The effect of improved metabolic syndrome parameters on live birth.

OBJECTIVE: To determine whether improvements in metabolic syndrome before ovarian stimulation with intrauterine insemination affects live birth among women with obesity and unexplained infertility after fertility treatment. DESIGN: Secondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE). SUBJECTS: Three hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention. INTERVENTION: The FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before ovarian stimulation with intrauterine insemination improved the live birth rate among women with obesity and unexplained infertility. Utilizing FIT-PLESE data, we compared the association between improved Metabolic Syndrome (by diagnostic criteria parameters and Metabolic Syndrome Z-scores) and live birth in a subset of women who have Metabolic Syndrome. MAIN OUTCOME MEASURES: Live birth by groups were compared using chi-square and Fisher's exact tests, and continuous variables were compared using Student's t-tests. Logistic regression was used to assess Metabolic Syndrome Z-score difference and live birth. RESULTS: 191 study participants were diagnosed with Metabolic Syndrome at baseline. Thirty of these women exhibited a decline in the number of metabolic syndrome parameters and 33 had decline in their Metabolic Syndrome Z-scores during the preconception lifestyle intervention phase. There were no statistically significant differences in live birth among those who exhibited decline in the number of metabolic parameters compared to those who had no decline (33.3% versus 19.9%; p=0.102). Those who improved their Metabolic Syndrome Z-score had a live birth rate of 17.2% compared to 20.8% of those whose Metabolic Syndrome Z-scores were worsened or unchanged (p=0.055). CONCLUSION: Analysis of the FIT-PLESE data was unable to demonstrate that women with improvement in Metabolic Syndrome prior to fertility treatment, as shown by decreased number of metabolic parameters and/or improved Metabolic Syndrome Z-scores, benefit with improved fertility and live birth outcomes.

Hypertension, Cardiovascular Risk Factors, and Uterine Fibroid Diagnosis in Midlife.

Importance: Fibroids are benign neoplasms associated with severe gynecologic morbidity. There are no strategies to prevent fibroid development. Objective: To examine associations of hypertension, antihypertensive treatment, anthropometry, and blood biomarkers with incidence of reported fibroid diagnosis in midlife. Design, Setting, and Participants: The Study of Women's Health Across the Nation is a prospective, multisite cohort study in the US. Participants were followed-up from enrollment (1996-1997) through 13 semiannual visits (1998-2013). Participants had a menstrual period in the last 3 months, were not pregnant or lactating, were aged 42 to 52 years, were not using hormones, and had a uterus and at least 1 ovary. Participants with prior fibroid diagnoses were excluded. Data analysis was performed from November 2022 to February 2024. Exposures: Blood pressure, anthropometry, biomarkers (cholesterol, triglycerides, and C-reactive protein), and self-reported antihypertensive treatment at baseline and follow-up visits were measured. Hypertension status (new-onset, preexisting, or never [reference]) and hypertension treatment (untreated, treated, or no hypertension [reference]) were categorized. Main Outcomes and Measures: Participants reported fibroid diagnosis at each visit. Discrete-time survival models estimated hazard ratios (HRs) and 95% CIs for associations of time-varying hypertension status, antihypertensive treatment, anthropometry, and biomarkers with incident reported fibroid diagnoses. Results: Among 2570 participants without a history of diagnosed fibroids (median [IQR] age at screening, 45 [43-48] years; 1079 [42.1%] college educated), 526 (20%) reported a new fibroid diagnosis during follow-up. Risk varied by category of hypertension treatment: compared with those with no hypertension, participants with untreated hypertension had a 19% greater risk of newly diagnosed fibroids (HR, 1.19; 95% CI, 0.91-1.57), whereas those with treated hypertension had a 20% lower risk (HR, 0.80; 95% CI, 0.56-1.15). Among eligible participants with hypertension, those taking antihypertensive treatment had a 37% lower risk of newly diagnosed fibroids (HR, 0.63; 95% CI, 0.38-1.05). Risk also varied by hypertension status: compared with never-hypertensive participants, participants with new-onset hypertension had 45% greater risk of newly diagnosed fibroids (HR, 1.45; 95% CI, 0.96-2.20). Anthropometric factors and blood biomarkers were not associated with fibroid risk. Conclusions and Relevance: Participants with untreated and new-onset hypertension had increased risk of newly diagnosed fibroids, whereas those taking antihypertensive treatment had lower risk, suggesting that blood pressure control may provide new strategies for fibroid prevention.

Acceptability and Feasibility of Initiating a Low Fat Eating Plan in Reproductive Aged Women with Obesity.

Adverse effects of obesity on reproduction are believed in part due to diet related factors leading to hyperlipidemia and hyperinsulinemia. It is unknown whether administration of a low fat eating plan, regardless of weight loss, will improve reproductive axis function in women with obesity. To develop an acceptable and feasible low fat eating plan for a diverse group of reproductive aged women with obesity. Focus groups to determine preferences and barriers to a planned dietary intervention providing very low fat (22% daily calories from fat) eucaloric food to control fat exposure, but not cause weight loss. Logistics of the intervention and monitoring over three menstrual cycles were discussed. Eighteen women enrolled into 4 different focus groups both live and video, 2 at the University of Colorado and 2 at the Morehouse School of Medicine. All participants expressed interest in implementing a low fat dietary intervention and were further interested in instruction on how to maintain healthy eating habits for future fertility. Provision of ethnically appropriate foods, social support to avoid lapses, and tasty alternatives to high fat foods were considered ideal aspects of a feasible intervention. Incentives and graduated compensation for adherence were considered desirable features. Women with obesity are interested in implementing dietary interventions that may improve their health and fertility. Given the diversity of responses based upon the demographics of our sample, it is important to assess geographical and cultural preferences prior to implementing of a dietary strategy.

Cost-effectiveness analysis of expectant versus active management for treatment of persistent pregnancies of unknown location.

BACKGROUND: Persistent pregnancies of unknown location (PUL) are defined by abnormally trending serum human chorionic gonadotropin with nondiagnostic ultrasound. There is no consensus on optimal management. OBJECTIVE: This study was designed to assess the cost-effectiveness between three primary management strategies for persistent pregnancies of unknown location: (1) expectant management, (2) empirical two-dose methotrexate, (3) uterine evacuation followed by methotrexate, if indicated. STUDY DESIGN: We conducted a prospective economic evaluation performed concurrently with the Expectant versus Active Management for Treatment of Persistent Pregnancies of Unknown Location (ACT or NOT) multicenter randomized trial conducted from July 2014 to June 2019. Participants were randomized 1:1:1 to expectant management, two-dose methotrexate, or uterine evacuation. The analysis was from the healthcare sector perspective with a 6-week time horizon following randomization. Costs were expressed in 2018 U.S. dollars. Effectiveness was measured in quality-adjusted life-years (QALYs) and the rate of salpingectomy. Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves were generated. Sensitivity analyses were performed to assess the robustness of the analysis. RESULTS: Methotrexate had the lowest mean cost, $875, followed by expectant management $1085, and uterine evacuation $1902 (p=0.001). Expectant management had the highest mean QALY (0.1043) followed by methotrexate (0.1031) and uterine evacuation (0.0992) (p=0.0001). Salpingectomy rate was higher for expectant management compared to methotrexate (9.4% vs 1.2%; p=0.02) and expectant management compared to uterine evacuation (9.4% vs 8.1%; p=0.04). Uterine evacuation, with highest costs and lowest QALYs, was dominated by both expectant management and methotrexate. In the base case analysis, expectant management was not cost-effective compared to methotrexate at a willingness-to-pay of $150,000/QALY given an ICER of $175,083/QALY gained (95% CI, -$1,666,825-2,676,375). Threshold analysis demonstrated methotrexate administration would have to cost $214 (an increase of $16 or 8%) to favor expectant management. Expectant management would also be favorable in lower risk patient populations with rates of laparoscopic surgical management for ectopic pregnancy not exceeding 4% of pregnancies of unknown location. Based on the cost-effectiveness acceptability curves, the probability expectant management was cost-effective compared to methotrexate at a willingness-to-pay of $150,000/QALY gained was 50%. Results were dependent on the cost of surgical intervention, and the expected rate of methotrexate failure. CONCLUSION: Management of pregnancies of unknown location with a two-dose methotrexate protocol may be cost-effective compared to expectant management and uterine evacuation. While uterine evacuation was dominated, expectant management versus methotrexate results were sensitive to modest changes in treatment costs of both methotrexate and surgical management.

Fezolinetant treatment of moderate-to-severe vasomotor symptoms due to menopause: effect of intrinsic and extrinsic factors in two phase 3 studies (SKYLIGHT 1 and 2).

OBJECTIVE: This study aimed to assess the efficacy of the neurokinin 3 receptor antagonist, fezolinetant, according to several intrinsic (individual related) and extrinsic (external influence) factors that may influence the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) using pooled 12-week data from SKYLIGHT 1 and 2. METHODS: SKYLIGHT 1 and 2 were two phase 3, randomized, double-blind studies conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg. After 12 weeks, placebo participants were rerandomized to receive fezolinetant 30 mg or 45 mg, whereas those receiving fezolinetant continued on the same dose. Change in VMS frequency from baseline to week 12 was used to assess efficacy according to several intrinsic and extrinsic factors. Overall efficacy and safety were also investigated. RESULTS: Overall, 1,022 individuals were included. Fezolinetant was efficacious in reducing VMS frequency across all intrinsic and extrinsic factors. Efficacy was most notable for participants who self-identify as Black (least squares mean difference for fezolinetant 45 mg versus placebo, -3.67; 95% CI, -5.32 to -2.01), current smokers (-3.48; -5.19 to -1.77), and current alcohol users (-3.48; -4.42 to -2.54). Overall efficacy was -2.51 (95% CI, -3.20 to -1.82) for fezolinetant 45 mg versus placebo. Similar findings were observed for the fezolinetant 30 mg dose. Comparable incidences of treatment-emergent adverse events were observed for placebo (132 of 342 individuals [38.6%]), fezolinetant 30 mg (132 of 340 individuals [38.8%]), and fezolinetant 45 mg (135 of 340 individuals [39.7%]). CONCLUSIONS: None of the intrinsic and extrinsic factors analyzed substantially reduced the efficacy response to fezolinetant in SKYLIGHT 1 and 2. These data provide additional confidence for using fezolinetant in a diverse population of individuals with VMS.

Effectiveness of preconception weight loss interventions on fertility in women: a systematic review and meta-analysis.

IMPORTANCE: Weight loss before conception is recommended for women with overweight or obesity to improve fertility outcomes, but evidence supporting this recommendation is mixed. OBJECTIVE: To examine the effectiveness of weight loss interventions using lifestyle modification and/or medication in women with overweight or obesity on pregnancy, live birth, and miscarriage. DATA SOURCES: An electronic search of MEDLINE, Embase, Cochrane Library, including Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature was conducted through July 6, 2022, via Wiley. STUDY SELECTION AND SYNTHESIS: Randomized controlled trials examining weight loss interventions through lifestyle and/or medication in women with overweight or obesity planning pregnancy were included. Random-effects meta-analysis was conducted, reporting the risk ratio (RR) for each outcome. Subgroup analyses were conducted by intervention type, type of control group, fertility treatment, intervention length, and body mass index (BMI). MAIN OUTCOME(S): Clinical pregnancy, live birth, and miscarriage events. RESULT(S): A narrative review and meta-analysis were possible for 16 studies for pregnancy (n = 3,588), 13 for live birth (n = 3,329), and 11 for miscarriage (n = 3,248). Women randomized and exposed to a weight loss intervention were more likely to become pregnant (RR = 1.24, 95% CI 1.07-1.44; I2 = 59%) but not to have live birth (RR = 1.19, 95% CI 0.97-1.45; I2 = 69%) or miscarriage (RR = 1.17, 95% CI 0.79-1.74; I2 = 31%) compared with women in control groups. Subgroup analyses revealed women randomized to weight loss interventions lasting 12 weeks or fewer (n = 9, RR = 1.43; 95% CI 1.13-1.83) and women with a BMI ≥ 35 kg/m2 (n = 7, RR = 1.54; 95% CI, 1.18-2.02) were more likely to become pregnant compared with women in the control groups. Miscarriage was higher in intervention groups who underwent fertility treatment (n = 8, RR 1.45; 95% CI 1.07-1.96). CONCLUSION(S): Pregnancy rates were higher in women undergoing preconception weight loss interventions with no impact on live birth or miscarriage rates. Findings do not support one-size-fits-all recommendation for weight loss through lifestyle modification and/or medication in women with overweight or obesity immediately before conception to improve live birth or miscarriage outcomes.

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review.

Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials.

OBJECTIVE: To assess the effect of fezolinetant treatment on health-related quality of life using pooled data from SKYLIGHT 1 and 2 studies. DESIGN: Prespecified pooled analysis. SETTING: USA, Canada, Europe; 2019-2021. POPULATION: 1022 women aged ≥40 to ≤65 years with moderate-to-severe vasomotor symptoms (VMS; minimum average seven hot flushes/day), seeking treatment for VMS. METHODS: Women were randomised to 12-week double-blind treatment with once-daily placebo or fezolinetant 30 or 45 mg. Completers entered a 40-week, active extension (those receiving fezolinetant continued that dose; those receiving placebo re-randomised to fezolinetant received 30 or 45 mg). MAIN OUTCOME MEASURES: Mean changes from baseline to weeks 4 and 12 on Menopause-Specific Quality of Life (MENQoL) total and domain scores, Work Productivity and Activity Impairment questionnaire specific to VMS (WPAI-VMS) domain scores, Patient Global Impression of Change in VMS (PGI-C VMS); percentages achieving PGI-C VMS of 'much better' (PGI-C VMS responders). Mean reduction was estimated using mixed model repeated measures analysis of covariance. RESULTS: Fezolinetant 45 mg mean reduction over placebo in MENQoL total score was -0.57 (95% confidence interval [CI] -0.75 to -0.39) at week 4 and -0.47 (95% CI -0.66 to -0.28) at week 12. Reductions were similar for 30 mg. MENQoL domain scores were also reduced and WPAI-VMS scores improved. Twice as many women receiving fezolinetant reported VMS were 'much better' than placebo based on PGI-C VMS assessment. CONCLUSIONS: Fezolinetant treatment was associated with improvement in overall QoL, measured by MENQoL, and work productivity, measured by WPAI-VMS. A high proportion receiving fezolinetant felt VMS were 'much better' based on PGI-C VMS responder analysis.

Association of duration of embryo culture with risk of large for gestational age delivery in cryopreserved embryo transfer cycles.

OBJECTIVE: To examine the relationship between the day of embryo cryopreservation and large for gestational age (LGA) infants in women undergoing frozen embryo transfers (FETs) after cryopreservation on days 2-7 after fertilization and to compare the risk of the day of embryo cryopreservation to other possible risk factors of LGA after FET cycles. DESIGN: Retrospective cohort study. SETTING: Society of Assisted Reproduction Clinical Outcomes Reporting System. PATIENTS: Women undergoing FET cycles. INTERVENTION: Day of cryopreservation. MAIN OUTCOME MEASURE: Singleton LGA infant. RESULTS: A total of 33,030 (18.2%) FET cycles in the study group (n = 181,592) resulted in LGA infants during the study period of 2014-2019. There was an increase in LGA risk when cryopreservation was performed from day 2 (13.7%) to days 3-7 (14.4%, 15.0%, 18.2%, 18.5%, and 18.9%). In the log-binomial model, the risk increased compared with days 2-3 combined when cryopreservation was performed on days 5-7 (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.22-1.44 for day 5, aRR 1.34, 95% CI 1.23-1.46 for day 6, and aRR 1.42, 95% CI 1.25-1.61 for day 7). Other factors most associated with LGA risk in the log-binomial model were preterm parity of >3 compared with 0 (aRR 1.82, 95% CI 1.24-2.69) and body mass index (BMI) of >35 kg/m2 compared with normal weight (aRR 1.94, 95% CI 1.88-2.01). Increasing gravity, parity, BMI, number of oocytes, and embryo grade were also associated with LGA in this model. Asian, Black, Hispanic, and combined Hawaiian and Pacific Islander were protective factors in the model compared with White patients. Low BMI (<18.5 kg/m2) was also considered a protective factor in the model compared with normal BMI. CONCLUSION: Duration of embryo culture was associated with an increased risk of LGA in this study cohort when controlling for known confounders such as maternal BMI and parity. This study sheds new light on the possible link between FET and LGA infants.

The Fit After Baby randomized controlled trial: An mHealth postpartum lifestyle intervention for women with elevated cardiometabolic risk.

BACKGROUND: Postpartum women with overweight/obesity and a history of adverse pregnancy outcomes are at elevated risk for cardiometabolic disease. Postpartum weight loss and lifestyle changes can decrease these risks, yet traditional face-to-face interventions often fail. We adapted the Diabetes Prevention Program into a theory-based mobile health (mHealth) program called Fit After Baby (FAB) and tested FAB in a randomized controlled trial. METHODS: The FAB program provided 12 weeks of daily evidence-based content, facilitated tracking of weight, diet, and activity, and included weekly coaching and gamification with points and rewards. We randomized women at 6 weeks postpartum 2:1 to FAB or to the publicly available Text4baby (T4B) app (active control). We measured weight and administered behavioral questionnaires at 6 weeks, and 6 and 12 months postpartum, and collected app user data. RESULTS: 81 eligible women participated (77% White, 2% Asian, 15% Black, with 23% Hispanic), mean baseline BMI 32±5 kg/m2 and age 31±5 years. FAB participants logged into the app a median of 51/84 (IQR 25,71) days, wore activity trackers 66/84 (IQR 43,84) days, logged weight 17 times (IQR 11,24), and did coach check-ins 5.5/12 (IQR 4,9) weeks. The COVID-19 pandemic interrupted data collection for the primary 12-month endpoint, and impacted diet, physical activity, and body weight for many participants. At 12 months postpartum women in the FAB group lost 2.8 kg [95% CI -4.2,-1.4] from baseline compared to a loss of 1.8 kg [95% CI -3.8,+0.3] in the T4B group (p = 0.42 for the difference between groups). In 60 women who reached 12 months postpartum before the onset of the COVID-19 pandemic, women randomized to FAB lost 4.3 kg [95% CI -6.0,-2.6] compared to loss in the control group of 1.3 kg [95% CI -3.7,+1.1] (p = 0.0451 for the difference between groups). CONCLUSIONS: There were no significant differences between groups for postpartum weight loss for the entire study population. Among those unaffected by the COVID pandemic, women randomized to the FAB program lost significantly more weight than those randomized to the T4B program. The mHealth FAB program demonstrated a substantial level of engagement. Given the scalability and potential public health impact of the FAB program, the efficacy for decreasing cardiometabolic risk by increasing postpartum weight loss should be tested in a larger trial.

Mathematical recapitulation of the end stages of human ovarian aging.

Ovarian aging in women can be described as highly unpredictable within individuals but predictable across large populations. We showed previously that modeling an individual woman's ovarian reserve of primordial follicles using mathematical random walks replicates the natural pattern of growing follicles exiting the reserve. Compiling many simulations yields the observed population distribution of the age at natural menopause (ANM). Here, we have probed how stochastic control of primordial follicle loss might relate to the distribution of the preceding menopausal transition (MT), when women begin to experience menstrual cycle irregularity. We show that identical random walk model conditions produce both the reported MT distribution and the ANM distribution when thresholds are set for growing follicle availability. The MT and ANM are shown to correspond to gaps when primordial follicles fail to grow for 7 and 12 days, respectively. Modeling growing follicle supply is shown to precisely recapitulate epidemiological data and provides quantitative criteria for the MT and ANM in humans.

A high-fat eucaloric diet induces reprometabolic syndrome of obesity in normal weight women.

We examined the effects of 1 month of a eucaloric, high-fat (48% of calories) diet (HFD) on gonadotropin secretion in normal-weight women to interrogate the role of free fatty acids and insulin in mediating the relative hypogonadotropic hypogonadism of obesity. Eighteen eumenorrheic women (body mass index [BMI] 18-25 kg/m2) were studied in the early follicular phase of the menstrual cycle before and after exposure to an HFD with frequent blood sampling for luteinizing hormone (LH) and follicle-stimulating hormone (FSH), followed by an assessment of pituitary sensitivity to gonadotropin-releasing hormone (GnRH). Mass spectrometry-based plasma metabolomic analysis was also performed. Paired testing and time-series analysis were performed as appropriate. Mean endogenous LH (unstimulated) was significantly decreased after the HFD (4.3 ± 1.0 vs. 3.8 ± 1.0, P < 0.01); mean unstimulated FSH was not changed. Both LH (10.1 ± 1.0 vs. 7.2 ± 1.0, P < 0.01) and FSH (9.5 ± 1.0 vs. 8.8 ± 1.0, P < 0.01) responses to 75 ng/kg of GnRH were reduced after the HFD. Mean LH pulse amplitude and LH interpulse interval were unaffected by the dietary exposure. Eucaloric HFD exposure did not cause weight change. Plasma metabolomics confirmed adherence with elevation of fasting free fatty acids (especially long-chain mono-, poly-, and highly unsaturated fatty acids) by the last day of the HFD. One-month exposure to an HFD successfully induced key reproductive and metabolic features of reprometabolic syndrome in normal-weight women. These data suggest that dietary factors may underlie the gonadotrope compromise seen in obesity-related subfertility and therapeutic dietary interventions, independent of weight loss, may be possible.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Sex Hormones, the Stool Microbiome, and Subclinical Atherosclerosis in Women With and Without HIV.

CONTEXT: Cardioprotective roles of endogenous estrogens may be particularly important in women with HIV, who have reduced estrogen exposure and elevated cardiovascular disease risk. The gut microbiome metabolically interacts with sex hormones, but little is known regarding possible impact on cardiovascular risk. OBJECTIVE: To analyze potential interplay of sex hormones and gut microbiome in cardiovascular risk. METHODS: Among 197 postmenopausal women in the Women's Interagency HIV Study, we measured 15 sex hormones in serum and assessed the gut microbiome in stool. Presence of carotid artery plaque was determined (B-mode ultrasound) in a subset (n = 134). We examined associations of (i) sex hormones and stool microbiome, (ii) sex hormones and plaque, and (iii) sex hormone-related stool microbiota and plaque, adjusting for potential confounders. RESULTS: Participant median age was 58 years and the majority were living with HIV (81%). Sex hormones (estrogens, androgens, and adrenal precursors) were associated with stool microbiome diversity and specific species, similarly in women with and without HIV. Estrogens were associated with higher diversity, higher abundance of species from Alistipes, Collinsella, Erysipelotrichia, and Clostridia, and higher abundance of microbial ß-glucuronidase and aryl-sulfatase orthologs, which are involved in hormone metabolism. Several hormones were associated with lower odds of carotid artery plaque, including dihydrotestosterone, 3α-diol-17G, estradiol, and estrone. Exploratory mediation analysis suggested that estrone-related species, particularly from Collinsella, may mediate the protective association of estrone with plaque. CONCLUSION: Serum sex hormones are significant predictors of stool microbiome diversity and composition. The gut microbiome may play a role in estrogen-related cardiovascular protection.

Menopause-Biology, consequences, supportive care, and therapeutic options.

Menopause is the cessation of ovarian function, with loss of reproductive hormone production and irreversible loss of fertility. It is a natural part of reproductive aging. The physiology of the menopause is complex and incompletely understood. Globally, menopause occurs around the age of 49 years, with geographic and ethnic variation. The hormonal changes of the menopause transition may result in both symptoms and long-term systemic effects, predominantly adverse effects on cardiometabolic and musculoskeletal health. The most effective treatment for bothersome menopausal symptoms is evidence-based, menopausal hormone therapy (MHT), which reduces bone loss and may have cardiometabolic benefits. Evidence-based non-hormonal interventions are also available for symptom relief. Treatment should be individualized with shared decision-making. Most MHT regimens are not regulator approved for perimenopausal women. Studies that include perimenopausal women are needed to determine the efficacy and safety of treatment options. Further research is crucial to improve menopause care, along with research to guide policy and clinical practice.

Moderate and increased physical activity is not detrimental to live birth rates among women with unexplained infertility and obesity.

Objective: To determine if moderate physical activity is associated with live birth rates in women with unexplained infertility and obesity. Design: Secondary analysis of the Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial. Setting: US fertility centers, 2015-2019. Patients: A total of 379 women participated in Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial, a lifestyle modification program with increased physical activity (phase I, 16 weeks) and up to three cycles of clomiphene citrate treatment and intrauterine insemination (phase II). Interventions: Participants were instructed to add 500 steps/day weekly until a maximum of 10,000 steps/day was reached and maintained. Participants were stratified as active (top third, N = 125) and less active (lower third, N = 125) on the basis of the average number of steps per day recorded using a FitBit activity tracker. Main Outcome Measures: Live birth rate. Results: Active participants were more physically active at the time of enrollment than less active participants (average baseline steps per day, 8,708 [7,079-10,000] vs. 4,695 [3,844-5,811]; P ≤ 0.001) and were more likely to reach 10,000 steps/day than less active participants (average steps per day, 10,526 [9,481-11,810] vs. 6,442 [4,644-7,747]; P ≤ 0.001), although both groups increased their average steps per day by a similar amount (1,818 vs.1,747; P = 0.57). There was no difference in live birth rates (24/125 [19.2%] vs. 25/125 [20%]; P = 0.87) between active and less active participants nor were there differences in clinical pregnancy rates (P = 0.45) or miscarriage rates (P = 0.49) between the two groups. Conclusions: Active participants were more likely to achieve the physical activity goal, although this was not associated with benefit or harm with respect to live birth. Clinical Trial Registration Number: ClinicalTrials.gov (NCT02432209), first posted: May 4, 2015.