Associations of testosterone and sex hormone binding globulin with adipose tissue hormones in midlife women

Objective: Regulators of adipose tissue hormones remain incompletely understood, but may include sex hormones. As adipose tissue hormones have been shown to contribute to numerous metabolic and cardiovascular disorders, understanding their regulation in midlife women is of clinical importance. Therefore, we assessed the associations between testosterone (T) and sex hormone binding globulin (SHBG) with leptin, high molecular weight (HMW) adiponectin, and the soluble form of the leptin receptor (sOB‐R) in healthy midlife women. Design and Methods: Cross‐sectional analyses were performed using data from 1,881 midlife women (average age 52.6 (±2.7) years) attending the sixth Annual follow‐up visit of the multiethnic Study of Women's Health Across the Nation. Results: T was weakly negatively associated with both HMW adiponectin and sOB‐R ( r = −0.12 and r = −0.10, respectively; P < 0.001 for both), and positively associated with leptin ( r = 0.17; P < 0.001). SHBG was more strongly and positively associated with both HMW adiponectin and sOB‐R ( r = 0.29 and r = 0.24, respectively; P < 0.001 for both), and more strongly and negatively associated with leptin ( r = −0.27; P < 0.001). Adjustment for fat mass, insulin resistance, or waist circumference only partially diminished associations with HMW adiponectin and sOB‐R, but attenuated associations with leptin. In conclusion, in these midlife women, lower SHBG values, and to a lesser extent, higher T levels, were associated with lower, or less favorable, levels of adiponectin and sOB‐R, independent of fat mass. Conclusions: These data suggest that variation in these adipose hormones resulting from lower SHBG levels, and possibly, though less likely, greater androgenicity, may contribute to susceptibility for metabolic and cardiovascular outcomes during midlife in women.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97532/1/20256_ftp.pd

Melatonin Patterns and Levels During the Human Menstrual Cycle and After Menopause

Context: Melatonin may play a role in the regulation of the human menstrual cycle and may decline with menopause and/or aging. Objective: The objective of this work is to investigate the relations between melatonin and the menstrual cycle, menopause, and aging. Methods: This was a cross-sectional and longitudinal analysis of 20 participants from the Study of Women\u27s Health Across the Nation (SWAN) Daily Hormone Study (DHS). The outcome measure was first-morning urine assay of 6-sulfatoxymelatonin (aMT6s), a gauge of melatonin. For each participant, aMT6s was measured daily during one premenopausal cycle with evidence of luteal activity (ELA) and one postmenopausal collection with no evidence of luteal activity (NELA). Results: In addition to the organized patterns of hormone metabolites (estrone conjugates [E1c], and pregnanediol glucuronide [PdG]) and gonadotropins that characterized ovulatory menstrual cycles, there was a late luteal rise in aMT6s. In NELA collections, there was no periodicity of E1c, PdG, gonadotropins, or aMT6s. The strongest predictors of aMT6s levels were PdG values 11 to 12 days prior to aMT6s (beta = 1.46, P = .001 and beta = 1.44, P = .001, respectively). E1c and gonadotropins were not statistically significantly associated with aMT6s. Mean aMT6s in premenopause was 53.5 ng/mL, greater than the mean of 37.4 ng/mL in postmenopausal samples from the same women (P = .0002). Conclusions: This study confirms a late luteal melatonin rise, likely signaled by progesterone, which may influence menstrual cycle pacemaker control. Melatonin declined from premenopause to postmenopause. A high correlation between menopause transition stage and age precludes distinction between the influences of ovarian and chronological aging

Successful pregnancy after transient ovarian failure following treatment of symptomatic leiomyomata

Objective: To report a case of transient ovarian failure after treatment of symptomatic leiomyomata and review other iatrogenic causes of transient ovarian failure.Design: Case report and literature review.Setting: University-affiliated private practice.Patient(s): A 35-year-old woman with symptomatic leiomyomata.Intervention(s): Bilateral uterine artery embolization with subsequent abdominal myomectomy to treat unchanged regular heavy menstrual flow.Main Outcome Measure(s): Ovarian function.Result(s): Because medical therapy failed to control her menorrhagia, the patient proceeded with uterine artery embolization. She had persistent menorrhalgia after bilateral uterine artery embolization and underwent exploratory laparotomy and myomectomy. After surgery, she had amenorrhea, hot flushes, and elevated FSH levels for 3 months. Ovarian function recovered after a short course of oral contraceptives, and the patient conceived without assistance.Conclusion(s): Several interventions can affect normal ovarian function and can lead to permanent or transient ovarian failure. Possible causes of transient ovarian failure are radioactive iodine treatment, radiation, chemotherapy, pelvic surgery, stress, and uterine artery embolization. Before these interventions are applied, the possibility of ovarian failure and available preventive measures should be discussed with the patient. (C) 2002 by American Society for Reproductive Medicine

Comparison of SWAN and WISE Menopausal Status Classification Algorithms

Background: Classification of menopausal status is important for epidemiological and clinical studies as well as for clinicians treating midlife women. Most epidemiological studies, including the Study of Women's Health Across the Nation (SWAN), classify women based on self-reported bleeding history. Methods: The Women's Ischemia Syndrome Evaluation (WISE) study developed an algorithm using menstrual and reproductive history and serum hormone levels to reproduce the menopausal status classifications assigned by the WISE hormone committee. We applied that algorithm to women participating in SWAN and examined characteristics of women with concordant and discordant SWAN and WISE classifications. Results: Of the 3215 SWAN women with complete information at baseline (1995–1997), 2466 (76.7%) received concordant classifications (kappa = 0.52); at the fifth annual follow-up visit, of the 1623 women with complete information, 1154 (72.7%) received concordant classifications (kappa = 0.57). At each time point, we identified subgroups of women with discordant SWAN and WISE classifications. These subgroups, ordered by chronological age, showed increasing trends for menopausal symptoms and follicle-stimulating hormone (FSH) and a decreasing trend for estrogen (p < 0.001). Conclusions: The WISE algorithm is a useful tool for studies that have access to blood samples for hormone data unrelated to menstrual cycle phase, with or without an intact uterus, and no resources for adjudication. Future studies may want to combine aspects of the SWAN and WISE algorithms by adding hormonal measures to the series of bleeding questions in order to determine more precisely where women are in the perimenopausal continuum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63232/1/jwh.2006.15.1184.pd

Relation of cardiovascular risk factors in women approaching menopause to menstrual cycle characteristics and reproductive hormones in the follicular and luteal phases

CONTEXT: Menstrual cycle characteristics may be associated with cardiovascular disease (CVD) risk. OBJECTIVE: The objective of this study was to describe the relationships between menstrual cycle characteristics and daily reproductive hormone measures with CVD risk factors in middle-aged women. DESIGN AND SETTING: Cross-sectional associations were examined between CVD risk factors and urinary LH, FSH, estrone conjugates, and pregnanediol glucuronide (Pdg) measured across one menstrual cycle or 50 d. PARTICIPANTS: Menstruating women (n = 500) who were free from diabetes or past stroke or heart attack enrolled in the Daily Hormone Study-Study of Women\u27s Health across the Nation were studied. MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, hemostatic, and metabolic factors were measured. RESULTS: Few differences existed in risk factors between women with evidence of luteal activity and those with no evidence of luteal activity. Associations between elevated CVD risk factors and long cycle length were reduced substantially by age and BMI adjustments. Those with lower estrone conjugate and PdG averaged across the follicular phase had higher waist circumference, triglycerides, insulin, plasminogen activator inhibitor type-1, tissue type plasminogen activator-antigen, and factor VIIc levels in age- and BMI-adjusted analyses (P \u3c 0.05). CONCLUSIONS: In midlife menstruating women, a longer cycle length was related to CVD risk factors, in large part through their common association with BMI. More favorable levels of metabolic and hemostatic factors were associated with higher levels of follicular-phase estrogen, a pattern consistent with a more competent ovary, and higher levels of follicular-phase PdG, perhaps of adrenal origin. Metabolic and hemostatic factors may be sensitive to hormonal variation during the early perimenopausal transition

Efficacy and Safety of Fezolinetant in Moderate-to-Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT.

CONTEXT Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. OBJECTIVE We aimed to assess efficacy/safety of fezolinetant for treatment of moderate-to-severe VMS associated with menopause. METHODS In this double-blind, placebo-controlled, 12-week (W) phase 3 trial with a 40W active treatment extension (NCT04003142; SKYLIGHT 2) women aged 40-65 years with minimum average 7 moderate-to-severe VMS/day were randomized to 12 weeks' once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to W4 and W12 in VMS frequency and severity. Safety was also assessed. RESULTS Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, -1.82 (0.46; P < .001); 45 mg, -2.55 (0.46; P < .001); W12: 30 mg, -1.86 (0.55; P < .001); 45 mg, -2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, -0.15 (0.06; P<.05); 45 mg, -0.29 (0.06; P < .001); W12: 30 mg, -0.16 (0.08; P <.05); 45 mg, -0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1; maintained through W52. Serious TEAEs were infrequent; these were reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. CONCLUSIONS Daily fezolinetant 30 mg and 45 mg were efficacious and well-tolerated for treating moderate-to-severe VMS associated with menopause

Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome

Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation

Preconceptional antithyroid peroxidase antibodies, but not thyroid-stimulating hormone, are associated with decreased live birth rates in infertile women

OBJECTIVE: To study whether preconceptual thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) antibodies are associated with poor reproductive outcomes in infertile women. DESIGN: Secondary analysis of data from two multicenter, randomized, controlled trials conducted by the Reproductive Medicine Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Multivariable logistic regression analyses were performed to assess the association between preconceptual TSH levels and anti-TPO antibodies. SETTING: Not applicable. PATIENT(S): Serum samples from 1,468 infertile women were utilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative conception, clinical pregnancy, miscarriage, and live birth rates were calculated. RESULT(S): Conception, clinical pregnancy, miscarriage, and live birth rates did not differ between patients with TSH ≥2.5 mIU/L vs. TSH < 2.5 mIU/L. Women with anti-TPO antibodies had similar conception rates (33.3% vs. 36.3%) but higher miscarriage rates (43.9% vs. 25.3%) and lower live birth rates (17.1% vs. 25.4%) than those without anti-TPO antibodies. Adjusted, multivariable logistic regression models confirmed elevated odds of miscarriage (odds ratio 2.17, 95% confidence interval 1.12-4.22) and lower odds of live birth (oddr ratio 0.58, 95% confidence interval 0.35-0.96) in patients with anti-TPO antibodies. CONCLUSION(S): In infertile women, preconceptional TSH ≥2.5 mIU/L is not associated with adverse reproductive outcomes; however, anti-TPO antibodies are associated with increased risk of miscarriage and decreased probability of live birth. CLINICAL TRIAL REGISTRATION NUMBER: PPCOS II NCT00719186; AMIGOS NCT01044862

Characterization of Vascular Disease Risk in Postmenopausal Women and Its Association with Cognitive Performance

Objectives: While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables. Methods: A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ε4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification. Results: The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were “low-risk” and 38% “high-risk”. Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-ε4 was higher in the high-risk class compared with rates in the low-risk class. Conclusion: Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies