Study Objectives:The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network conducted three randomized clinical trials (RCTs) testing six interventions treating vasomotor symptoms (VMS), and also collected self-reported sleep outcomes. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects relative to control in women with comparably severe insomnia symptoms and VMS. Methods:We analyzed pooled individual-level data from 546 peri- and postmenopausal women with Insomnia Severity Index (ISI) ≥ 12, and ≥14 bothersome VMS/week across the four RCTs. Interventions included the following: escitalopram 10-20 mg/day; yoga; aerobic exercise; 1.8 g/day omega-3 fatty acids; oral 17-beta-estradiol 0.5-mg/day; venlafaxine XR 75-mg/day; and cognitive behavioral therapy for insomnia (CBT-I). Outcome measures were ISI and Pittsburgh Sleep Quality Index (PSQI) over 8-12 weeks of treatment. Results:CBT-I produced the greatest reduction in ISI from baseline relative to control at -5.2 points (95% CI -7.0 to -3.4). Effects on ISI were similar for exercise at -2.1 and venlafaxine at -2.3 points. Comparably small decreases in ISI were observed with escitalopram, yoga, and estradiol. The largest reduction in PSQI from baseline was with CBT-I at -2.7 points (-3.9 to -1.5), although PSQI decreases of 1.2 to 1.6 points were significantly better than control with escitalopram, exercise, yoga, estradiol, and venlafaxine. Omega-3 supplements did not improve insomnia symptoms. Conclusions:This study's findings support current recommendations for CBT-I as a first line treatment in healthy midlife women with insomnia symptoms and moderately bothersome VMS.

Objective:The aim of this study was to identify temporal associations of anxiety dimensions with menopausal hot flashes in women progressing through the menopausal transition. We hypothesized that associations of both somatic and affective dimensions of anxiety with hot flashes increased in the menopausal transition, and that somatic anxiety was an independent risk factor for menopausal hot flashes. Methods:Hot flashes, anxiety symptoms, hormone levels, and other psychosocial variables were assessed annually for 14 years of follow-up. The 233 women were premenopausal at baseline and continued through 1 year or more after the final menstrual period. Anxiety dimensions were assessed with the Zung Anxiety Scale, a validated measure of affective anxiety and somatic anxiety. Summed item scores were divided by the number of items rated, so that ranges of the two dimensions were comparable. Results:Seventy-two percent of the sample reported moderate/severe hot flashes during the 14-year interval. There was no significant interaction between anxiety dimensions and menopausal stages. When adjusted for menopausal stage, the magnitude of association between somatic anxiety and hot flashes, however, dramatically increased (odds ratio [OR], 3.03; 95% CI, 2.12-4.32; P < 0.001), whereas the association between affective anxiety and hot flashes increased to a lesser extent (OR, 1.27; 95% CI, 1.03-1.57; P = 0.024). Women with high levels of somatic anxiety (top third of the sample) had the greatest risk of hot flashes (P < 0.001). When the anxiety dimensions were considered in combination, the additive effect of high affective anxiety symptoms was minimal, with no significant difference between the group with high affective/low somatic symptoms and the low symptom group in incident hot flashes at each menopausal stage (P = 0.54). In multivariable analysis, somatic anxiety increased the risk of hot flashes more than three times (OR, 3.13; 95% CI, 2.16-4.53; P < 0.001), but affective anxiety was not significantly associated with hot flashes after adjustment for other study variables (OR, 1.19; 95% CI, 0.96-1.48; P = 0.117). Time-lagged somatic anxiety scores significantly predicted hot flashes, with a 71% increase in risk (OR, 1.71; 95% CI, 1.21-2.41; P = 0.002). Time-lagged affective anxiety scores did not predict hot flashes (OR, 1.06; 95% CI, 0.87-1.31; P = 0.58). Conclusions:This study showed a strong predictive association of somatic anxiety with the risk of menopausal hot flashes. The temporal associations suggest that somatic anxiety is not simply a redundant measure of hot flashes but predicts the risk of menopausal hot flashes and may be a potential target in clinical management of perimenopausal women.

STUDY OBJECTIVES Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes. DESIGN 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17β estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks. SETTING Academic research centers. PARTICIPANTS 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day. MEASUREMENTS AND RESULTS Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine). CONCLUSIONS Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality. CLINICAL TRIAL REGISTRATION NCT01418209 at www.clinicaltrials.gov.

OBJECTIVES:To characterize the time course, duration of improvement, and clinical predictors of placebo response in treatment of menopausal hot flashes.METHODS:Data were pooled from two trials conducted in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network, providing a combined placebo group (n = 247) and a combined active treatment group (n = 297). Participants recorded hot flash frequency in diaries twice daily during treatment (Weeks 0-8) and subsequent follow-up (Weeks 9-11). The primary outcome variable was clinically significant improvement, defined as a 50% or greater decrease in hot flash frequency from baseline and calculated for each week in the study. Subgroups were defined a priori using standard clinical definitions for significant improvement and partial improvement. Clinical and demographic characteristics of the participants were evaluated as predictors of improvement.RESULTS:Clinically significant improvement with placebo accrued each treatment week, with 33% significantly improved at Week 8. Of placebo responders who were improved at both Weeks 4 and 8, 77% remained clinically improved at Week 11 after treatment ended. Independent predictors of significant placebo improvement in the final multivariable model were African American race (odds ratio [OR] = 5.61, 95% confidence interval [CI] = 2.41-13.07, p < .001), current smokers (OR = 2.30, 95% CI = 1.05-5.06, p = .038), and hot flash severity in screening (OR = 1.45, 95% CI = 1.00-2.10, p = .047).CONCLUSIONS:Clinically significant improvement with placebo accrued throughout treatment with a time course similar to improvement with active drug. A meaningful number of participants in the placebo group sustained a clinically significant response after stopping placebo pills. The results suggest that nonspecific effects are important components of treatment and warrant further studies to optimize their contributions in clinical care.

Objective: This study aims to evaluate the effects of low-dose estradiol (E-2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.Methods: A double-blind, placebo-controlled, randomized trial of low-dose oral 17 beta-E-2 0.5 mg/day and venlafaxine XR 75 mg/day, versus identical placebo, was conducted among 339 women (aged 40-62 y) experiencing two or more vasomotor symptoms (VMS) per day (mean [SD], 8.07 [5.29]) who were recruited at three clinical sites from November 2011 to October 2012. The primary trial outcome, as reported previously, was frequency of VMS at 8 weeks. Here, we report on secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and from measures of pain (Pain, Enjoyment in life, and General activity scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder Questionnaire-7), and perceived stress (Perceived Stress Scale).Results: Treatment with both E-2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E-2: mean difference at 8 wk, -0.4; 95% CI, -0.7 to -0.2; P < 0.001; venlafaxine: mean difference at 8 wk, -0.2; 95% CI, -0.5 to 0.0; P = 0.04). Quality-of-life domain analyses revealed that E-2 had beneficial treatment effects on all domains of the MENQOL except for the psychosocial domain, whereas venlafaxine benefits were observed only in the psychosocial domain. Neither E-2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.Conclusions: Both low-dose E-2 and venlafaxine are effective pharmacologic agents for improving menopause-related quality of life in healthy women with VMS.

This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials.Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and ω-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network's structure and governance are also discussed.The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.

Objective: This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials.Methods: Established in response to a National Institutes of Health request for applications, the network was charged with conducting rapid throughput randomized trials of novel and understudied available interventions postulated to alleviate vasomotor and other menopausal symptoms. Included are descriptions of and rationale for criteria used for interventions and study selection, common eligibility and exclusion criteria, common primary and secondary outcome measures, consideration of placebo response, establishment of a biorepository, trial duration, screening and recruitment, statistical methods, and quality control. All trial designs are presented, including the following: (1) a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effectiveness of the selective serotonin reuptake inhibitor escitalopram in reducing vasomotor symptom frequency and severity; (2) a two-by-three factorial design trial to test three different interventions (yoga, exercise, and omega-3 supplementation) for the improvement of vasomotor symptom frequency and bother; and (3) a three-arm comparative efficacy trial of the serotonin-norepinephrine reuptake inhibitor venlafaxine and low-dose oral estradiol versus placebo for reducing vasomotor symptom frequency. The network's structure and governance are also discussed.Conclusions: The methods used in and the lessons learned from the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health trials are shared to encourage and support the conduct of similar trials and to encourage collaborations with other researchers.

IMPORTANCEEstrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.OBJECTIVETo determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).DESIGN, SETTING, AND PARTICIPANTSIn total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.INTERVENTIONSParticipants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.MAIN OUTCOMES AND MEASURESThe primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.RESULTSCompared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.CONCLUSIONS AND RELEVANCELow-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.TRIAL REGISTRATIONclinicaltrials.gov Identifier: NCT01418209.

The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration.

OBJECTIVE:Reproductive hormone levels are associated with body size, and the association between estradiol and body size varies over the menopausal transition. This study aims to delineate these relationships using quantitative measures of visceral and subcutaneous fat.METHODS:Early follicular hormones (follicle stimulating hormone (FSH), estradiol, luteinizing hormone, dehydroepiandrosterone sulfate, testosterone) and T-1 weighted abdominal MRI images were obtained in a cross-sectional assessment of 77 women in the Penn Ovarian Aging Study. Fat volume (cm(3)) was quantified using validated software (Amira) and divided into tertiles of visceral and subcutaneous fat volume for analysis. Multivariable linear regression models compared hormone values between tertiles adjusting for race, age, and menopausal status.RESULTS:In adjusted models, estradiol was positively associated with visceral fat tertiles (geometric mean (GM) estradiol (pg/ml): Low 13.0, Mid 17.5, High 26.7, p = 0.006) while FSH was inversely associated with visceral fat tertiles (GM FSH (mIU/ml): Low 42.8, Mid 43.2, High 30.8, p = 0.03). The association of estradiol with visceral and subcutaneous fat tertiles varied by menopausal status (p < 0.001). In the early transition, estradiol was similar across tertiles of fat; postmenopause, estradiol was positively associated with visceral fat. Other hormones were not associated with fat measures.CONCLUSIONS:Estradiol was associated with quantitative measures of visceral fat and varies by menopausal status. This finding suggests that visceral fat may be an important mediator in hormone changes over the menopausal transition.

Objective: To determine whether measures of ovarian reserve differ between females exposed to cancer therapies in a dose-dependent manner as compared with healthy controls of similar age and late reproductive age.Design: Cross-sectional analysis of data from a prospective cohort study.Setting: University medical center.Patient(s): Seventy-one cancer survivors aged 15-39 years; 67 healthy, similarly aged unexposed subjects; and 69 regularly menstruating women of late reproductive age (40-52 years).Intervention(s): None.Main Outcome Measure(s): Early follicular-phase hormones (FSH, E-2, inhibin B, antimullerian hormone [AMH]) and ovarian ultrasound measurements (ovarian volume and antral follicle counts [AFC]) were compared using multivariable linear regression.Result(s): In adjusted models, FSH, AMH, and AFC differed between exposed vs. unexposed subjects (FSH 11.12 mIU/mL vs. 7.25 mIU/mL; AMH 0.81 ng/mL vs. 2.85 ng/mL; AFC 14.55 vs. 27.20). In participants with an FSH <10 mIU/mL, survivors had lower levels of AMH and AFC compared with controls. Alkylating agent dose score was associated with increased levels of FSH and decreased levels of AMH. Exposure to pelvic radiation was associated with impairment in FSH, AMH, AFC, and ovarian volume. Antimullerian hormone was similar in women previously exposed to high-dose cancer therapy and 40-42-year-old controls.Conclusion(s): Measures of ovarian reserve are impaired in a dose-dependent manner among cancer survivors compared with unexposed females of similar age. Reproductive hormone levels in menstruating survivors exposed to high-dose therapy are similar to those in late-reproductive-age women. The predictive value of measures for pregnancy and menopause must be studied.

OBJECTIVE:To determine the rate of change of antimüllerian hormone (AMH) level in the late reproductive years and its associations with time to menopause (TTM). We hypothesized that the rate of change between two measures of AMH reflects follicular atresia and varies among women independent of age. DESIGN:A14-year follow-up. SETTING:A randomly identified, population-based cohort (Penn Ovarian Aging Study). PATIENT(S):Two measures of AMH were evaluated in survival analysis of 293 women. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Time to menopause. RESULT(S):The rate of AMH change was a strong independent predictor of TTM in multivariable analysis after adjusting for AMH baseline, age, and smoking (hazard ratio for 1 SD change = 1.82, 95% confidence interval 1.56-2.14). Among women with similar AMH levels, TTM differed by approximately 2 years when compared between a slow and fast rate of AMH change. A significant interaction of AMH rate of change and age indicated that a faster decrease in AMH level was associated with an increased risk of menopause in women aged 35-39 years (hazard ratio 6.97, 95% confidence interval 3.81-12.72), with less dramatic but significant associations in women aged 40-44 and 45-48 years. CONCLUSION(S):The AMH rate of change was independently associated with TTM in late reproductive-age women and increased the precision of estimates of TTM when included with an AMH baseline level and age. The rate of AMH change may be a more direct surrogate than age and increases the precision of estimates of TTM during this clinically important time period.

Objective: To estimate the effect of escitalopram (10-20 mg/d) versus placebo for reducing hot flash interference in daily life and understand correlates and predictors of reductions in hot flash interference, a key measure of quality of life.Design: Multisite, randomized, double-blind, placebo-controlled clinical trial.Setting: MsFLASH clinical sites in Boston, Indianapolis, Oakland, and Philadelphia.Patient(s): A total of 205 midlife women (46% African-American) who met criteria participated.Intervention(s): After baseline, women were randomized to one pill of escitalopram 10 mg/d (n = 104) or placebo (n = 101) with follow-up at 4 and 8 weeks. At week 4, those not achieving 50% fewer hot flashes were increased to two pills daily (20 mg/d or 2 placebo pills).Main Outcome Measure(s): The Hot Flash Related Daily Interference Scale; correlates were variables from hot flash diaries; predictors were baseline demographics, clinical variables, depression, anxiety, sleep quality, and hot flashes.Result(s): Compared to placebo, escitalopram significantly reduced hot flash interference by 6.0 points at week 4 and 3.4 points at week 8 more than placebo. Reductions in hot flash interference correlated with changes in hot flash diary variables. However, baseline variables did not significantly predict reductions in hot flash interference.Conclusion(s): Escitalopram (10-20 mg/d) for 8 weeks improves women's quality of life and this benefit did not vary by demographic, clinical, mood, sleep, or hot flash variables.Clinical Trial Registration Number: NCT00894543. (Fertil Steril (R) 2012;97:1399-404. (C) 2012 by American Society for Reproductive Medicine.)

Objective: To evaluate the effects of escitalopram 10-20 mg/day on menopause-related quality of life and pain in healthy menopausal women with hot flashes.Study design: A double-blind, placebo-controlled randomized trial of escitalopram 10-20 mg/day vs. identical placebo was conducted among 205 women ages 40-62 years with an average of >= 4 daily hot flashes recruited at 4 clinical sites from July 2009 to June 2010.Main outcome measures: The primary trial outcomes, reported previously, were the frequency and severity of vasomotor symptoms at 8 weeks. Here, we report on the pre-specified secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and the pain intensity and interference scale (PEG).Results: Outcome data were collected on 97% of randomized women and 87% of women took at least 70% of their study medication. Treatment with escitalopram resulted in significantly greater improvement in total MENQOL scores (mean difference at 8 weeks of -0.41; 95% confidence interval (CI) -0.71 to -0.11; p < 0.001). as well as Vasomotor. Psychosocial, and Physical domain scores with the largest difference seen in the Vasomotor domain (mean difference -0.75; 95% CI -1.28 to -0.22; p = 0.02). There was no significant treatment group difference for the Sexual Function domain. Escitalopram treatment resulted in statistically significant improvements in PEG scores compared to placebo (mean treatment group difference at 8 weeks of -0.33; 95% CI -0.81 to 0.15; p = 0.045).Conclusions: Treatment with escitalopram 10-20 mg/day in healthy women with vasomotor symptoms significantly improved menopause-related quality of life and pain. (C) 2012 Elsevier Ireland Ltd. All rights reserved.