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

BACKGROUND: Persistent pregnancies of unknown location are defined by abnormally trending serum human chorionic gonadotropin with nondiagnostic ultrasound. There is no consensus on optimal management. OBJECTIVE: This study aimed to assess the cost-effectiveness of 3 primary management strategies for persistent pregnancies of unknown location: (1) expectant management, (2) empirical 2-dose methotrexate, and (3) uterine evacuation followed by methotrexate, if indicated. STUDY DESIGN: This was a prospective economic evaluation performed concurrently with the Expectant versus Active Management for Treatment of Persistent Pregnancies of Unknown Location multicenter randomized trial that was conducted from July 2014 to June 2019. Participants were randomized 1:1:1 to expectant management, 2-dose methotrexate, or uterine evacuation. The analysis was from the healthcare sector perspective with a 6-week time horizon after randomization. Costs were expressed in 2018 US dollars. Effectiveness was measured in quality-adjusted life years and the rate of salpingectomy. Incremental cost-effectiveness ratios 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=.001). Expectant management had the highest mean quality-adjusted life years (0.1043), followed by methotrexate (0.1031) and uterine evacuation (0.0992) (P=.0001). The salpingectomy rate was higher for expectant management than for methotrexate (9.4% vs 1.2%, respectively; P=.02) and for expectant management than for uterine evacuation (9.4% vs 8.1%, respectively; P=.04). Uterine evacuation, with the highest costs and the lowest quality-adjusted life years, was dominated by both expectant management and methotrexate. In the base case analysis, expectant management was not cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year given an incremental cost-effectiveness ratio of $175,083 per quality-adjusted life year gained (95% confidence interval, -$1,666,825 to $2,676,375). Threshold analysis demonstrated that methotrexate administration would have to cost $214 (an increase of $16 or 8%) to favor expectant management. Moreover, expectant management would 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 of expectant management being cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year gained was 50%. The results were dependent on the cost of surgical intervention and the expected rate of methotrexate failure. CONCLUSION: The management of pregnancies of unknown location with a 2-dose methotrexate protocol may be cost-effective compared with expectant management and uterine evacuation. Although uterine evacuation was dominated, expectant management vs methotrexate results were sensitive to modest changes in treatment costs of both methotrexate and surgical management.

The relationship of circulating proteins in early pregnancy with preterm birth.

BACKGROUND: Preterm birth (PTB) (< 37 completed weeks' gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to the inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. OBJECTIVES: The objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks' gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic. STUDY DESIGN: Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. RESULTS: The complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade. CONCLUSION: Using a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy.

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT00154180 and NCT00623311.

Cardiometabolic measures and cognition in early menopause - Analysis of baseline data from a randomized controlled trial.

OBJECTIVE: The relationships between cardiometabolic indices and cognition were examined in recently menopausal women. METHODS: Cross-sectional analysis of baseline data from the KEEPS (Kronos Early Estrogen Prevention Study)-Cognitive ancillary study (n = 621). Cognitive performance was assessed by the Modified Mini Mental Status (3MS) score (primary outcome). Physical cardiometabolic indices included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and blood pressure (BP). Biochemical cardiometabolic indices included serum levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL (non-HDL-C), triglycerides (TG), fasting serum glucose (FSG), and insulin resistance (HOMA-IR). Socio-demographic variables included age, race/ethnicity, education, and lifestyle (physical activity, smoking). Central adiposity was defined as WC > 88 cm (>35 in) and WHR > 0.8. Separate stepwise multivariable analyses (GLM, ordinal logistic regression and logistic regression) assessed relationships between 3MS scores (as continuous, in tertiles and dichotomized at 90 respectively) with the measures of central adiposity (predictor variables); socio-demographic variables (age, time since menopause, race, educational status and lifestyle) and cardiometabolic variables (BP, lipids, FSG, HOMA-IR and hs-CRP) were examined as covariates. The final multivariable models included time since menopause, race, ethnicity, educational status, strenuous exercise, BMI ≥30 kg/m2, non-HDL-C and hs-CRP as covariates. Due to the high collinearity between the two indices of central adiposity, within each analytic strategy, separate models examined the respective associations of WC > 88 cm and WHR > 0.8 with 3MS score. RESULTS: On adjusted analyses, indices of central adiposity were independent predictors of significantly lower 3MS scores (p < 0.05). Consistency in this relationship was observed across the three different multivariable regression analytic approaches (GLM, ordinal and logistic regression). CONCLUSIONS: Among recently menopausal women, WC > 88 cm and WHR > 0.8 were associated with significantly lower cognitive function, as reflected by lower 3MS scores. The mechanisms that might explain the observed negative implications of central adiposity for cognitive function warrant further study.

Pre-IVF treatment with a GnRH antagonist in women with endometriosis (PREGNANT): study protocol for a prospective, double-blind, placebo-controlled trial.

INTRODUCTION: Infertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing fertility treatment for endometriosis-associated infertility compared with other etiologies of infertility. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, double-blind, placebo-controlled trial to study the efficacy of GnRH antagonist pretreatment for women with endometriosis who are undergoing IVF. A total of 814 patients with endometriosis undergoing fertility treatment will be enrolled and randomised 1:1 into two groups: elagolix 200 mg two times per day or placebo for 8 weeks, prior to undergoing IVF. All participants will then undergo IVF treatment per local protocols. The primary outcome is live birth. Secondary outcomes include oocyte number, fertilisation rate, embryo morphology and implantation rates, as well as rates of known endometriosis-related obstetrical outcomes (pregnancy-induced hypertension, antepartum haemorrhage, caesarean delivery and preterm birth). ETHICS AND DISSEMINATION: The PREGnant trial was approved by the Institutional Review Board at Johns Hopkins University. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04173169.

NAMS 2021 Utian Translational Science SymposiumSeptember 2021, Washington, DCCharting the path to health in midlife and beyond: the biology and practice of wellness.

ABSTRACT: Charting the Path to Health in Midlife and Beyond: The Biology and Practice of Wellness was a Translational Science Symposium held on Tuesday, September 21, 2021. Foundational psychosocial and behavioral approaches to promote healthy aging and strategies to disseminate this information were discussed. The following synopsis documents the conversation, describes the state of the science, and outlines a path forward for clinical practice. Wellness, in its broadest sense, prioritizes an orientation toward health, and an embrace of behaviors that will promote it. It involves a journey to improve and maintain physical and mental health and overall well-being to fully engage and live one's best life. It is more about recognizing and optimizing what one can do than what one cannot do and emphasizes the individual's agency over changing what they are able to change. Wellness is therefore not a passive state but rather an active goal to be sought continually. When viewed in this fashion, wellness is accessible to all. The conference addressed multiple aspects of wellness and embraced this philosophy throughout.

NAMS 2019 Pre-Meeting Symposium, September 2019, Chicago Illinois: The Perimenopause.

The North American Menopause Society held the 2019 Pre-Meeting Symposium on September 25, 2019, in Chicago, Illinois, to review the current state of the science related to the physiology of the perimenopause and to address management of the most prevalent and pressing clinical issues. The perimenopause, as defined by the Stages of Reproductive Aging Workshop + 10, encompasses the menopause transition as well as the first year following menopause, the final menstrual period. This phase in the continuum of women's reproductive lives had been one of the least well understood. Fortunately, contributions from a number of prospective, longitudinal, decades-long studies have provided a better understanding of the perimenopause, whereas posing important new questions related to symptom interaction and linkages between symptoms and long-term health. There is now added clarity to distinguish the effects of reproductive hormonal changes from aging. The variation in symptoms, including vasomotor symptoms, among women over time including differences in experiences by ethnicity and race, provides paradigm shifts in clinical perspective. Refinements in understanding the character, timing, and potential predictive markers for menstrual cycles during the transition have emerged. From the perspective of myriad clinical management challenges, significant progress in recommendations for evaluation and therapeutic approaches has been achieved. Finally, recognizing the menopause transition as an opportunity to initiate positive lifestyle changes to enhance future health was emphasized.

Increased Body Mass Index Is Associated With A Nondilutional Reduction in Antimüllerian Hormone.

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.

Androgenicity and fertility treatment in women with unexplained infertility.

OBJECTIVE: To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. DESIGN: Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. SETTING: Multicenter university-based clinical practices. PATIENT(S): Nine hundred couples with unexplained infertility were included. Women were 18-40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. RESULT(S): When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. CONCLUSION(S): In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01044862.

The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?

OBJECTIVE: The Kronos Early Estrogen Prevention Study (KEEPS) was designed to address gaps in understanding the effects of timely menopausal hormone treatments (HT) on cardiovascular health and other effects of menopause after the premature termination of the Women's Health Initiative. METHOD: The KEEPS was a randomized, double-blinded, placebo-controlled trial to test the hypothesis that initiation of HT (oral conjugated equine estrogens [o-CEE] or transdermal 17ß-estradiol [t-E2]) in healthy, recently postmenopausal women (n = 727) would slow the progression of atherosclerosis as measured by changes in carotid artery intima-media thickness (CIMT). RESULTS: After 4 years, neither HT affected the rate of increase in CIMT. There was a trend for reduced accumulation of coronary artery calcium with o-CEE. There were no severe adverse effects, including venous thrombosis. Several ancillary studies demonstrated a positive effect on mood with o-CEE, and reduced hot flashes, improved sleep, and maintenance of bone mineral density with both treatments. Sexual function improved with t-E2. There were no significant effects of either treatment on cognition, breast pain, or skin wrinkling. Variants of genes associated with estrogen metabolism influenced the age of menopause and variability in effects of the HT on CIMT. Platelet activation associated with the development of white matter hyperintensities in the brain. CONCLUSIONS: KEEPS and its ancillary studies have supported the value and safety of the use of HT in recently postmenopausal women and provide a perspective for future research to optimize HT and health of postmenopausal women. The KEEPS continuation study continues to pursue these issues.

Association of pelvic organ prolapse and fractures in postmenopausal women: analysis of baseline data from the Women's Health Initiative Estrogen Plus Progestin trial.

OBJECTIVE: Testing a hypothesis that pelvic organ prolapse (POP) is a focal manifestation of disordered connective tissue, we evaluated whether there is an association between POP and history of fracture. DESIGN: This was a case-control study. Baseline data were from postmenopausal women aged 60 years or older enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Distinct variants (cystocele, rectocele, and uterovaginal) and severity (mild, moderate, or severe) of POP were recognized. A history of "fracture after age 55" was considered as the event of interest. RESULTS: Moderate to severe POP was identified in 9% of 11,096 participants aged 60 years or older. Women with moderate to severe rectocele were significantly more likely to report fracture (odds ratio: 1.37, 95% CI: 1.06-1.77, P = 0.02) compared with those with absent to mild prolapse. Of the subset of participants who underwent bone mineral density assessment, those with moderate to severe prolapse demonstrated significantly lower whole-body bone mineral density ([beta] = -0.03, SE 0.02); this difference was of borderline significance (P = 0.05) compared with that for participants with absent to mild POP. Multivariate logistic regression analysis confirmed an independent association between moderate to severe rectocele and fracture (odds ratio: 1.45, 95% CI: 1.08-1.95, P = 0.01). CONCLUSIONS: We demonstrate a relationship between moderate to severe POP and low bone mineral density in postmenopausal women enrolled in the Women's Health Initiative Estrogen Plus Progestin trial. Our findings of an association between clinically significant (moderate to severe) POP, specifically rectocele, and a history of fracture suggest that suboptimal collagen status purported to associate with POP may also involve bone collagen and hence translate into skeletal compromise.

Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline.

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.

Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS).

Importance: Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition. Objective: To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women. Design, Setting, and Participants: Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017. Interventions: Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17ß-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month. Main Outcomes and Measures: Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated. Results: The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF. Conclusions and Relevance: Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known. Trial Registration: clinicaltrials.gov Identifier: NCT00154180.

Sex hormones in women with and without migraine: Evidence of migraine-specific hormone profiles.

OBJECTIVE: To compare daily sex hormone levels and rates of change between women with history of migraine and controls. METHODS: History of migraine, daily headache diaries, and daily hormone data were collected in ovulatory cycles of pre- and early perimenopausal women in the Study of Women's Health Across the Nation. Peak hormone levels, average daily levels, and within-woman day-to-day rates of decline over the 5 days following each hormone peak were calculated in ovulatory cycles for conjugated urinary estrogens (E1c), pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone. Comparisons were made between migraineurs and controls using 2-sample t tests on the log scale with results reported as geometric means. RESULTS: The sample included 114 women with history of migraine and 223 controls. Analyses of within-woman rates of decline showed that E1c decline over the 2 days following the luteal peak was greater in migraineurs for both absolute rate of decline (33.8 [95% confidence interval 28.0-40.8] pg/mgCr vs 23.1 [95% confidence interval 20.1-26.6] pg/mgCr, p = 0.002) and percent change (40% vs 30%, p < 0.001). There was no significant difference between migraineurs and controls in absolute peak or daily E1c, pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone levels. Secondary analyses demonstrated that, among migraineurs, the rate of E1c decline did not differ according to whether a headache occurred during the cycle studied. CONCLUSIONS: Migraineurs are characterized by faster late luteal phase E1c decline compared to controls. The timing and rate of estrogen withdrawal before menses may be a marker of neuroendocrine vulnerability in women with migraine.

Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial.

CONTEXT: Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent. OBJECTIVE: To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS). DESIGN: A retrospective cohort. SETTING: Secondary analysis of randomized controlled trial data. PARTICIPANTS: Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS. INTERVENTIONS: Serum 25OHD levels were measured in stored sera. MAIN OUTCOME MEASURES: Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI. RESULTS: Likelihood for LB was reduced by 44% for women if the 25OHD level was < 30 ng/mL (<75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI. CONCLUSIONS: In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Attenuation of preoptic area glutamate release correlates with reduced luteinizing hormone secretion in middle-aged female rats.

Glutamate (Glu) and its receptors are involved in the maturation and maintenance of the neural mechanisms governing the preovulatory LH surge of young, reproductive-aged rodents and nonhuman primates. Little is known about the role of Glu in the delayed onset and reduced peak amplitude of the LH surge that characterizes female rodents during early reproductive senescence. The present study tested the hypothesis that the delayed and attenuated LH surge observed in middle-aged female rats is associated with altered hypothalamic Glu release. We used intracerebral microdialysis in young (3-4 months) and middle-aged (9-11 months) female rats to monitor changes in medial preoptic area Glu release and jugular vein catheters to monitor changes in serum LH levels. All animals were ovariectomized and injected with estradiol and progesterone in doses sufficient to produce a robust LH surge in most (approximately 70%) young rats. In both young and middle-aged females that surged, extracellular Glu levels were higher than in those that did not surge. Among animals that surged, the onset of the LH surge was significantly delayed, and the amplitude of the surge was significantly reduced in middle-aged compared with young rats. Middle-aged females also had significantly reduced extracellular Glu levels throughout the day of the LH surge when compared with young females. These data strongly suggest that age-related hypothalamic dysfunction contributes to reproductive aging independent of gonadal failure. We propose that reduced medial preoptic area Glu transmission contributes to reproductive aging by attenuating excitatory input to GnRH neurons.

Menopause and exercise.

OBJECTIVE: Accumulating data suggest that regular physical exercise reduces mortality and extends the functional life span of men and women. This review seeks to describe the current state of the medical literature on this topic. METHODS: A narrative review of the current medical literature including randomized clinical trials and clinical guidelines that address the benefits of physical fitness and regular exercise on the health of midlife and postmenopausal women. RESULTS: Reduction and avoidance of obesity and its related comorbidities (hypertension, glucose intolerance, dyslipidemia, and heart disease) are one major benefit of exercise. However, long-term physical exercise is also associated with reduced rates of cancer, dementia and cognitive decline, adverse mood and anxiety symptoms, and reduction of osteoporosis, osteopenia, falls, and fractures. Beneficial physical activity includes exercise that will promote cardiovascular fitness (aerobic), muscle strength (resistance), flexibility (stretching), and balance (many of the preceding, and additional activities such as yoga). CONCLUSIONS: Given that it is unambiguously beneficial, inexpensive, and minimal risk, maintaining a healthy exercise regimen should be a goal for every participant to enhance lifelong wellness. Clinicians should use a number of behavioral strategies to support the physical fitness goals of their participants.

Evidence for prolonged and unique amenorrhea-related symptoms in women with premature ovarian failure/primary ovarian insufficiency.

OBJECTIVE: This study aims to describe premature ovarian failure (POF)/primary ovarian insufficiency (POI) symptoms experienced by women from a non-clinic-based sample of members of a POF/POI-specific support group. METHODS: Two hundred ninety women were surveyed for 6 weeks. The survey included demographics, health history, and a validated menopause-related quality-of-life questionnaire. Symptom prevalence was described. RESULTS: One hundred sixty (55%) women aged 18 to 63 years (mean [SD], 39.3 [7.3] y) responded. Age at diagnosis ranged from 10 to 39 years (median [interquartile range], 30 [24-35] y). Most respondents were white (87%), college educated (76%), and employed full time (61%). Among women reporting a history of depression (43%), 26% reported that depression occurred more than 5 years before POF/POI diagnosis. Of 29 commonly assessed menopausal symptoms, women reported a mean (SD) of 14.7 (7.4) symptoms; symptom scores did not substantially decrease with time since diagnosis, and relationship with age at diagnosis was negligible. Other common symptoms included mood swings and mental fog (>75%); hair loss, dry eyes, cold intolerance, and joint clicking (>50%); tingling in limbs and low blood pressure (∼33%); hypothyroidism (17%); hypoglycemia (16%); and gluten allergies (10%). Ninety unique symptoms were written in as free text. CONCLUSIONS: Symptom checklists created for age-appropriate postmenopausal women do not adequately capture the scope of symptoms observed in this sample. Menopausal symptoms do not seem to diminish across time in women with POF/POI, in contrast to women with age-appropriate menopause. Depression is very commonly reported in this sample, with some women clearly experiencing depression well before their diagnosis of POF/POI. Hypothyroidism in this sample is more than three times the population mean.