evaluation of threatened abortion. However, an initial progesterones value below the reference range and HCG values below 10,000 mIU/ml between the 8th and 15th week of pregnancy was in every case always followed by spontaneous abortion. A hormonal test of fetoplacental origin is recommended for monitoring threatened abortion.
The concentration of human beta-endorphin (beta h-EP)) was measured in various hypothalamic nuclei, in extrahypothalamic brain regions and in the anterior and posterior lobes of the pituitary using a specific radioimmunoassay (RIA) The beta h-EP concentrations in the arcuate nucleus (169 +/- 35 pg/100 micrograms protein, n = 7) and median eminence (163 +/- 32 pg/100 micrograms protein, n = 6) were among the highest in the 17 brain areas examined. The immunoreactive beta h-EP in the hypothalamus corresponded to authentic beta h-EP, as determined by gel exclusion chromatography. By chromatography and RIA the beta h-EP concentrations in anterior (1.53 X 10(5) +/- 0.51 X 10(5) pg/100 micrograms protein, n = 3) and posterior (1.41 X 10(5) +/- 0.38 X 10(5) g/100 micrograms protein, n - 5) pituitary were found to be approximately 1,000-fold higher than in hypothalamus. Within the pituitary beta h-EP was localized throughout the anterior lobe, in the pars intermedia and in that part of the posterior lobe nearest the pars intermedia, as judged by immunocytochemistry. Dense immunocytochemical staining was found along the perimeter of many blood vessels. Beta h-EP and adrenocorticotropin (ACTH) were co-localized in the same pituitary cells. The present data represent the first unequivocal localization and quantitation of beta h-EP in human brain and in the separate lobes of the human pituitary.
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 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.
Fertility AwarenessClinical IndicatorsProgesterone CriteriaBasal Body Temperature
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)
Reproductive EndocrinologyProgesteroneHormonal Changes Before LaborRIA vs CPB Methodology
Conflicting results have been published regarding changes in plasma progesterone during the last trimester of pregnancy. Some have demonstrated a fall in plasma progesterone before labor, and this has been taken as a possible explanation of the onset of labor. It has been suggested that the various results could be due to differences in methods for progesterone determination. In this study the progesterone levels were determined by both RIA and CPB. In 11 women the plasma progesterone, human placenta lactogen, and serum estriol were measured weekly during the last trimester of normal pregnancies and immediately after delivery. All samples were analysed radioimmunologically. In order to compare the radioimmunoassay and competitive protein binding techniques (RIA and CPB), the progesterone levels were determined by both methods. This was also done for 80 successive plasma progesterone routine samples drawn from women who were not pregnant or who were in the early stages of pregnancy. Both methods showed a significant rise in the plasma progesterone level during the last 6 weeks before spontaneous labor. However, the values obtained were lower when assayed by CPB than by RIA, presumably because of a higher specificity and a cross reaction in RIA. Serum estriol exhibited increasing values throughout pregnancy, but without a significant rise during the last few weeks. Plasma HPL settled at a constant level during the last few weeks before labor.
PregnancyHormone MonitoringSpontaneous AbortionProgesterone Levels in Pregnancy
Plasma progesterone, 17-hydroxyprogesterone, 20alpha hydroxypregn-4-en-3-one levels were determined twice weekly up to 16 weeks gestation, where possible, in a twin pregnancy, in two patients who aborted spontaneously and in three patients who were treated with 'progesterone supplements' because of abnormal vaginal cytology. There was no correlation between vaginal smears and the plasms hormone levels and there was no evidence to suggest that progesterone supplements influenced clinical outcome. Compared with normal mean values the only difference was a significantly rise in progesterone and 20alpha hydroxypregn-4-en-3-one levels in the twin pregnancy after the 12th week and a precipitate fall in all hormone levels just prior to abortion. Plasma hormone levels could not be used to predict outcome.
Observations of random obstetrical cases out of a large-volume practice are presented to demonstrate the often overlooked effects of filling the urinary bladder for obstetrical sonography. The effects, predominantly evident in the second trimester, perssure effects on the lower uterine segment, displacement of the cervix and/or corpus of the uterus, rotation, flexion, version, and tilting of the uterus. These events may affect the perception of placenta location and fetal position. This is especially important in the diagnosis of placenta previa in the second trimester. Many instances of placental "migration" may be due to this phenomenon. Implications for amniocentesis are briefly discussed.
PregnancyFetal Growth RetardationHormone LevelsEstrogen and Progesterone in Pregnancy
Plasma levels of progesterone (P), oestradiol (OE2), unconjugated oestriol (OE3) and total OE3 were measured in blood samples taken from patients with fetal growth retardation, pre-eclampsia and other complications of pregnancy. The levels were compared with the 24-hour urinary excretion levels of total oestrogen (OE) in these patients, and with the plasma levels found in 31 normal pregnant patients from whom blood samples were taken serially from 21 weeks gestation onwards. There was good correlation between plasma unconjugated and total OE, levels, and urinary OE levels (r = 0.77). In 12 patients with fetal growth retardation and no other abnormality, levels of all hormones were significantly lower than normal; unconjugated OE3, total OE3, and urinary OE levels were significantly less than 1 SD below the normal mean. In 22 patients with mild or moderate pre-eclampsia who were delivered of normal birth weight infants none of the hormone levels were significantly different from normal. In 12 patients with mild or moderate pre-eclampsia in association with fetal growth retardation OE2, unconjugated OE3 and urinary OE levels were significantly lower than normal, and total OE3 levels were significantly less than 1 SD below the normal mean. In 12 patients with severe pre-eclampsia, OE2, levels were significantly less than 1 SD below the normal mean and unconjugated OE3, total OE3, and urinary OE levels were significantly less than 2 SD below the normal mean. In studies of diurnal and day-to-day variation the coefficients of variation for P were respectively 12.7 per cent and 14.2 per cent, for OE2, 11 per cent and 12.7 per cent, for unconjugated OE3, 15.6 per cent and 14.1 per cent, and for total OE3, 15 per cent and 15.8 per cent. It was concluded that measurements of plasma total OE, and urinary OE were probably of comparable value and that the plasma estimation had much to commend it.
A clinical description of luteinized unruptured follicles is presented. This abnormality in ovulation is characterized by normal endocrinologic 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.
There are two biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Most T3 is produced extrathyroidally, so that alterations in circulating thyroid hormone concentrations may occur as a result of both thyroidal and extrathyroidal abnormalities. Extrathyroidal T4 conversion to T3 is decreased in patients with different acute and chronic illnesses. When T4 conversion to T3 is impaired and serum T3 concentrations decline, serum concentrations of biologically inactive 3,3',5'-triiodothyronine (reverse T3) increase. In this review, we present current information on thyroidal and extrathyroidal T4 and T3 production in normal subjects and patients with various thyroid diseases and other illnesses, consider the physiologic significance of these changes, and discuss the value and interpretation of various iodothyronine measurements.
DiagnosticsProgesterone vs Endometrial BiopsyLuteal Phase EvaluationOvulation Assessment
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.
Reproductive EndocrinologyPreterm LaborHormonal FactorsProgesterone and Estradiol in Pregnancy
A total of 30 to 50 per cent of premature labors occur without identifiable predisposing conditions. To evaluate the hormonal status of these pregnancies, serum progesterone (P) and estradiol (E2) were measured by radioimmunoassay singly in 60 premature labor patients and serially in 19 normal pregnancies. Premature labor patients as a group have significantly lower P and E2 levels than controls. Pregnancies complcated by idiopathic premature labor (IPL) (p less than 0.01), premature labor secondary to abruptio-marginal separation (A-MS) (p less than 0.05), and premature rupture of membranes (PROM) (p less than 0.05) have significantly lower P levels than controls. Patients with IPL and A-MS have significantly lower P levels (p less than 0.01) than PROM patients. No significant change in P or E2 occurs immediately prior to normal term labor. Conclusions are that (1) premature labor patients have significantly lower Pand E2 levels than controls, (2) the degree of P depression varies according to the type of premature labor and (3) IPL is characterized by premature labor with no identifiable predisposing factors.
Serum progesterone was measured by competitive protein-binding assay in 331 cases of normal pregnancy ranging from 6 to 42 weeks. Serial estimations of serum progesterone were performed in nine cases of severe hypertensive disorder of pregnancy, eight cases of twin pregnancy, three cases of twin pregnancy complicated by severe hypertensive disorder of pregnancy, three cases of triplet pregnancy, three cases of previous bad obstetric history, one case of anencephaly, and seven cases of intrauterine fetal death. Serum progesterone remained within normal range in severe hypertensive disorder of pregnancy and the levels were indistinguishable in cases of fetal growth retardation from those without growth retardation. In twin and triplet pregnancies, serum progesterone was within normal range or elevated and was usually higher than normal in twin pregnancies after weeks 33 to 34. Serum progesterone levels were normal in anencephalic pregnancy and in most cases of intrauterine fetal death. The findings are discussed with reference to placental hormonal activity. It is concluded that serum progesterone is a poor index of placental function.
Reproductive EndocrinologyTestosterone and Breast CancerPlasma Hormone MeasurementHormonal Risk Factors
Multiple plasma-hormone concentrations were measured in sequential plasma-samples from six women with breast cancer and were compared to concentrations in six control women matched for age, years since menopause, and parity. All hormone concentrations in all the women studied were within normal limits. However, within the normal range the plasma-testosterone concentrations in each cancer patient were significantly higher than in each matched control.
Reproductive EndocrinologyLuteal Phase DefectLuteal Phase InsufficiencyHistologic Dating
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.
Progesterone metabolites and estriol were determined in urine and faeces collected daily from three pregnant women (33–37 weeks) before and during ampicillin administration (2 g/day orally).
Two of the three subjects showed marked changes in their faecal steroid excretion during the faecal progesterone-metabolite pattern changed from containing 69–79% unconjugated metabolites and 19–26% glucuronides under control conditions, to high steroid sulphate content (28–44%); the faecal elimination of 3β-hydroxy-5α-pregnan-20-one and 5α-pregnane-3β,20α-diol glucuronide all but ceased; two 16α-hydroxylated progesterone metabolites were detected in significant amounts in faeces during ampicillin administration but not under normal conditions. Steroid sulphate hydrolysis, epimerization of 3α,5αto 3β,5α-steroids and 16α-dehydroxylation are all well known actions of intestinal bacteria on biliary steroids. It thus seems clear that the changes found in the faecal progesterone metabolite pattern are due to the reduction of the intestinal flora by ampicillin.
Under control conditions the bulk of the faecal estriol was unconjugated. During ampicillin administration this excretion remained unchanged but in addition large quantities of conjugated estriol appeared in the faeces, apparently as a result of inhibition of bacterial deconjugation.
Ampicillin administration also caused decreased urinary excretion of estriol and pregnanediol glucuronide. It seems likely that these well documented effects of ampicillin on urinary steroid excretion are caused by an interruption of the enterohepatic circulation of steroids which results from the inhibition of intestinal steroid metabolism described above.
PregnancyChromosomal AbnormalitiesKaryotype AnalysisRetrospective and Prospective
Epidemiologic studies, retrospective and prospective, were done on 1500 abortions collected from 1966-1972. No secular or seasonal variations were observed. From the analysis of the relative frequencies of the different types of chromsome anomalies it is estimated that 1 out of every 2 conceptions has a chromosome anomaly. Maternal-age influence was found only for the autosomal trisomy group, mainly D and G trisomies. No effect of oral contraceptives were discovered. An increased frequency of chromosome anomalies occurred after ovulation-inducing therapy and after occupational exposure of the father to irradiation. No variations in the fertility rate and in the frequency of congenital malformations in births following abortions was noted. The incidence of recurring abortion was mainly influenced by the reproductive history of the couple before the karyotyped abortion.
Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.
Reproductive EndocrinologyPlasma Levels in PregnancyProgesterone SecretionRadioimmunoassay
The plasma concentration of progesterone (P) has been measured by radioimmunoassay in maternal peripheral vein (M.P.V.) at early pregnancy and in M.P.V. umbilical artery (U.A.) and umbilical vein (U.V.) at term pregnancy. In early preganacy marked hour-to-hour fluctuation of plasma progesterone was noted. At term pregnancy plasma P levels of U.V. were higher than those of U.A. and the umbilical venous arterial differences of plasma P did not differ between male and femal fetuses. Administration of hydrocortisone and ACTH to patients scheduled to undergo cesarean section had no effect on M.P.V., U.A., and U.V. plasma P concentration. On the basis of the differences between U.V. and U.A. plasma P concentrations and reported umbilical flow it was estimated that the secretion rate of P into the fetal circulation is approximately 23 mg. per 24 hr. and would amount to approximately 10 per cent of the reported total daily production rate of P at term pregnancy. The fraction of P which is unbound to the plasma proteins was estimeated by equilibrium dialysis at 37 degrees C. The per cent unbound P in M.P.V. plasma of pregnant patients at term was not different from that of nonpregnant patients but was 40 per cent lower than that in umbilical cord plasma (P LESS THAN 0.01), and the ratio between the concentrations of unbound P and estradiol in M.P.V. increased as pregnancy progressed. Plasma P in re-eclamptic patients who subsequently sustained intrauterine fetal death had no value in assessing placental function.
5alpha-Pregnane-3,20-dione and progesterone were isolated from a pregnancy plasma pool and were identified by using a combination of chromatographic techniques and mass spectrometry. Antibodies to progesterone were obtained in rabbits by immunization with progesterone-1alpha-carboxyethyl-thioether-thyroglobulin. The raised antibodies were of high affinity and one of them cross-reacted (137%) with 5alpha-pregnane-3,20-dione. This property was used to develop radioimmunoassays for measuring circulating levels of both progesterone and 5alpha-pregnane-3,20-dione in pregnancy plasma. The levels of both progesterone and 5alpha-pregnane-3,20-dione increase throughout pregnancy, but a highly significant increase is observed only after the 32nd week of gestation.
To develop a practical yet statistically valid means of indicating ovulation and adequacy of corpus luteum function concentrations of plasma progesterone (P) were measured daily during the luteal phase of 30 normal and abnormal menstrual cycles. During a normal cycle any 3 P measurements taken from 11 days before the first day of the following menses (M) to Day M-4 gave a total equal to or greater than 15 ng/ml. An abnormal cycle was considered one in which the total P (for 3 measurements) was less than 15 ng. Individual levels were often at 3 ng/ml in normal cycle and above 3 ng/ml in abnormal cycles indicating that the single P measurement proposed by Israel et. al. would not always be valid.
PregnancyGestational Trophoblastic DiseaseProgesterone in Abnormal PregnancyProgesterone
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.
Reproductive EndocrinologyPlasma Levels in PregnancyProgesterone MonitoringProgesterone Measurement
Lindberg BS et al., 1974·Acta Obstet Gynecol Scand
Plasma progesterone levels were estimated by competitive protein binding in 815 samples from healthy pregnant women with uncomplicated pregnancies. This series includes 32 patients who were followed serially throughout pregnancy. The mean level increased from 47 ng/ml in week 22 to 148 ng/ml in week 41. The spread was large. Individual patients showed very large variations between two consecutive weeks.
Diurnal variations were examined in 7 patients and short-time variations during one hour in 5 patients. Large but non-systematic variations were found in most cases. The maximal difference between values observed over a 24-hour-period was 123 ng/ml and during one hour 150 ng/ml.
Plasma progesterone levels were studied in 87 cases of toxemia of pregnancy, 6 cases of hypertension, 54 cases of Rh-immunization, 37 cases of diabetes and 5 cases of fetal growth retardation of unknown origin. The results indicate that no constant changes occur in plasma progesterone levels in these groups or in cases of impending fetal death.
As the normal limits are very wide, the intraindividual variations large, and the progesterone values in high risk pregnancies are inconclusive, plasma progesterone estimates during the latter part of pregnancy seem to be of limited value.
During human pregnancy large amounts of progesterone are produced by the placenta (1, 14). The production rate during the third trimester lies between 200 and 300 mg/day (9). Part of the progesterone produced is metabolized to pregnanediol and excreted in the urine as the 3-glucuronidate (16). The percentage of conversion to pregnanediol seems to vary with the stage of gestation and is influenced by pathological alterations in risk pregnancies (2, 5).
Large day to day variations in the urinary pregnanediol levels have been found. It is thus hardly surprising that the clinical value of serial determinations of urinary pregnanediol in late pregnancy has been limited.
Recently useful methods for the assay of progesterone in plasma have been developed and applied to physiological and clinical studies. A number of reports dealing with the prognostic value of progesterone determinations in complicated pregnancies have been published (8, 12, 17). The number of cases investigated is, however, small and the results are, in many respects, inconclusive. The aim of the present investigation was to determine the normal limits during the latter half of uncomplicated pregnancies, circadian and short-time variations, and to evaluate the prognostic value of progesterone determinations in plasma in high risk pregnancies.
General OB/GYNOrthostatic SyndromesBradykinin Metabolism
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. (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.
To describe normal relationships between the various plasma unconjugated estrogens and progesterone during the second half of human pregnancy, the plasma concentrations of progesterone, 17-hydroxyprogesterone (17-OHP), and unconjugated estrone (E1), estradiol (E2), and estriol (E3) were measured in 126-310 normal women. Progesterone and unconjugated E1, E2, and E3 increased gradually throughout later pregnancy; 17-OHP increased only after the thirty-third week. At term the mean value of progesterone was 9 times higher than that 17-OHP. Throughout pregnancy the mean value of E2 was higher than that of E1 or E3. During the second half of pregnancy the ratios of progesterone to estradiol and estriol and of estradiol to estriol remained unchanged, indicating no preferential increase of plasma concentration of maternal or fetal hormones.
A study was undertaken to determine whether solitary progesterone as says performed on serum samples obtained in the midluteal phase would provide the clinician with a convenient indicator that ovulation had occurred in that cycle. After a normal luteal-phase range was establish ed, single luteal-phase serum progesterone sampling was performed in 51 infertile women with regular menses and 35 oligomenorrheic women undergoing clomiphene citrate therapy. In the follicular phase of the cycle, progesterone levels were consistently less than 2 ng/ml. Between 11 and 4 days prior to the onset of menses in presumptively ovulatory cycles, serum progesterone levels were always 3 ng/ml or greater. Progesterone values in this range were always accompanied by a secretory endometrium and can be considered presumptive evidence of ovulation. This rapid, easily performed technique enables 1 technician to assay 30 or more samples for progesterone in a single working day and the results are available within 24 hours. This assay technique is easier to perform and more reproducible than a urinary pregnanediol assay, and it is expected that clinical laboratories will soon perform serum progesterone assays as a routine procedure.
Fertility AwarenessCervical Mucus AnalysisNuclear Magnetic ResonanceGlandular Secretions
Plasma levels of progesterone* were measured during normal human pregnancy by a sensitive and rapid competitive protein binding technique. During the first half of gestation 440 determinations in 321 women and in the second half of gestation, 209 determinations in 160 women were performed.
The average plasma level of progesterone in the 5th week of gestation was 24.8 ± 7.3 (s) ng/ml which is above the normal range of the luteal plateau of the menstrual cycle (10–20 ng/ml). Between the 5th and the 9th week of gestation the plasma concentration decreased significantly. From the 9th to the 32nd week of gestation the plasma level of progesterone increased from 16.7 ± 7.4 (s) to 125.2 ± 37.9 (s) ng/ml. During the last 8 weeks of gestation the plasma levels of progesterone did not show any significant rise. One woman was followed up from the day of ovulation to the 8th week of gestation. An increase in progesterone levels was observed about 10 days after ovulation. Morning samples of progesterone, which were taken before the 20th week of gestation, when the woman was still in bed, were found to be somewhat higher than levels found during the remainder of the day.
Progesterone concentrations in a few abnormal pregnancies are also reported.
A method to measure plasma progesterone by gas-liquid chromatography is presented. The procedure allows for the preparation of a plasma progesterone extract clean enough for accurate submicrogram quantification by gas-liquid chromatography. In a gas chromatograph equipped with a hydrogen flame detector, the instrument modifications and operating conditions as outlined make possible the measurement of 0.001 μg (1 ng.) of progesterone standard on a stable recorder base line. In biologic samples the sensitivity of the assay is in the order of 0.01 μg (10 ng.) of progesterone.
Gonadotrophins were prepared from human postmenopausal urine with the kaolin-acetone method and purified by adsorption of impurities on diethylamine ethyl cellulose (DEAE-C).
The last step, namely chromatography on the column of permutit, resulted in a significantly improved specific activity.
The immunoelectrophoresis showed that the purified HMG is not homogeneous and that the constituents are glycoproteins which migrate into the region α1, α2and β globulins.
DiagnosticsProgesterone MeasurementPlasma Levels in PregnancySteroid Hormone Assays
A modification of Short's method for the determination of plasma progesterone is described, which allows the estimation of 0.5–1.0 μg per sample. The reliability of the method is tested and plasma levels in cord and peripheral blood during pregnancy are reported.
Normal Pregnancy. Eleven pregnant women were studied at weekly intervals for periods ranging from 24 to 32 weeks. Three hundred and ten estimations were done in this group. An additional 68 assays were made in 40 patients at various stages of pregnancy, a total of 378 estimations being done in 51 patients, 189 in primigravidae and an equal number in multigravidae. Two of the patients in the first group had been attending the sterility clinic before becoming pregnant. None of the patients were suffering from hypertension …
Reproductive EndocrinologyFSH TherapyGonadotropin TreatmentEstrogen and Pregnanediol Excretion
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.
PREGNANEDIOL was first isolated by Marrian (1) in 1929, when he was engaged in thepurification of “oestrin” from pregnancy urine. He described the properties of this new “unidentified solid alcohol” very precisely, and his first analyses came surprisingly near to the right formula, C21H36O2,at a time when the greater part of steroid chemistry was still unknown. To-day, looking back on twenty years of chemical, biologic, and clinical research, it is comparatively easy to see the principal features of the interesting pattern which centers around the pregnanediol molecule. The first clue to the biologic significance of pregnanediol is given by its structural formula which shows a striking resemblance to that of the corpus luteum hormone, progesterone. Pregnanediol is nothing else but reduced progesterone, with all the double bonds of the latter saturated by hydrogen. Thus, the obvious inference would be that urinary pregnanediol is a metabolite of progesterone. This important fact is the reason why so many workers are interested in pregnanediol determinations.
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.