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Abstract Context Menopause, the permanent cessation of menses, reflects oocyte depletion and loss of gonadal steroids. It is preceded by a transition state, the perimenopause, which is characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns. The goal of this mini-review is to discuss the basic pathophysiology of the menopausal transition and the hormonal and nonhormonal management of clinicopathology attributed to it. Evidence Acquisition A Medline search of epidemiologic, population-based studies, and studies of reproductive physiology was conducted. A total of 758 publications were screened. Evidence Synthesis The reproductive hormonal milieu of the menopausal transition precipitates bothersome vasomotor symptoms, mood disruption, temporary cognitive dysfunction, genitourinary symptoms, and other disease processes that reduce the quality of life of affected women. The endocrine tumult of the menopause transition also exposes racial and socioeconomic disparities in the onset, severity, and frequency of symptoms. Hormone therapy (HT) treatment can be effective for perimenopausal symptoms but its use has been stymied by concerns about health risks observed in postmenopausal HT users who are older than 60 and/or women who have been postmenopausal for greater than 10 years. Conclusions The menopause transition is a disruptive process that can last for over a decade and causes symptoms in a majority of women. It is important for clinicians to recognize early signs and symptoms of the transition and be prepared to offer treatment to mitigate these symptoms. Many safe and effective options, including HT, are available.

Cosponsoring Associations:The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.Objective:To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA).Participants:The participants include an Endocrine Society–appointed task force of eight experts, a methodologist, and a medical writer.Evidence:This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.Consensus Process:One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline.Conclusions:FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof.

Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 × 10(-2) (95% CI, -8.27 × 10(-2) to -2.44 × 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 × 10(-2) (95% CI, -5.09 × 10(-2) to -9.34 × 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. ClinicalTrials.gov NCT00154180 and NCT00623311.

Vasomotor symptoms of menopause (VMS), otherwise known as hot flashes, can significantly impact women’s quality of life. Up to 87% of women report hot flashes during or after their menopause transition, and can last for a median duration of 7.4 years. The current mainstay of treatment and the most effective treatment for VMS is hormone therapy with estrogen. However, hormone therapy is not without risk, and the discovery of an effective nonhormonal treatment option with neurokinin B receptor antagonists for VMS provides an encouraging and potentially practice-changing treatment option for all women. This review will discuss the pathophysiology and mechanism of action, as well as review the current compounds in development targeting the neurokinin receptors.

The gut microbiome is an important contributor to human health, shaped by many endogenous and exogenous factors. The gut microbiome displays sexual dimorphism, suggesting influence of sex hormones, and also has been shown to change with aging. Yet, little is known regarding the influence of menopause - a pivotal event of reproductive aging in women - on the gut microbiome. Here, we summarize what is known regarding the interrelationships of female sex hormones and the gut microbiome, and review the available literature on menopause, female sex hormones, and the gut microbiome in humans. Taken together, research suggests that menopause is associated with lower gut microbiome diversity and a shift toward greater similarity to the male gut microbiome, however more research is needed in large study populations to identify replicable patterns in taxa impacted by menopause. Many gaps in knowledge remain, including the role the gut microbiome may play in menopause-related disease risks, and whether menopausal hormone therapy modifies menopause-related change in the gut microbiome. Given the modifiable nature of the gut microbiome, better understanding of its role in menopause-related health will be critical to identify novel opportunities for improvement of peri- and post-menopausal health and well-being.

This double-blind, multicenter, randomized trial showed that letrozole, as compared with clomiphene, was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. The polycystic ovary syndrome, which is diagnosed on the basis of hyperandrogenism, oligo-ovulation with associated oligomenorrhea, and polycystic ovaries on ultrasonography, affects 5 to 10% of reproductive-age women and is the most common cause of anovulatory infertility. 1 Although the syndrome is a complex reproductive–metabolic disorder, the hypothalamic–pituitary axis has been the target of first-line ovulation-induction therapy. Clomiphene citrate, a selective estrogen-receptor modulator that antagonizes the negative feedback of estrogen at the hypothalamus with a consequent increase in ovarian stimulation by endogenous gonadotropin, has been used for this indication for decades. Clomiphene has drawbacks, including its overall poor efficacy (only a . . .

This trial compared letrozole with gonadotropin or clomiphene in women with unexplained infertility. Letrozole resulted in a significantly lower frequency of multiple gestation, but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. Therapeutic options for couples with unexplained infertility include assisted reproductive technologies, such as in vitro fertilization (IVF) and embryo transfer, and empirical ovarian stimulation combined with intrauterine insemination. The high cost and limited insurance coverage of IVF in all but a few locales in the United States make it an unattainable option for most infertile couples. 1 Empirical ovarian stimulation has been thought to promote childbearing by increasing the number of ova ovulated, as well as possibly by enhancing implantation, placentation, or both through hormonal effects on the endometrium. 2 – 4 However, empirical ovarian stimulation (with clomiphene or particularly with gonadotropin) is . . .

Abstract Context Controversy exists regarding if and how body mass index (BMI) impacts antimüllerian hormone (AMH) in women with and without polycystic ovary syndrome (PCOS). Understanding the BMI-AMH relationship has critical implications for clinical interpretation of laboratory values and could illuminate underlying ovarian physiology. Objective To test the hypotheses that (1) BMI is associated with reduced AMH in PCOS and ovulatory controls (OVAs) and (2) the reduction in AMH is not accounted for by dilutional effects. Design/Setting Multicenter cohort. Participants Women aged 25 to 40 years from 2 clinical populations: 640 with PCOS, 921 women as OVAs. Main Outcome Measures Ovarian reserve indices: AMH, antral follicle count (AFC), and AMH to AFC ratio (AMH/AFC) as a marker of per-follicle AMH production. Results In both cohorts, increasing BMI and waist circumference were associated with reductions in AMH and AMH/AFC, after adjusting for age, race, smoking, and site in multivariate regression models. Increasing BMI was associated with reduced AFC in PCOS but not OVAs. Body surface area (BSA), which unlike BMI is strongly proportional to plasma volume, was added to investigate a potential dilutive effect of body size on AMH concentrations. After controlling for BSA, BMI retained independent associations with AMH in both cohorts; BSA no longer associated with AMH. Conclusions In an adjusted analysis, BMI, but not BSA, was associated with reduced AMH; these data do not support a role for hemodilution in mediating the relationship between increased body size and reduced AMH. Decreased AMH production by the follicle unit may be responsible for reduced AMH with increasing BMI.

Abstract Background A test that helps predict the time to the final menstrual period (FMP) has been sought for many years. Objective To assess the ability of antimullerian hormone (AMH) measurements to predictions the time to FMP. Design Prospective longitudinal cohort study. Setting The Study of Women’s Health Across the Nation. Participants and Measurements AMH and FSH were measured in 1537 pre- or early perimenopausal women, mean age 47.5 ± 2.6 years at baseline, then serially until 12 months of amenorrhea occurred. AMH was measured using a 2-site ELISA with a detection limit of 1.85 pg/mL. Main Outcome Measure Areas under the receiver operating curves (AUC) for AMH-based and FSH-based predictions of time to FMP, stratified by age. Probabilities that women would undergo their FMP in the next 12, 24, or 36 months across a range of AMH values were assessed. Results AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for AMH-based than FSH-based models. The probability that a woman with an AMH <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an AMH >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old. Conclusions AMH measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.