Management of menopause: a view towards prevention.

Women spend approximately one-third of their lives with menopause, which occurs around 50 years of age. It is now appreciated that several important metabolic and cardiovascular disease risks emerge during the menopausal transition. Many important conditions occur 10-15 years after menopause, including weight gain and obesity, metabolic syndrome, diabetes, osteoporosis, arthritis, cardiovascular disease, dementia, and cancer; therefore, the occurrence of menopause heralds an important opportunity to institute preventative strategies. These strategies will lead to improved quality of life and decreased mortality. Various strategies are presented for treating symptoms of menopause and diseases that are asymptomatic. Among several strategies is the use of hormone therapy, which has efficacy for symptoms and osteoporosis, and can improve metabolic and cardiovascular health. When instituted early, which is key, in younger postmenopausal women (under 60 years) oestrogen has been found to consistently decrease mortality with a favourable risk-benefit profile in low-risk women. Prospective data show that long-term therapy might not be required for this benefit.

Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois.

The North American Menopause Society (NAMS) organized the Workshop on Normal Ranges for Estradiol in Postmenopausal Women from September 23 to 24, 2019, in Chicago, Illinois. The aim of the workshop was to review existing analytical methodologies for measuring estradiol in postmenopausal women and to assess existing data and study cohorts of postmenopausal women for their suitability to establish normal postmenopausal ranges. The anticipated outcome of the workshop was to develop recommendations for establishing normal ranges generated with a standardized and certified assay that could be adopted by clinical and research communities. The attendees determined that the term reference range was a better descriptor than normal range for estradiol measurements in postmenopausal women. Twenty-eight speakers presented during the workshop.

Is There Really Increased Cardiovascular Morbidity in Women with Polycystic Ovary Syndrome?

For some time, it has been assumed that women with polycystic ovary syndrome (PCOS) are at increased risk of developing cardiovascular disease (CVD). This has largely been on the basis of having many risk factors, including abnormal lipid profile, insulin resistance, and markers of inflammation. However, despite having these and other risk factors, we argue here, in the view of the authors, that there is no credible evidence that there is greater CVD morbidity in all women with PCOS. We analyze the existing data and discuss that overall CVD risk decreases with age when more CVD events are likely to occur, and introduce the possibility that there may be some unknown inherent protective factor(s) in women with PCOS. It appears that only obesity and/or diabetes mellitus significantly increase CVD risk in women with PCOS, and that most of the data showing an increased rate of CVD are reported in younger women with PCOS where the absolute risk is small. It is also suggested that the CVD risk is predominantly in women with the "classic" features of PCOS, including menstrual irregularity and hyperandrogenism, particularly in the presence of obesity and diabetes, and should not be generalized to all women with PCOS using Rotterdam criteria. Strategies for a healthy lifestyle, which should be a lifelong goal for all women with PCOS, become particularly important to prevent obesity and diabetes.

Features of polycystic ovary syndrome (PCOS) in women with functional hypothalamic amenorrhea (FHA) may be reversible with recovery of menstrual function.

OBJECTIVE: Since features of polycystic ovary syndrome (PCOS) have been found to be prevalent in women with functional hypothalamic amenorrhea (FHA), we wished to determine what happens to these features after recovery of menstrual function in FHA Design: Prospective cohort study. Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. METHODS: Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. We measured serum estradiol, LH, FSH, testosterone, DHEAS, anti-Mullerian hormone (AMH), body mass index, and ovarian morphology on transvaginal ultrasound. RESULTS: At baseline, 12 of the 28 women (43%) had increased AMH (>4.7 ng/mL), and higher testosterone and larger ovaries compared to the other 16 women with normal AMH. One year after recovery of menstrual function, in the 12 women with increased AMH, serum AMH, testosterone and ovarian size decreased, while LH and estradiol increased. At one year, only one of the 12 women in the high AMH group developed clinical features of PCOS. CONCLUSIONS: In the majority of women with FHA who have PCOS-like features, these features may be due to the hypothalamic state and appear to be reversible. Few women may develop clinical PCOS after recovery.

Repeated doses of GnRH antagonist at midcycle in artificial frozen embryo transfer cycles may not affect pregnancy outcomes.

No significant differences in outcomes have been found between protocols of endometrial preparation for frozen embryo transfer (FET), though gonadotropin releasing hormone (GnRH) antagonists may have detrimental effects on the endometrium. We conducted a retrospective cohort noninferiority study at a single academic center of women receiving multiple doses of mid-cycle GnRH antagonist (GAnt) to those receiving GnRH agonist (GAg) to determine if there are detrimental effects of GnRH antagonists. 1047 FET cycles were identified, detailed data was available in 840 cycles: 610 GAg and 230 GAnt cycles. Patients undergoing GAnt cycles were older (40 ± 6.6 versus 37 ± 5.1 years, p < 0.0001), more often used donor oocyte (36% versus 18.6%, p < 0.0001), and more often exhibited diminished ovarian reserve (49.1% versus 36.2%, p = 0.0009). Clinical pregnancy rates (CPRs) per transfer and implantation rates (IRs) were similar for GAnt and GAg cycles. There was a trend for higher pregnancy and IRs with GAg cycles in younger women (CPR 38.8% versus 26.7%, p = 0.16; IR 36% versus 23.3%, p = 0.07). Stratifying by diagnosis, CPR and IR were similar in GAnt and GAg cycles. A GAnt protocol of endometrial preparation for FET is not inferior to a GAg protocol regardless of patient age, use of donor oocyte, or infertility diagnosis.

Hormone-replacement therapy: current thinking.

For several decades, the role of hormone-replacement therapy (HRT) has been debated. Early observational data on HRT showed many benefits, including a reduction in coronary heart disease (CHD) and mortality. More recently, randomized trials, including the Women's Health Initiative (WHI), studying mostly women many years after the the onset of menopause, showed no such benefit and, indeed, an increased risk of CHD and breast cancer, which led to an abrupt decrease in the use of HRT. Subsequent reanalyzes of data from the WHI with age stratification, newer randomized and observational data and several meta-analyses now consistently show reductions in CHD and mortality when HRT is initiated soon after menopause. HRT also significantly decreases the incidence of various symptoms of menopause and the risk of osteoporotic fractures, and improves quality of life. In younger healthy women (aged 50-60 years), the risk-benefit balance is positive for using HRT, with risks considered rare. As no validated primary prevention strategies are available for younger women (<60 years of age), other than lifestyle management, some consideration might be given to HRT as a prevention strategy as treatment can reduce CHD and all-cause mortality. Although HRT should be primarily oestrogen-based, no particular HRT regimen can be advocated.

Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause.

In the late 1980s, several observational studies and meta-analyses suggested that hormone replacement therapy (HRT) was beneficial for prevention of osteoporosis, coronary heart disease, dementia and decreased all-cause mortality. In 1992, the American College of Physicians recommended HRT for prevention of coronary disease. In the late 1990s and early 2000s, several randomized trials in older women suggested coronary harm and that the risks, including breast cancer, outweighed any benefit. HRT stopped being prescribed at that time, even for women who had severe symptoms of menopause. Subsequently, reanalyzes of the randomized trial data, using age stratification, as well as newer studies, and meta-analyses have been consistent in showing that younger women, 50-59 years or within 10 years of menopause, have decreased coronary disease and all-cause mortality; and did not have the perceived risks including breast cancer. These newer findings are consistent with the older observational data. It has also been reported that many women who abruptly stopped HRT had more risks, including more osteoporotic fractures. The current data confirm a "timing" hypothesis for benefits and risks of HRT, showing that younger have many benefits and few risks, particularly if therapy is predominantly focused on the estrogen component. We discuss these findings and put into perspective the potential risks of treatment, and suggest that we may have come full circle regarding the use of HRT. In so doing we propose that HRT should be considered as part of a general prevention strategy for women at the onset of menopause.

Increased anti-Mullerian hormone levels and ovarian size in a subgroup of women with functional hypothalamic amenorrhea: further identification of the link between polycystic ovary syndrome and functional hypothalamic amenorrhea.

BACKGROUND: Functional hypothalamic amenorrhea is a disorder characterized by cessation of menstrual cycles in the absence of organic disease. In most patients, it occurs in adult life after a stressful event and may be related to a condition of mild chronic energy deprivation. The endocrine pattern is characterized by low estrogen levels with an absent response to a progestogen challenge test and low-normal gonadotropin levels. A few studies have shown that some of these women may have some features of polycystic ovary syndrome; these features include an increased androgen response to gonadotropins, increased anti-Mullerian hormone levels, and altered ovarian morphology or increased ovarian size. These findings suggest a link between these 2 completely different disorders: functional hypothalamic amenorrhea and polycystic ovary syndrome. The importance of the possible coexistence of these disorders in some women is important for follow-up of these women and in their treatment if they desire to become pregnant. OBJECTIVE: To determine whether a subgroup of well-characterized women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. STUDY DESIGN: Retrospective analysis of women with functional hypothalamic amenorrhea. Forty consecutive patients and 28 normal age-matched control patients were studied. Blood was obtained for serum anti-Mullerian hormone, androgens, and other hormone levels and all women had ovarian ultrasonographic measurements. RESULTS: In the entire group of women with functional hypothalamic amenorrhea, anti-Mullerian hormone and ovarian volume were greater than in control patients. In 13 patients (32.5%), anti-Mullerian hormone was elevated (>4.7 ng/mL, levels consistent with polycystic ovary syndrome) and in this group, ovarian volume was significantly greater than in the remaining patients with functional hypothalamic amenorrhea. Four of the 13 women with functional hypothalamic amenorrhea who had elevated anti-Mullerian hormone levels (10%), also had ovarian volume ≥10 cc (consistent with polycystic ovarian syndrome). In these patients all studied androgens were in the upper normal range or slightly elevated despite low-normal gonadotropins; mean total testosterone was significantly greater than in the other patients with increased anti-Mullerian hormone values with normal ovarian size (P<.05.) Six other women with functional hypothalamic amenorrhea who had increased anti-Mullerian hormone also had isolated elevations of some androgen levels, but mean testosterone and ovarian size were normal. CONCLUSIONS: As many as 10% of women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. Because no signs or symptoms of this disorder were reported by these women before the appearance of the amenorrhea, it does not seem to be a coincidental relationship. The possibility that functional hypothalamic amenorrhea favors the appearance of polycystic ovary syndrome or more likely, that a mild (ovulatory) phenotype of polycystic ovary syndrome predisposes to the development of functional hypothalamic amenorrhea should be considered. Possible mechanisms are unclear and need to be investigated but may involve common vulnerabilities such as psychologic and mood disturbances.

Human embryos commonly form abnormal nuclei during development: a mechanism of DNA damage, embryonic aneuploidy, and developmental arrest.

STUDY QUESTION: What is the prevalence and developmental significance of morphologic nuclear abnormalities in human preimplantation embryos? SUMMARY ANSWER: Nuclear abnormalities are commonly found in human IVF embryos and are associated with DNA damage, aneuploidy, and decreased developmental potential. WHAT IS KNOWN ALREADY: Early human embryonic development is complicated by genomic errors that occur after fertilization. The appearance of extra-nuclear DNA, which has been observed in IVF, may be a result of such errors. However, the mechanism by which abnormal nuclei form and the impact on DNA integrity and embryonic development is not understood. STUDY DESIGN, SIZE, DURATION: Cryopreserved human cleavage-stage embryos (n = 150) and cryopreserved blastocysts (n = 105) from clinical IVF cycles performed between 1997 and 2008 were donated for research. Fresh embryos (n = 60) of poor quality that were slated for discard were also used. Immunohistochemical, microscopic and cytogenetic analyses at different developmental stages and morphologic grades were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos were fixed and stained for DNA, centromeres, mitotic activity and DNA damage and imaged using confocal microscopy. Rates of abnormal nuclear formation were compared between morphologically normal cleavage-stage embryos, morphologically normal blastocysts, and poor quality embryos. To control for clinical and IVF history of oocytes donors, and quality of frozen embryos within our sample, cleavage-stage embryos (n = 52) were thawed and fixed at different stages of development and then analyzed microscopically. Cleavage-stage embryos (n = 9) were thawed and all blastomeres (n = 62) were disaggregated, imaged and analyzed for karyotype. Correlations were made between microscopic and cytogenetic findings of individual blastomeres and whole embryos. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of microscopic nuclear abnormalities was lower in blastocysts (5%; 177/3737 cells) than in cleavage-stage embryos (16%, 103/640 blastomeres, P < 0.05) and highest in arrested embryos (65%; 44/68 blastomeres, P < 0.05). DNA damage was significantly higher in cells with microscopic nuclear abnormalities (γH2AX (phosphorylated (Ser139) histone H2A.X): 87.1%, 74/85; replication protein A: 72.9%, 62/85) relative to cells with normal nuclear morphology (γH2AX: 9.3%, 60/642; RPA: 5.6%, 36/642) (P < 0.05). Blastomeres containing nuclear abnormalities were strongly associated with aneuploidy (Fisher exact test, two-tailed, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: The embryos used were de-identified, and the clinical and IVF history was unknown. WIDER IMPLICATIONS OF THE FINDINGS: This study explores a mechanism of abnormal embryonic development post-fertilization. While most of the current data have explored abnormal meiotic chromosome segregation in oocytes as a primary mechanism of reproductive failure, abnormal nuclear formation during early mitotic cell division in IVF embryos also plays a significant role. The detection of abnormal nuclear formation may have clinical application in noninvasive embryo selection during IVF. STUDY FUNDING/COMPETING INTERESTS: The study was supported by Columbia University and the New York Stem Cell Foundation. Authors declare no competing interest.

Chemerin as a marker of body fat and insulin resistance in women with polycystic ovary syndrome.

Adipocytokines may alter normal metabolic function and play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). We prospectively evaluated a cohort of obese and non-obese women with PCOS and non-PCOS controls for both novel (chemerin and omentin-1) and established (leptin and adiponectin) adipokines. Compared with age-matched controls, non-obese women with PCOS had decreased serum omentin-1 (191.1 ng/ml versus 269.7 ng/ml, p = 0.0001), while serum chemerin was not significantly altered in women with PCOS (53.95 ng/ml versus 48.61 ng/ml, p = 0.11). The findings were similar in the entire group of women with PCOS. However, in women with PCOS, chemerin correlated with leptin (r = 0.508, p = 0.004), adiponectin (r = -0.36, p = 0.014), and the leptin/adiponectin (L/A) ratio (r = 0.605, p < 0.0001), while there were no such correlations with omentin-1. In women with PCOS, chemerin correlated with BMI (r = 0.317, p = 0.034), abdominal subcutaneous fat (r = 0.451, p = 0.0019), and insulin resistance (HOMA-IR, r = 0.428, p = 0.0034), while omentin-1 did not correlate with any parameter. These data suggest that chemerin although not significantly elevated in women with PCOS correlates with adiposity and insulin resistance, and it is the single best adipokine measured in this regard. Chemerin, through its inflammatory role as a chemo-attractant in adipose tissue, may be an important determinant of insulin resistance in PCOS.

Preliminary evidence that cinnamon improves menstrual cyclicity in women with polycystic ovary syndrome: a randomized controlled trial.

OBJECTIVE: To determine the effect of cinnamon on menstrual cyclicity and metabolic dysfunction in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: In a prospective, placebo controlled, double-blinded randomized trial, 45 women with PCOS were randomized (1:1) to receive cinnamon supplements (1.5 g/d) or placebo for 6 months. Menstrual cyclicity (average cycles/month) during the 6 months study period was compared between the 2 groups using the Mann-Whitney U test. Changes in menstrual cyclicity and insulin resistance between baseline and the 6 month study period were compared between the 2 groups using Wilcoxon signed rank tests. RESULTS: The 45 women were randomized, 26 women completed 3 months of the study, and 17 women completed the entire 6 months of the study. During the 6 month intervention, menstrual cycles were more frequent in patients taking cinnamon compared with patients taking placebo (median, 0.75; interquartile range, 0.5-0.83 vs median, 0.25; interquartile range, 0-0.54; P = .0085; Mann Whitney U). In patients taking cinnamon, menstrual cyclicity improved from baseline (+ 0.23 cycles/month 95% confidence interval, 0.099-0.36), yet did not improve for women taking placebo. (P = .0076, Wilcoxon signed rank). Samples (n = 5) of serum from the luteal phase in different patients within the cinnamon group were thawed and ovulatory progesterone levels (>3 ng/mL) confirmed. Luteal phase progesterone levels (>3 ng/mL, n = 5) confirmed ovulatory menses. Measures of insulin resistance or serum androgen levels did not change for either group. CONCLUSION: These preliminary data suggest that cinnamon supplementation improves menstrual cyclicity and may be an effective treatment option for some women with PCOS.

Where are we 10 years after the Women's Health Initiative?

The media attention surrounding the publication of the initial results of WHI in 2002 led to fear and confusion regarding the use of hormonal therapy (HT) after menopause. This led to a dramatic reduction in prescriptions for HT in the United States and around the world. Although in 2002 it was stated that the results pertained to all women receiving HT, subsequent studies from the Women's Health Initiative (WHI) and others clearly showed that younger women and those close to menopause had a very beneficial risk-to-benefit ratio. Indeed, the results showed similar protective effects for coronary disease and a reduction in mortality that had been shown in earlier observational studies, which had also focused on younger symptomatic women. In younger women, the increased number of cases of venous thrombosis and ischemic stroke was low, rendering them "rare" events using World Health Organization nomenclature. Breast cancer rates were also low and were found to be decreased with estrogen alone. In women receiving estrogen and progestogen for the first time in the WHI, breast cancer rates did not increase significantly for 7 years. Other data suggest that other regimens and the use of other progestogens may also be safer. It has been argued that in the 10 years since WHI, many women have been denied HT, including those with severe symptoms, and that this has significantly disadvantaged a generation of women. Some reports have also suggested an increased rate of osteoporotic fractures since the WHI. Therefore, the question is posed as to whether we have now come full circle in our understanding of the use of HT in younger women. Although it is appropriate to treat women with symptoms at the onset of menopause, because there is no proven therapy for primary prevention, in some women the use of HT for this role may at least be entertained.

Best practices of ASRM and ESHRE: a journey through reproductive medicine.

BACKGROUND: The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) are the two largest societies in the world whose members comprise the major experts and professionals working in the field of reproductive medicine and embryology. These societies have never before had a joint scientific meeting. METHOD(S): A 3-day meeting was planned and took place in March of 2012. The goal was to present and debate key topics, as well as modes of practice in reproductive medicine and to discuss recent developments in the field. RESULT(S): Presentations by members of ASRM and ESHRE were of three types: 'state of the art' lectures, 'back-to-back' presentations of two points of view and debates. CONCLUSION(S): For the first time, ASRM and ESHRE held a joint meeting where a special emphasis was given to presentations on the hottest topics in the field. Although different opinions and approaches sometimes exist on the two sides of the Atlantic, an appreciation and acceptance of these differences was evident, and there was more commonality than divergence of opinion.

Ovarian adipocytokines are associated with early in vitro human embryo development independent of the action of ovarian insulin.

PURPOSE: We aimed to characterize the association between levels of serum and follicular fluid (FF) adipocytokines, reflected by the leptin to adiponectin ratio (L:A ratio), and oocyte quality and in vitro embryo development in women undergoing assisted reproduction. We also aimed to assess whether follicular hormonal pathways mediate this interaction. METHODS: We prospectively collected FF from up to four individual preovulatory follicles (n = 76) and fasting sera from women (n = 31) without endocrinopathies undergoing in vitro fertilization (IVF) at a university-based center for assisted reproduction. Leptin, total adiponectin, insulin, insulin-like growth factor 1 (IGF-1), and ovarian steriods were measured using enzyme immunoassay. Oocyte maturity, fertilization, and embryo development were assessed. RESULTS: FF leptin was similar to serum levels while FF adiponectin was lower. FF leptin (27.10 ± 4.05 ng/mL) and the L:A ratio (11.48E-3 ± 2.57E-3) were related to FF insulin (R (2) = 0.370 and 0.419, p < 0.001) but not to ovarian steroids or IGF-1, whereas FF adiponectin ( 4.22 ± 0.52 ug/mL) correlated only with leptin (R (2) = -0.138, p = 0.001). Oocytes from a high FF L:A ratio environment were 81 % (RR 1.81 [95%CI 0.97-3.37]) more likely to undergo successful cleavage and 117 % (RR 2.17 [95 % CI 1.06-4.44]) more likely to obtain viable cleavage morphology compared to a low FF L:A ratio environment, even when adjusted for FF insulin, an independent predictor of cleavage. CONCLUSIONS: Certain adipocytokines, particularly the L:A ratio in the FF of the preovulatory follicle, are related to successful in vitro embryo development. This action may be independent of FF insulin.

A 20-year follow-up of young women with polycystic ovary syndrome.

OBJECTIVE: To determine whether hormonal, metabolic, and anthropomorphic parameters change over 20 years in women with polycystic ovary syndrome (PCOS). METHODS: One hundred ninety-three women with PCOS, aged 20-25 years, were diagnosed according to Rotterdam criteria, divided into four phenotypes (A-D), and followed at 5-year intervals for 20 years. Androgens, gonadotropins, insulin, glucose, body mass index, waist circumference, and ovarian volume were measured. RESULTS: At diagnosis, 57% had classic features (phenotype A), 9% had classic features without ovarian findings (phenotype B), 26% had the ovulatory phenotype (C), and 7% were nonhyperandrogenic (D). After 10 years, androgens decreased (P<.05); at 15 years, waist circumference increased (P<.05); at 20 years, ovarian volume decreased (P<.01). Serum luteinizing hormone and follicle-stimulating hormone decreased nonsignificantly and fasting insulin and quantitative insulin-sensitivity check index were unchanged. Eighty-five women (44%) were ovulatory at 20 years, and 18 women (8%) could no longer be diagnosed as having PCOS. CONCLUSION: After 20 years of follow-up in women with PCOS, androgens and ovarian volume decreased and there were more ovulatory cycles suggesting a milder disorder, whereas metabolic abnormalities persisted and waist circumference increased. LEVEL OF EVIDENCE: II.

Associations between markers of inflammation and physiological and pharmacological levels of circulating sex hormones in postmenopausal women.

OBJECTIVE: Hormone therapy has been shown to reduce markers of vascular inflammation in . C-reactive protein (CRP), a marker of generalized inflammation, is raised by oral estradiol therapy (ET). It is not known how sex hormone concentrations relate to the markers of inflammation in postmenopausal women taking or not taking hormone therapy. METHODS: This observational study includes postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial. Multiple measures of serum sex hormone and sex hormone-binding globulin(SHBG) levels from 107 postmenopausal women taking oral ET and 109 taking placebo for 2 years were correlated with markers of inflammation over the same time period using generalized estimating equations. RESULTS: Levels of soluble intercellular adhesion molecule-1 were significantly inversely associated with estrone(P = 0.05), total and free estradiol (P = 0.008 and 0.02, respectively), and SHBG (P = 0.03) only among oral ET users. Serum homocysteine levels were also inversely associated with estrone (P = 0.001) and total and free estradiol (P = 0.0006 and 0.0009, respectively) in ET-treated women only. No such associations were observed among women taking placebo. CRP was positively associated with estrogens and SHBG among women taking oral ET but inversely associated with SHBG among the placebo group. CONCLUSIONS: The inverse associations of estrogens with soluble intercellular adhesion molecule-1 and homocysteine support an anti-inflammatory property of estrogen, which was observed only at pharmacological levels in postmenopausal women. The positive associations between estrogens and CRP in the ET-treated women can be explained by the first-pass hepatic effect rather than a proinflammatory response.