Search

The aim of this study was to quantify changes in serum total estradiol (E2) and estrone (E1) concentrations with initiation of low-dose oral estradiol treatment and evaluate whether changes in concentrations mediate the effect of treatment in reducing vasomotor symptom (VMS) frequency.We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17β estradiol ( n = 72) and placebo ( n = 99) groups of a randomized clinical trial.From baseline to W8, women in the low-dose estradiol group had a fourfold increase in E2, resulting in a W8 E2 of 23 pg/mL, and a fivefold increase in E1, resulting in a W8 E1 of 110.7 pg/mL. In contrast, E2 and E1 among women in the placebo group were unchanged from baseline to W8. Changes in E2 and E1 from baseline to W8 met criteria for mediating the effect of low-dose estradiol treatment on VMS frequency. With change in estrogen concentration added to treatment assignment in a regression model predicting W8 VMS frequency, the effect of treatment with low-dose estradiol versus placebo was attenuated, with change in E2 representing a 44.1% reduction ( P = 0.03) and change in E1 representing a 69.5% reduction ( P = 0.02) in total intervention effect.Among perimenopausal and postmenopausal women with VMS, treatment with low-dose oral estradiol versus placebo results in four- to fivefold increases in serum E2 and E1. The increases in serum E2 and E1 with low-dose oral estradiol treatment seem to mediate in part the effect of treatment in reducing VMS frequency.

To evaluate whether single measurements of serum estradiol (EWe analyzed baseline data from two clinical trials conducted in 2012-2017: MsFLASH 03 (178 peri-/post-menopausal women aged 40-62 years with bothersome vasomotor symptoms, mean age 54) and MsFLASH 05 (181 post-menopausal women aged 45-70 years with moderate-to-severe vulvovaginal symptoms, mean age 61).Symptom bother (hot flushes or flashes, night sweats, sweating, aching in muscles and joints, change in sexual desire, vaginal dryness during intercourse, and avoiding intimacy) in the past month was assessed using the Menopause-Specific Quality of Life questionnaire. Using logistic regression, we calculated the area under the receiver operating characteristic curve (AUC) values for EAUC values (95% confidence interval) ranged between 0.51 (0.41-0.60) and 0.62 (0.53, 0.72) for MsFLASH 03 and between 0.51 (0.42, 0.59) and 0.64 (0.53, 0.75) for MsFLASH 05. There was little evidence of associations between serum hormone levels and bother by a given menopausal symptom.These findings do not support the clinical utility of a single measurement of serum of E

ImportanceThe best approach to identify younger postmenopausal women for osteoporosis screening is uncertain. The Fracture Risk Assessment Tool (FRAX), which includes self-identified racial and ethnic information, and the Osteoporosis Self-assessment Tool (OST), which does not, are risk assessment tools recommended by US Preventive Services Task Force guidelines to identify candidates for bone mineral density (BMD) testing in this age group.ObjectiveTo compare the ability of FRAX vs OST to discriminate between younger postmenopausal women who do and do not experience incident fracture during a 10-year follow-up in the 4 racial and ethnic groups specified by FRAX.Design, Setting, and ParticipantsThis cohort study of Women’s Health Initiative participants included 67 169 women (baseline age range, 50-64 years) with 10 years of follow-up for major osteoporotic fracture (MOF; including hip, clinical spine, forearm, and shoulder fracture) at 40 US clinical centers. Data were collected from October 1993 to December 2008 and analyzed between May 11, 2022, and February 23, 2023.Main Outcomes and MeasuresIncident MOF and BMD (in a subset of 4607 women) were assessed. The area under the receiver operating characteristic curve (AUC) for FRAX (without BMD information) and OST was calculated within each racial and ethnic category.ResultsAmong the 67 169 participants, mean (SD) age at baseline was 57.8 (4.1) years. A total of 1486 (2.2%) self-identified as Asian, 5927 (8.8%) as Black, 2545 (3.8%) as Hispanic, and 57 211 (85.2%) as White. During follow-up, 5594 women experienced MOF. For discrimination of MOF, AUC values for FRAX were 0.65 (95% CI, 0.58-0.71) for Asian, 0.55 (95% CI, 0.52-0.59) for Black, 0.61 (95% CI, 0.56-0.65) for Hispanic, and 0.59 (95% CI, 0.58-0.59) for White women. The AUC values for OST were 0.62 (95% CI, 0.56-0.69) for Asian, 0.53 (95% CI, 0.50-0.57) for Black, 0.58 (95% CI, 0.54-0.62) for Hispanic, and 0.55 (95% CI, 0.54-0.56) for White women. For discrimination of femoral neck osteoporosis, AUC values were excellent for OST (range, 0.79 [95% CI, 0.65-0.93] to 0.85 [95% CI, 0.74-0.96]), higher for OST than FRAX (range, 0.72 [95% CI, 0.68-0.75] to 0.74 [95% CI, 0.60-0.88]), and similar in each of the 4 racial and ethnic groups.Conclusions and RelevanceThese findings suggest that within each racial and ethnic category, the US FRAX and OST have suboptimal performance in discrimination of MOF in younger postmenopausal women. In contrast, for identifying osteoporosis, OST was excellent. The US version of FRAX should not be routinely used to make screening decisions in younger postmenopausal women. Future investigations should improve existing tools or create new approaches to osteoporosis risk assessment for this age group.

Background The association of cognitive function with symptoms of psychological distress during the coronavirus disease 2019 (COVID-19) pandemic or adherence to COVID-19 protective health behaviors is not well-understood. Methods We examined 2 890 older women from the Women’s Health Initiative cohort. Prepandemic (ie, within 12 months prior to pandemic onset) and peripandemic global cognitive function scores were assessed with the modified Telephone Interview for Cognitive Status (TICS-m). Anxiety, stress, and depressive symptom severity during the pandemic were assessed using validated questionnaires. We examined adherence to protective behaviors that included safe hygiene, social distancing, mask wearing, and staying home. Multivariable models were adjusted for age, race, ethnicity, education, region of residence, alcohol intake, and comorbidities. Results Every 5-point lower prepandemic TICS-m score was associated with 0.33-point mean higher (95% confidence interval [CI], 0.20, 0.45) perceived stress and 0.20-point mean higher (95% CI, 0.07, 0.32) depressive symptom severity during the pandemic. Higher depressive symptom severity, but not anxiety or perceived stress, was associated with a 0.69-point (95% CI, −1.13, −0.25) mean decline in TICS-m from the prepandemic to peripandemic period. Every 5-point lower peripandemic TICS-m score was associated with 12% lower odds ratio (OR, 0.88; 95% CI, 0.80, 0.97) of practicing safe hygiene. Conclusions Among older women, we observed that: (a) lower prepandemic global cognitive function was associated with higher stress and depressive symptom severity during the pandemic; (b) higher depressive symptom severity during the pandemic was associated with cognitive decline; and (c) lower global cognitive function during the pandemic was associated with lower odds of practicing safe hygiene.

OBJECTIVE: To evaluate the relationship between diurnal salivary cortisol patterns and distress from heart palpitations in midlife women. METHODS: We analyzed baseline data from 293 women who were eligible for a 3×2 factorial trial of exercise or yoga vs. routine activity, and omega-3 fish oil vs. placebo for vasomotor symptoms. Women self-collected salivary cortisol using swabs at four time points over two consecutive days and reported distress from heart racing or pounding during the past two weeks using a single item. Sample description and covariate data included demographics, clinical data, vasomotor symptom frequency from daily diaries, medication use, and validated questionnaires on depression, stress, and insomnia (Patient Health Questionnaire-8, Perceived Stress Scale, and Insomnia Severity index). Data were analyzed using descriptive statistics, chi-square and t-tests, and repeated measure linear regression models. RESULTS: Participants were on average 54.6 (SD=3.6) years old, most were white (67%),, most were postmenopausal (84%), and 26% reported distress related to palpitations. In adjusted models, the morning (wake plus 30-minute) geometric mean daily salivary cortisol concentrations were significantly more blunted in those with distress from palpitations compared to those without distress (p≤0.03). When all covariates were controlled, distress from palpitations was the sole significant predictor of wake plus 30-minute cortisol (−0.25 [−0.45 to −0.04], p=0.02). CONCLUSIONS: Palpitations among midlife women may be associated with blunted morning cortisol, and this relationship is not explained by demographics, clinical variables, vasomotor symptoms, medications, depression, stress, or insomnia.

Background: Use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has been postulated to reduce cancer risk by inhibition of tumor progression, vascularization, and metastasis. The renin–angiotensin system is upregulated in colorectal cancers; however, the association of ACEi and ARB use with colorectal cancer risk is not well understood. Methods: The study population was 142,812 Women's Health Initiative participants free of colorectal cancer who reported on ACEi and ARB use at baseline; 2,216 incident colorectal cancers were diagnosed during 10 years of follow-up. Cox regression models estimated adjusted HRs and 95% confidence intervals for associations relative to nonuse among normotensive women, untreated hypertensive women, and hypertensive women treated with other antihypertensive medications. Results: HRs among women who used any ACEi or ARB compared with nonuse in the three referent groups ranged between 0.97 and 1.01. Findings were similar for increased ACEi/ARB duration and for medications examined as separate classes or individually. Conclusions: In this large prospective study of women, no associations of ACEi or ARB use with colorectal cancer risk were observed. Impact: Choice of drug in the large population of aging women who will be prescribed ACEi and ARB should be made without factoring in any benefit on colorectal cancer risk.

Background National guidelines promote physical activity to prevent cardiovascular disease (CVD), yet no randomized controlled trial has tested whether physical activity reduces CVD. Methods The Women’s Health Initiative (WHI) Strong and Healthy (WHISH) pragmatic trial used a randomized consent design to assign women for whom cardiovascular outcomes were available through WHI data collection (N = 18 985) or linkage to the Centers for Medicare and Medicaid Services (N30 346), to a physical activity intervention or “usual activity” comparison, stratified by ages 68–99 years (in tertiles), U.S. geographic region, and outcomes data source. Women assigned to the intervention could “opt out” after receiving initial physical activity materials. Intervention materials applied evidence-based behavioral science principles to promote current national recommendations for older Americans. The intervention was adapted to participant input regarding preferences, resources, barriers, and motivational drivers and was targeted for 3 categories of women at lower, middle, or higher levels of self-reported physical functioning and physical activity. Physical activity was assessed in both arms through annual questionnaires. The primary outcome is major cardiovascular events, specifically myocardial infarction, stroke, or CVD death; primary safety outcomes are hip fracture and non-CVD death. The trial is monitored annually by an independent Data Safety and Monitoring Board. Final analyses will be based on intention to treat in all randomized participants, regardless of intervention engagement. Results The 49 331 randomized participants had a mean baseline age of 79.7 years; 84.3% were White, 9.2% Black, 3.3% Hispanic, 1.9% Asian/Pacific Islander, 0.3% Native American, and 1% were of unknown race/ethnicity. The mean baseline RAND-36 physical function score was 71.6 (± 25.2 SD). There were no differences between Intervention (N = 24 657) and Control (N = 24 674) at baseline for age, race/ethnicity, current smoking (2.5%), use of blood pressure or lipid-lowering medications, body mass index, physical function, physical activity, or prior CVD (10.1%). Conclusion The WHISH trial is rigorously testing whether a physical activity intervention reduces major CV events in a large, diverse cohort of older women. Clinical Trials Registration Number: NCT02425345

Postmenopausal women with genitourinary symptoms of menopause are often prescribed vaginal estradiol or moisturizer for symptom improvement, but the impact of these treatments on the local microenvironment is poorly understood.To compare changes in the vaginal microbiota, metabolome, and pH among women using low-dose vaginal estradiol tablet or low pH moisturizer gel for 12-weeks vs low pH placebo.This is a post hoc prespecified secondary analysis of a 12-week multicenter randomized clinical trial among postmenopausal women with moderate to severe genitourinary symptoms. Women were enrolled between April 2016 and February 2017; final follow-up visits occurred in April 2017. Data were analyzed from November 2018 to July 2021.Ten-μg vaginal estradiol plus placebo gel vs placebo tablet plus vaginal moisturizer vs dual placebo.The main outcome measures were changes in the diversity and composition of the vaginal microbiota, changes in the metabolome, and pH.Of 302 postmenopausal women from the parent trial, 144 women (mean [SD] age, 61 [4] years) were included in this analysis. After 12 weeks, the microbiota was dominated with Lactobacillus and Bifidobacterium communities among 36 women (80%) in the estradiol group, compared with 16 women (36%) using moisturizer and 13 women (26%) using placebo (P .001). The composition of vaginal fluid metabolites also varied after 12-weeks among women in the estradiol group with significant changes in 90 of 171 metabolites measured (53%) (P .001), including an increase in lactate. The 12-week pH among women in the estradiol group was lower vs placebo (median [IQR] pH, 5 [4.5-6.0] vs 6 [5.5-7.0]; P = .005) but not the moisturizer group vs placebo (median [IQR] pH, 6 [5.5-6.5]; P = .28). There was a decrease in pH from baseline to 12-weeks within the moisturizer (median [IQR] pH, 7 [6.0-7.5] vs 6 [5.5-6.5]; P .001) and placebo (median [IQR] pH, 7 [7.0-7.5] vs 6 [5.5-7.0]; P .001) groups. Women with high-diversity bacterial communities at baseline exhibited greater median change in pH compared with women with low-diversity communities (median [IQR] change, -1 [-2 to -0.5] vs -0.3 [-1.1 to 0], P = .007).This secondary analysis of a randomized clinical trial found that use of vaginal estradiol tablets resulted in substantial changes in the vaginal microbiota and metabolome with a lowering in pH, particularly in women with high-diversity bacterial communities at baseline. Low pH moisturizer or placebo did not significantly impact the vaginal microbiota or metabolome despite lowering the vaginal pH. Estradiol use may offer additional genitourinary health benefits to postmenopausal women.ClinicalTrials.gov Identifier: NCT02516202.

Background and Objective: Both periodontal disease and inflammatory bowel disease (IBD), are chronic inflammatory conditions, which are mediated by a complex interplay among a dysbiotic microbiota, dysregulated host immune-inflammatory responses, and lifestyle factors. Despite substantial differences in physical and chemical environments, rather strong correlations have been detected between microbial compositions of the oral cavity and stool. In this study, we tested the hypothesis that oral health conditions are affected by the presence of IBD. Materials and Methods: We analyzed the data from 73,621 women who were enrolled in the Women's Health Initiative observational cohort study and completed a follow-up questionnaire that surveyed oral health status specifically at year 5. Among these, 880 reported IBD at the baseline, including 47% who were symptomatic cases and 27% who were on immunosuppressive treatment. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IBD and medication status for self-reported oral health outcomes, using logistic regression models, adjusted for selected covariates. Results: IBD was not associated with periodontal disease history itself in a multivariable model; however, poorer self-rated oral health was modestly associated with the presence of IBD (OR = 1.15, 95% CI: 1.01–1.30). Likewise, more frequent eating limitations due to teeth were associated with the presence of IBD history (OR = 1.22, 95% CI: 1.07–1.39). When IBD cases were limited to those who were symptomatic, the associations with these two self-rated oral health outcomes were more pronounced with ORs of 1.28 (95% CI: 1.07–1.54) and 1.36 (95% CI: 1.07–1.54), respectively. Immunosuppressive treatment had little effect on these risk estimates. Conclusions: Among this nation-wide cohort of women 50–79 years of age, history of IBD was associated with poorer perceived oral health status.

Objective 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 menopause-related quality of life (QOL) measures. A fourth RCT assessed an intervention for insomnia symptoms among women with VMS. We describe these seven interventions' effects on menopause-related QOL relative to control in women with VMS. Methods We pooled individual-level data from 1,005 peri- and postmenopausal women with 14 or more VMS/week across the four RCTs. Interventions included escitalopram 10 to 20 mg/d; yoga/aerobic exercise; 1.8 g/d omega-3-fatty acids; oral 17-beta-estradiol 0.5 mg/d; venlafaxine XR 75 mg/d; and cognitive behavioral therapy for insomnia (CBT-I). Outcomes measures were the Menopause-specific Quality of Life scale and its subscales. Results Significant improvements in total Menopause-specific Quality of Life from baseline were observed with estradiol, escitalopram, CBT-I, and yoga, with mean decreases of 0.3 to 0.5 points relative to control. The largest improvement in the vasomotor subscale was observed with estradiol (-1.2 points), with more modest but significant effects seen with escitalopram, yoga, and CBT-I. Significant improvements in the psychosocial subscale were observed for escitalopram, venlafaxine, and CBT-I. For the physical subscale, the greatest improvement was observed for CBT-I and exercise, whereas for the sexual subscale, the greatest improvement was observed for CBT-I, with yoga and estradiol demonstrating smaller effects. Conclusions These results suggest that for menopause-related QOL, women have a variety of treatment strategies to choose from and can select an approach based on most bothersome symptoms and individual preferences.

Objective The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network was funded by the National Institutes of Health to find new ways to alleviate the most common, bothersome menopausal symptoms by designing and conducting multiple concurrent clinical intervention studies, accommodating a wide scope of populations and intervention strategies. Methods Trials were conducted in Boston, Indianapolis, Minneapolis, Oakland, Philadelphia, and Seattle, with the Data Coordinating Center in Seattle, and were designed with standardized eligibility criteria and endpoints. Primary outcomes focused on vasomotor symptoms, sleep quality and insomnia symptoms, and vaginal symptoms. Secondary outcomes included quality of life, sexual function, and mood. Results We completed five randomized clinical trials and three ancillary studies, testing nine interventions in over 1,300 women and collecting nearly 16,000 bio-specimens. Escitalopram, venlafaxine hydrochloride extended release, and low-dose estradiol diminished hot flashes by approximately 50% as compared with a 30% decrease by placebo. No benefits on vasomotor symptoms were observed with yoga or exercise compared with usual activity, nor with omega-3 supplementation compared with placebo. Cognitive behavioral therapy for insomnia reduced self-reported insomnia symptoms and improved overall sleep quality compared with menopause education control. We did not find significant benefit from a vaginal estradiol tablet or a vaginal moisturizer compared with placebo tablet and gel in diminishing the severity of vaginal symptoms. Conclusions The MsFLASH trials contributed substantially to our understanding of bothersome menopausal symptom treatment. It is important that clinicians counseling women about available treatment options consider all therapies-both nonhormonal and hormonal.

Using data from the Women's Health Initiative Observational Study (WHI-OS), to determine the role of estrogen formulation, dose, route of delivery, and its combination with different progestogens on the risk for hypertension in the WHI-OS.After excluding women with diagnosed hypertension, receiving antihypertensive medication, presenting with elevated blood pressure ( ≥ 140/90), and those not taking menopausal hormone therapy at baseline, 19,986 women remained eligible for the analyses. Using hierarchal modeling, proportional hazard rate calculation, and linear and logistic regression analyses, we evaluated incident treated hypertension and mean systolic and diastolic blood pressure changes at 3 years. Multivariable models were adjusted for age, race/ethnicity, education, smoking, physical activity, body mass index, history of treated diabetes, history of prescription medicines for high cholesterol, alcohol intake, hysterectomy, and bilateral oophorectomy.At 3 years, and compared with conjugated estrogens (CEE) with or without a progestin, the odds for newly treated hypertension were lower in women who used transdermal estradiol (0.85, 95% CI, 0.73-1.00) or oral estrone sulphate dominant preparations (0.83, 0.72-0.96). The odds of incident treated hypertension after 3 years did not vary according to dose of estrogen. The mean measured systolic blood pressure was minimally lower with transdermal estradiol (-1.20, 95% CI, -1.97 to -0.44) mm Hg and other oral Estrone dominant preparations (-0.83, 95% CI, -1.51 to -0.16) mm Hg at 3 years. For a given estrogen type, the magnitudes of the hazard ratio were similar for estrogen-alone compared with estrogen plus a progestogen. For women 10 or more years past menopause when they entered, the HR for incident self-reported treated hypertension was 1.26 (95% CI, 1.09-1.46) with higher dose CEE compared with 0.625 mg CEE. It was 0.87 (95% CI, 0.68-1.13) when given to women who were10 years after menopause when they entered the WHI-OS.The risk of treated hypertension differed by formulation, dose, and years since menopause.Video Summary:http://links.lww.com/MENO/A795.

Importance The burden of fractures among postmenopausal women is high. Although nontraumatic fractures are strong risk factors for future fracture, current clinical guidelines do not address traumatic fractures. Objective To determine how future fracture risk varies according to whether an initial fracture is traumatic or nontraumatic. Design, Setting, and Participants We conducted a prospective observational study using data from the Women’s Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, September 2020 to March 2021), which enrolled postmenopausal women aged 50 to 79 years at baseline at 40 US clinical centers. The WHI Clinical Trials and WHI Bone Density Substudy, conducted at 3 of the clinical centers, asked participants to report the mechanism of incident fractures. Of 75 335 participants, information regarding incident fracture and covariates was available for 66 874 participants (88.8%), who comprised the analytic sample of this study. Mean (SD) follow-up was 8.1 (1.6) years. Interventions None. Main Outcomes and Measures Incident clinical fractures were self-reported at least annually and confirmed using medical records. Participants reported the mechanism of incident fracture as traumatic or nontraumatic. Results Among the 66 874 participants in the analytic sample (mean [SD] age, 63.1 [7.0] years and 65.3 [7.2] years among women without and with clinical fracture, respectively), 7142 participants (10.7%) experienced incident fracture during the study follow-up period. The adjusted hazard ratio (aHR) of subsequent fracture after initial fracture was 1.49 (95% CI, 1.38-1.61). Among women whose initial fracture was traumatic, the association between initial fracture and subsequent fracture was significantly increased (aHR, 1.25; 95% CI, 1.06-1.48). Among women whose initial fracture was nontraumatic, the association between initial fracture and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68). Confidence intervals for associations between initial fracture and subsequent fracture were overlapping for traumatic and nontraumatic initial fracture strata. Conclusions and Relevance In this cohort study, among postmenopausal women older than 50 years, fracture was associated with a greater risk of subsequent fracture regardless of whether the fracture was traumatic or nontraumatic. These findings suggest that clinical osteoporosis assessment should include high-trauma as well as low-trauma fractures.

BackgroundThe MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) Network recruited into five randomized clinical trials (n = 100–350) through mass mailings. The fifth trial tested two interventions for postmenopausal vulvovaginal symptoms (itching, pain, irritation, dryness, or pain with sex) and thus required a high level of sensitivity to privacy concerns. For this trial, in addition to mass mailings we pilot tested a social media recruitment approach. We aimed to evaluate the feasibility of recruiting healthy midlife women with bothersome vulvovaginal symptoms to participate in the Vaginal Health Trial through Facebook advertising.MethodsAs part of a larger advertising campaign that enrolled 302 postmenopausal women for the 12-week randomized, double-blind, placebo-controlled Vaginal Health Trial from April 2016 to February 2017, Facebook advertising was used to recruit 25 participants. The target population for recruitment by mailings and by Facebook ads included women aged 50–70 years and living within 20 miles of study sites in Minneapolis, MN and Seattle, WA. Design of recruitment letters and Facebook advertisements was informed by focus group feedback. Facebook ads were displayed in the “newsfeed” of targeted users and included a link to the study website. Response rates and costs are described for both online ads and mailing.ResultsFacebook ads ran in Minneapolis for 28 days and in Seattle for 15 days, with ads posted and removed from the site as needed based on clinic flow and a set budget limit. Our estimated Facebook advertising reach was over 200,000 women; 461 women responded and 25 were enrolled at a cost of US$14,813. The response rate per estimated reach was 0.22%; costs were US$32 per response and US$593 per randomized participant. The social media recruitment results varied by site, showing greater effectiveness in Seattle than in Minneapolis. We mailed 277,000 recruitment letters; 2166 women responded and 277 were randomized at a cost of US$98,682. The response rate per letter sent was 0.78%; costs were US$46 per response and US$356 per randomized participant. Results varied little across sites.ConclusionRecruitment to a clinical trial testing interventions for postmenopausal vaginal symptoms is feasible through social media advertising. Variability in observed effectiveness and costs may reflect the small sample sizes and limited budget of the pilot recruitment study.

To evaluate the efficacy of two common interventions for bothersome postmenopausal vaginal symptoms on improving sexual frequency and pain.This is a post-hoc analysis of data from a 12-week double-blind placebo-controlled trial that randomized postmenopausal women (ages 45-70 years) with moderate-severe genitourinary discomfort to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), placebo tablet plus vaginal moisturizer (n = 100), or dual placebo (n = 100). Outcomes were proportion of sexually active women at 12 weeks, frequency of sexual activity, and pain severity with sexual activity (0-3 scale). Consistent with the original study design, comparisons were made between each active arm and the dual placebo arm.Most women enrolled in the trial, 294/302 (97%), had sufficient data to be included in this analysis. Mean age of participants was 61 years, most were white (88%), college educated (66%), and most reported sexual activity in the month before enrollment (81%). After 12 weeks of treatment, a similar proportion of women in the vaginal estrogen and dual placebo groups reported sexual activity in the past week (50% and 40%; P = 0.10) and the past month (78% and 84%, P = 0.52). Mean (standard deviation) pain with sexual activity scores at 12 weeks were similar between vaginal estrogen (1.0 [1.0]) and placebo (0.9 [0.9], P = 0.52] groups. The proportion sexually active at 12 weeks (35%) and mean (standard deviation) pain severity in the vaginal moisturizer group (1.1 [0.9]) did not differ from placebo (P = 0.36).Compared to placebo, neither low-dose vaginal estradiol nor vaginal moisturizer treatment over 12 weeks resulted in significantly greater increases in the proportions of women reporting sexual activity or improvement in pain scores with sexual activity.Clinical trials.gov: NCT02516202.

Background Atrial fibrillation (AF) is the most common arrhythmia in adults. Although vitamin D deficiency is associated with AF risk factors, retrospective studies of association with AF have shown mixed results. We sought to determine the efficacy of calcium and vitamin D (CaD) supplementation for AF prevention in a randomized trial. Methods We performed a secondary analysis of the Women’s Health Initiative trial on CaD supplementation versus placebo. We linked participants to their Medicare claims to ascertain incident AF. Results Among 16,801 included participants, there were 1,453 (8.6%) cases of incident AF over an average of 4.5 years, at an average rate of 19.9 events per 1,000 person-years. We found no significant difference in incident AF rates between the CaD and placebo arms (hazard ratio 1.02 for CaD vs placebo, 95% CI 0.92-1.13). After multivariate adjustment, there was no significant association between baseline 25-hydroxyvitamin D serum levels and incident AF (hazard ratio 0.92 for lowest subgroup vs highest subgroup, 95% CI 0.66-1.28). Conclusions We present the first analysis of a large randomized trial of daily vitamin D supplementation for AF prevention. We found that CaD had no effect on incidence of AF in Women’s Health Initiative CaD trial participants. We also found that baseline serum 25-hydroxyvitamin D level was not predictive of long-term incident AF risk.

The relationship between vitamin D and glaucoma is controversial. The objective of this study was to examine women from the Women's Health Initiative (WHI) to determine if there is an association between vitamin D and incident glaucoma in postmenopausal women. We examined the association between dietary vitamin D intake, vitamin D supplements and serum 25 hydroxyvitamin D (25(OH)D) levels and the risk of developing glaucoma. 143,389 postmenopausal women from the WHI including a subset with serum 25(OH) D measurements were examined to determine the association of dietary, supplemental and serum levels of vitamin D to the development of glaucoma. Dietary intakes of vitamin D, use of vitamin D supplements and serum levels of 25(OH) D were predictors examined for the main outcome of incident glaucoma. In multivariable models adjusted for demographic, clinical variables and medication use, dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and serum 25 (OH) D measurements were not significantly associated with incident glaucoma. In the CaD placebo-controlled intervention clinical trial, there was also no association in the active intervention arm with glaucoma. We conclude that dietary vitamin D intake, supplements and serum levels are not significantly related to the risk of developing glaucoma in postmenopausal women.

Background: Study to describe the degree of menopausal palpitation distress and its demographic, clinical, symptom, and quality-of-life (QOL) correlates. Analysis of existing, baseline, data from peri- and postmenopausal women, 42 to 62 years of age, who participated in the Menopause Strategies–Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials testing interventions for vasomotor symptoms (n = 759). Up to 46.8% of menopausal women report having palpitations, yet the symptom is relatively understudied. Little is known about palpitation distress or its correlates. Materials and Methods: Degree of distress from “heart racing or pounding” was self-reported over the past two weeks as “not at all,” “a little bit,” “moderately,” “quite a bit,” or “extremely.” Other measures included self-report forms, clinic-verified body mass index (BMI), vasomotor symptom diaries, and validated symptom and QOL tools. Results: The percentage who reported palpitation distress was 19.6%, 25.2%, and 33.5% in the three trials or 25.0% overall. In multivariate analysis, the odds of reporting palpitation distress was lower in past smokers (odds ratio [OR] = 0.59 [95% confidence interval (CI) 0.38–0.90]) and current smokers (OR = 0.48 [0.27–0.87]) relative to never-smokers and lower with every 5 kg/m(2) higher BMI (OR = 0.82 [0.69–0.98]).The odds of reporting palpitation distress was higher with every five point more severe insomnia (OR = 1.28 [1.05–1.54]), five point worse depressive symptoms (OR = 1.47 [1.11–1.95]), five point worse perceived stress (OR = 1.19 [1.01–1.39]), and one point worse menopausal QOL (OR = 1.29 [1.06–1.57]). Conclusions: Menopausal palpitation distress is common and associated with demographic, clinical, symptom, and QOL factors. Findings can be used for screening in clinical practice and to justify additional research on this understudied symptom.

BackgroundPrior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.MethodsBiomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women’s Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.ResultsAfter 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.ConclusionsCalibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.

Background We compared vaginal microbial communities in postmenopausal black and white women. Methods Shotgun sequencing of vaginal swabs from postmenopausal women self-identified as black or white was compared using MiRKAT. Results Vaginal community dominance by Lactobacillus crispatus or Lactobacillusgasseri was more common in 44 postmenopausal black women (n = 12, 27%) than among 44 matched white women (n = 2, 5%; P = .01). No individual taxa were significantly more abundant in either group. Conclusions We identified small overall differences in vaginal microbial communities of black and white postmenopausal women. L. crispatus dominance was more common in black women. Clinical Trials Registration NCT02516202 (MsFLASH05) and NCT01418209 (MsFLASH03).

Importance Repeated bone mineral density (BMD) testing to screen for osteoporosis requires resources. For patient counseling and optimal resource use, it is important for clinicians to know whether repeated BMD measurement (compared with baseline BMD measurement alone) improves the ability to discriminate between postmenopausal women who will and will not experience a fracture. Objective To assess whether a second BMD measurement approximately 3 years after the initial assessment is associated with improved ability to estimate fracture risk beyond the baseline BMD measurement alone. Design, Setting, and Participants The Women’s Health Initiative is a prospective observational study. Participants in the present cohort study included 7419 women with a mean (SD) follow-up of 12.1 (3.4) years between 1993 and 2010 at 3 US clinical centers. Data analysis was conducted between May 2019 and December 2019. Main Outcomes and Measures Incident major osteoporotic fracture (ie, hip, clinical spine, forearm, or shoulder fracture), hip fracture, baseline BMD, and absolute change in BMD were assessed. The area under the receiver operating characteristic curve (AU-ROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD were calculated to assess incident fracture risk discrimination during follow-up. Results Of 7419 participants, the mean (SD) age at baseline was 66.1 (7.2) years, the mean (SD) body mass index was 28.7 (6.0), and 1720 (23%) were nonwhite individuals. During the study follow-up (mean [SD] 9.0 [3.5] years after the second BMD measurement), 139 women (1.9%) experienced hip fractures, and 732 women (9.9%) experienced major osteoporotic fracture. In discriminating between women who experience hip fractures and those who do not, AU-ROC values were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD, and 0.73 (95% CI, 0.69-0.77) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar discrimination for hip fracture. For discrimination of major osteoporotic fracture, AU-ROC values were 0.61 (95% CI, 0.59-0.63) for baseline total hip BMD, 0.53 (95% CI, 0.51-0.55) for change in total hip BMD, and 0.61 (95% CI, 0.59-0.63) for the combination of baseline total hip BMD and change in total hip BMD. Femoral neck and lumbar spine BMD values had similar ability to discriminate between women who experienced major osteoporotic fracture and those who did not. Associations between change in bone density and fracture risk did not differ by subgroup, including diabetes, age, race/ethnicity, body mass index, or baseline BMD T score. Conclusions and Relevance The findings of this study suggest that a second BMD assessment approximately 3 years after the initial measurement was not associated with improved discrimination between women who did and did not experience subsequent hip fracture or major osteoporotic fracture beyond the baseline BMD value alone and should not routinely be performed.

ObjectiveCompare the effects of a vaginal estradiol tablet and a vaginal moisturizer, each to placebo, on menopause-related quality of life and mood in postmenopausal women with moderate-severe vulvovaginal symptoms.MethodsA total of 302 postmenopausal women enrolled in a 12-week, double-blind, placebo-controlled randomized trial were assigned to vaginal 10 μg estradiol tablet plus placebo gel (n = 102), vaginal moisturizer plus placebo tablet (n = 100), or dual placebo (n = 100). We measured change from randomization to 12 weeks in total score of the Menopause-Specific Quality of Life (MENQOL) questionnaire. We also evaluated the four MENQOL domains, depressive symptoms as measured by the Patient Health Questionnaire 8, and anxiety symptoms as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire.ResultsTreatment with vaginal estradiol resulted in significantly greater improvement in total MENQOL scores compared to dual placebo (mean difference between arms -0.3 at 12 weeks (95% confidence interval [CI] -0.5, 0.0; P = 0.01). A statistically significant group mean difference favoring vaginal estradiol was observed for the MENQOL sexual function domain (-0.4 at 12 weeks; 95% CI -1.0, 0.1; P = 0.005), but not for any of the other domains. Treatment with vaginal moisturizer did not provide greater improvement compared to placebo in total MENQOL scores (mean difference 0.2 at 12 weeks; 95% CI -0.1, 0.4; P = 0.38) or in any of the MENQOL domains. Neither treatment group showed improvement compared with placebo in the Patient Health Questionnaire 8 or Generalized Anxiety Disorder Questionnaire .ConclusionsTreatment with low-dose vaginal estradiol, but not vaginal moisturizer, modestly improved menopause-related quality of life and sexual function domain scores in postmenopausal women with moderate-severe vulvovaginal symptoms.

Half of all postmenopausal women report symptoms of vulvar, vaginal, or urinary discomfort with substantial impact on sexual function and quality of life; underlying mechanisms leading to symptoms are poorly understood.To examine the possibility that the vaginal microbiota and/or mucosal immune response contributes to the severity of bothersome vaginal symptoms, we conducted a substudy of samples from a randomized trial of vaginal treatment for genitourinary syndrome of menopause to compare these features between women whose symptoms improved and women whose symptoms did not improve.This is a secondary analysis of samples collected in a 12-week randomized trial of treatment with vaginal estradiol or moisturizer vs placebo for moderate-severe postmenopausal symptoms of vaginal discomfort. We randomly selected 20 women in each arm with ≥2-point decrease in most bothersome symptom severity (responders) and 20 matched controls with ≤1-point decrease (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal microbiota (16S ribosomal RNA gene sequencing), vaginal fluid metabolites (broad-based metabolomic profiling), vaginal fluid-soluble immune markers (Meso Scale Discovery), pH, and vaginal maturation index. We compared responders with nonresponders at baseline and across all visits using linear mixed models to evaluate associations with microbiota, metabolites, and immune markers, incorporating visit and participant-specific random effects while controlling for treatment arm.Here, the mean age of women was 61 years (n=120), and most women (92%) were White. At enrollment, no significant differences were observed between responders and nonresponders in age, most bothersome symptom type or severity, microbiota composition or diversity, Lactobacillus dominance, metabolome, or immune markers. There was a significant decrease in diversity of the vaginal microbiota in both responders and nonresponders (P.001) over 12 weeks. Although this change did not differ by responder status, diversity was associated with treatment arm: more women in the estradiol arm (63%) had Lactobacillus-dominant, lower diversity bacterial communities than women in the moisturizer (35%) or dual placebo (23%) arms (P=.001) at 12 weeks. The metabolome, vaginal maturation index, and measured immune markers were not associated with responder status over the 12 weeks but varied by treatment arm.Postmenopausal vaginal symptom severity was not significantly associated with vaginal microbiota or mucosal inflammatory markers in this small study. Women receiving vaginal estradiol experienced greater abundance of lactobacilli and lower vaginal pH at end of treatment.

The association between drinking 100% fruit juice and long-term weight gain is controversial and has been investigated in few studies. We examined whether 100% fruit juice consumption was associated with weight change in a large prospective cohort of postmenopausal women. We analyzed data from 49,106 postmenopausal women in the United States enrolled in the Women's Health Initiative between 1993 and 1998. Food frequency questionnaires at baseline and year 3 assessed food and beverage intake. Body weight was measured at in-person clinic visits. We used linear mixed effects modeling to determine the association between change in 100% fruit juice consumption and 3-year weight change over the same time period. Covariates of interest included age, demographic factors, smoking, body mass index, hormone replacement therapy, lifestyle factors, change in whole fruit intake, and change in sugar-sweetened beverage intake. The mean weight change was 3.2 lbs. over 3 years. In multivariable adjusted analyses, each 1 serving/day increase in 100% fruit juice intake was associated with a 3-year weight gain of 0.39 lbs. (95% confidence interval: 0.10, 0.69). In conclusion, an increase in 100% fruit juice consumption was associated with a small amount of long-term weight gain in postmenopausal women.

The ability of the fracture risk assessment tool (FRAX) to discriminate between women who do and do not experience major osteoporotic fractures (MOFs) is suboptimal. Adding common clinical risk factors may improve discrimination. We used data from the Women's Health Initiative, a prospective study of women aged 50 to 79 years at baseline (n = 99,413; n = 5722 in BMD subset) enrolled at 40 US clinical centers. The primary outcome was incident MOFs assessed annually during 10 years' follow‐up. For prediction of incident MOF, we examined the area under the receiver operatic characteristic curve (AUC) and net reclassification index (NRI) of the FRAX model alone and FRAX plus additional risk factors (singly or together: type 2 diabetes mellitus, frequent falls [≥2 falls in the past year], vasomotor symptoms, self‐reported physical function score [RAND 36‐item Health Survey subscale), and lumbar spine BMD). For NRI calculations, high risk was defined as predicted MOF risk ≥20%. We also assessed calibration as observed MOF events/expected MOF events. The AUC value for FRAX without BMD information was 0.65 (95% CI, 0.65 to 0.66). Compared with the FRAX model (without BMD), the AUC value was not improved by the addition of vasomotor symptoms, diabetes, or frequent falls, but was minimally increased by adding physical function score (AUC 0.66, 95% CI, 0.66 to 0.67). FRAX was well‐calibrated for MOF prediction. The NRI of FRAX + additional variables versus FRAX alone was 5.7% (p 0.99). Additional variables (diabetes, frequent falls, vasomotor symptoms, physical function score, or lumbar spine BMD) did not yield meaningful improvements in NRI or discrimination of FRAX for MOFs. Future studies should assess whether tools other than FRAX provide superior discrimination for prediction of MOFs. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

BACKGROUND: Guidelines recommend fracture risk assessment in postmenopausal women aged 50–64, but the optimal method is unknown. OBJECTIVES: To compare discrimination and calibration of the Fracture Risk Assessment Tool (FRAX) and Garvan fracture risk calculator for predicting fractures in postmenopausal women aged 50–64 at baseline. DESIGN: Prospective observational study. PARTICIPANTS: Sixty-three thousand seven hundred twenty-three postmenopausal women aged 50–64 years participating in the Women’s Health Initiative Observational Study and Clinical Trials. MAIN MEASURES: Incident hip fractures and major osteoporotic fractures (MOF) during 10-year follow-up. Calculated FRAX- and Garvan-predicted hip fracture and MOF fracture probabilities. KEY RESULTS: The observed 10-year hip fracture probability was 0.3% for women aged 50–54 years (n = 14,768), 0.6% for women aged 55–59 years (n = 22,442), and 1.1% for women aged 60–64 years (n = 25,513). At sensitivity thresholds ≥ 80%, specificity of both tools for detecting incident hip fracture during 10 years of follow-up was low: Garvan 30.6% (95% confidence interval [CI] 30.3–31.0%) and FRAX 43.1% (95% CI 42.7–43.5%). At maximal area under the receiver operating characteristic curve (AUC(c), 0.58 for Garvan, 0.65 for FRAX), sensitivity was 16.0% (95% CI 12.7–19.4%) for Garvan and 59.2% (95% CI 54.7–63.7%) for FRAX. At AUC(c) values, sensitivity was lower in African American and Hispanic women than among white women and lower in women aged 50–54 than those 60–64 years old. Observed hip fracture probabilities were similar to FRAX-predicted probabilities but greater than Garvan-predicted probabilities. At AUC(c) values (0.56 for both tools), sensitivity for identifying MOF was also low (range 26.7–46.8%). At AUC(c) values (0.55 for both tools), sensitivity for identifying any clinical fracture ranged from 18.1 to 34.0%. CONCLUSIONS: In postmenopausal women aged 50–64 years, the FRAX and Garvan fracture risk calculator discriminate poorly between women who do and do not experience fracture during 10-year follow-up. There is no useful threshold for either tool. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-018-4696-z) contains supplementary material, which is available to authorized users.

ObjectivesThis study prospectively examined physical activity levels and the incidence of heart failure (HF) in 137,303 women, ages 50 to 79 years, and examined a subset of 35,272 women who, it was determined, had HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF).BackgroundThe role of physical activity in HF risk among older women is unclear, particularly for incidence of HFpEF or HFrEF.MethodsWomen were free of HF and reported ability to walk at least 1 block without assistance at baseline. Recreational physical activity was self-reported. The study documented 2,523 cases of total HF, and 451 and 734 cases of HFrEF and HFpEF, respectively, during a mean 14-year follow-up.ResultsAfter controlling for age, race, education, income, smoking, alcohol, hormone therapy, and hysterectomy status, compared with women who reported no physical activity (reference group), inverse associations were observed across incremental tertiles of total physical activity for overall HF (hazard ratio [HR]: Tertile 1 = 0.89, Tertile 2 = 0.74, Tertile 3 = 0.65; trend p< 0.001), HFpEF (HR: 0.93, 0.70, 0.68; p< 0.001), and HFrEF (HR: 0.81, 0.59, 0.68; p= 0.01). Additional controlling for potential mediating factors included attenuated time-varying coronary heart disease (CHD) (nonfatal myocardial infarction, coronary revascularization) diagnosis but did not eliminate the inverse associations. Walking, the most common form of physical activity in older women, was also inversely associated with HF risks (overall: 1.00, 0.98, 0.93, 0.72; p< 0.001; HFpEF: 1.00, 0.98, 0.87, 0.67; p< 0.001; HFrEF: 1.00, 0.75, 0.78, 0.67; p=0.01). Associations between total physical activity and HF were consistent across subgroups, defined by age, body mass index, diabetes, hypertension, physical function, and CHD diagnosis. Analysis of physical activity as a time-varying exposure yielded findings comparable to those of baseline physical activity.ConclusionsHigher levels of recreational physical activity, including walking, are associated with significantlyreduced HF risk in community-dwelling older women.

Objectives Higher body mass index (BMI) is an important risk factor for atrial fibrillation (AF). The adipokines leptin, adiponectin and resistin are correlates of BMI, but their association with incident AF is not well known. We explored this relationship in a large cohort of postmenopausal women. Methods We studied an ethnically diverse cohort of community-dwelling postmenopausal women aged 50–79 who were nationally recruited at 40 clinical centres as part of the Women9s Health Initiative investigation. Participants underwent measurements of baseline serum leptin, adiponectin and resistin levels and were followed for incident AF. Adipokine levels were log transformed and normalised using inverse probability weighting. Cox proportional hazard regression models were used to estimate associations with adjustment for known AF risk factors. Results Of the 4937 participants included, 892 developed AF over a follow-up of 11.1 years. Those with AF had higher mean leptin (14.9 pg/mL vs 13.9 pg/mL), adiponectin (26.3 ug/mL vs 24.5 ug/mL) and resistin (12.9 ng/mL vs 12.1 ng/mL) levels. After multivariable adjustment, neither log leptin nor log adiponectin levels were significantly associated with incident AF. However, log resistin levels remained significantly associated with incident AF (HR=1.57 per 1 log (ng/mL) increase, p=0.006). Additional adjustment for inflammatory cytokines only partially attenuated the association between resistin and incident AF (HR=1.43, p=0.06 adjusting for C-reactive protein (CRP); HR=1.39, p=0.08 adjusting for IL-6). Adjusting for resistin partially attenuated the association between BMI and incident AF (HR=1.14 per 5 kg/m 2 , p=0.006 without resistin; HR=1.12, p=0.02 with resistin). Conclusions In women, elevated levels of serum resistin are significantly associated with higher rates of incident AF and partially mediate the association between BMI and AF. In the same population, leptin and adiponectin levels are not significantly associated with AF.

Objective Diurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes are associated with aberrant cortisol patterns similar to sleep-deficient individuals. Design Cross-sectional. Participants A total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes. Measurements Baseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (≤5·5, N = 103; >5·5-8·8, N = 103; >8·8, N = 100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates. Results Women were 67% White and 24% African American, with 7·6 (SD 3·9) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 75·0 (SD 44·8) total, 8·6 (SD 5·6) wake, 10·0 (SD 7·5) wake +30 min, 3·7 (SD 3·3) early afternoon and 1·6 (SD 1·8) bedtime. Wake + 30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 11·4(SD 7·3), 10·3 (SD 6·5) and 8·6 (SD 7·8), respectively, P = 0·003. Beside the early afternoon value (P = 0·02), cortisol values did not vary by hot flash frequency. Conclusion Taken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance.

1569 Background: Associations between dietary protein intake and breast cancer are unclear, in part due to limitations of dietary self-report. Women’s Health Initiative (WHI) investigators compared the accuracy of food frequency questionnaire (FFQ) data on energy and protein intake with objective measures of dietary intake using biomarkers (doubly labeled water for energy and urinary nitrogen for protein [n=544]). Subsequently, regression equations incorporating participant characteristics were developed acknowledging differential reporting dietary data errors based on participant characteristics (Neuhouser Am J Epidemiol). FFQ findings were then used to determine biomarker- adjusted animal vs vegetable protein ratios. Methods: We examined associations of energy and protein intake with breast cancer incidence and mortality in Women’s Health Initiative (WHI) participants 50-79 years of age at entry between1993-1998, with breast cancers verified by medical record review and survival enhanced by serial National Death Index (NDI) searches through 2016. Associations between sources of protein intake (animal versus vegetable) quintiles and breast cancer incidence and mortality were estimated using multivariable Cox proportional hazards regression. Results: With 100,024 eligible participants, after 14 years follow-up, women with higher total protein intake had greater body mass index, were more likely White, menopausal hormone therapy users with higher total energy intake and fat intake. With 6,340 incident breast cancers, 764 deaths from breast cancer and 2,059 deaths after breast cancer, higher vegetable protein intake was associated with significantly lower breast cancer incidence (P for linear trend = 0.01) while higher animal protein intake was associated with significantly higher breast cancer incidence (P for linear trend = 0.03). Higher vegetable protein intake was also associated with significantly lower risk of death after breast cancer (P

The human microbiome is a dynamic system that changes due to diseases, medication, change in diet, etc. The paired design is a common approach to evaluate the microbial changes while controlling for the inherent differences between people. For example, microbiome data may be collected from the same individuals before and after a treatment. Two challenges exist in analyzing this type of data. First, microbiome data are compositional such that the reads for all taxa in each sample are constrained to sum to a constant. Second, the number of taxa can be much larger than the sample size. Few statistical methods exist to analyze such data besides methods that test one taxon at a time. In this paper, we propose to first conduct a log-ratio transformation of the compositions, and then develop a generalized Hotelling's test (GHT) to evaluate whether the average microbiome compositions are equivalent in the paired samples. We replace the sample covariance matrix in standard Hotelling's statistic by a shrinkage-based covariance, calculated as a weighted average of the sample covariance and a positive definite target matrix. The optimal weighting can be obtained for many commonly used target matrices. We develop a permutation procedure to assess the statistical significance. Extensive simulations show that our proposed method has well-controlled type I error and better power than a few ad hoc approaches. We apply our method to examine the vaginal microbiome changes in response to treatments for menopausal hot flashes. An R package " GHT" is freely available at https://github.com/zhaoni153/GHT.

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.

Importance Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments. Objective To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms. Design, Setting, and Participants This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration. Interventions Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100). Main Outcomes and Measures The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score–Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH. Results The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, −1.4 (95% CI, −1.6 to −1.2); moisturizer, −1.2 (95% CI, −1.4 to −1.0); and placebo, −1.3 (95% CI, −1.5 to −1.1). No significant differences were seen between estradiol ( P = .25) or moisturizer ( P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) ( P = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo ( P = .17). Conclusions and Relevance Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms. Trial Registration clinicaltrials.gov Identifier:NCT02516202

OBJECTIVE To assess the impact of discontinuing oral hormone therapy (HT) on sexual activity, vaginal symptoms, and sexual activity components among participants in the estrogen-progestin therapy (EPT) and estrogen therapy (ET) trial of the Women's Health Initiative. METHODS Surveys were sent postintervention to those who were still taking study pills and agreed to continue in the study when the trials were stopped. Comparisons between former HT and placebo users were accomplished with chi-square tests for categorical variables and t tests for continuous variables. RESULTS In all, 13,902 women with mean age at survey 69.9 years (EPT trial, women with intact uterus) and 71.7 years (ET trial, women with history of hysterectomy) responded. Prevalence of sexual activity postintervention was not significantly different between former EPT and placebo users (36.0% vs 34.2%; P = 0.37). Sexual activity of former ET users was 5.6% higher than placebo users (27.6% vs 22.0%; P = 0.001). The majority of sexually active women overall maintained orgasmic capacity and sexual satisfaction. Former EPT users were 10% to 12% more likely than former placebo users to report decreased desire, arousal, intercourse, climax, and satisfaction with sexual activity, and also increased dryness and dyspareunia upon discontinuing study drugs (P

Essentials Venous thrombosis is the most common vascular complication of menopausal hormone use.We studied biomarkers to predict thrombosis with hormones in the Women's Health Initiative.Lower proteins C and S, and higher D‐dimer were related to thrombosis risk.The 25% of women with high D‐dimer had a six‐times greater risk of thrombosis with hormones. Background Oral menopausal hormone therapy causes venous thrombosis but whether biomarkers of thrombosis risk can identify women at risk is unknown. Methods We completed a nested case control study in the two Women's Health Initiative hormone trials; 27 347 women aged 50‐79 were randomized to hormone therapy (conjugated equine estrogen with or without medroxyprogesterone acetate) or placebo. With 4 years follow‐up, biomarkers were measured using stored baseline samples prior to starting treatment, and one‐year later, in 215 women who developed thrombosis and 867 controls. Results Overall, lower protein C and free protein S, and higher D‐dimer, prothrombin fragment 1.2 and plasmin‐antiplasmin complex were associated with risk of future thrombosis with odds ratios ranging from 1.9 to 3.2. Compared to women with normal biomarkers assigned to placebo, the risk of thrombosis with hormone therapy was increased among women with abnormal biomarkers, especially elevated D‐dimer, elevated plasmin‐antiplasmin, and low free protein S; the largest association was for D‐dimer: odds ratio 6.0 (95% CI 3.6‐9.8). Differences in associations by hormone use were not significant on the multiplicative scale. Considering a multi‐marker score of eight biomarkers, women with three or more abnormal biomarkers had 15.5‐fold increased odds of VT (95% CI 6.8‐35.1). One‐year changes in biomarkers were not robustly associated with subsequent thrombosis risk. Conclusion Abnormal levels of biomarkers of thrombosis risk identified women at increased risk of future venous thrombosis with oral menopausal hormone therapy. Findings support the potential for clinical use of D‐dimer testing in advance of hormone therapy prescription.

Aims High body mass index (BMI) is a risk factor for atrial fibrillation (AF). The aim of this study was to determine whether lean body mass (LBM) predicts AF. Methods and results The Women's Health Initiative is a study of post-menopausal women aged 50–79 enrolled at 40 US centres from 1994 to 1998. A subset of 11 393 participants at three centres underwent dual-energy X-ray absorptiometry. Baseline demographics and clinical histories were recorded. Incident AF was identified using hospitalization records and diagnostic codes from Medicare claims. A multivariable Cox hazard regression model adjusted for demographic and clinical risk factors was used to evaluate associations between components of body composition and AF risk. After exclusion for prevalent AF or incomplete data, 8832 participants with an average age of 63.3 years remained for analysis. Over the 11.6 years of average follow-up time, 1035 women developed incident AF. After covariate adjustment, all measures of LBM were independently associated with higher rates of AF: total LBM [hazard ratio (HR) 1.24 per 5 kg increase, 95% confidence intervals (CI) 1.14–1.34], central LBM (HR 1.51 per 5 kg increase, 95% CI 1.31–1.74), and peripheral LBM (HR 1.39 per 5 kg increase, 95% CI 1.19–1.63). The association between total LBM and AF remained significant after adjustment for total fat mass (HR 1.22 per 5 kg increase, 95% CI 1.13–1.31). Conclusion Greater LBM is a strong independent risk factor for AF. After adjusting for obesity-related risk factors, the risk of AF conferred by higher BMI is primarily driven by the association between LBM and AF.

ObjectiveThis study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.MethodsA double-blind, placebo-controlled, randomized trial of low-dose oral 17β-E2 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).ResultsTreatment with both E2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E2: 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 E2 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 E2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.ConclusionsBoth low-dose E2 and venlafaxine are effective pharmacologic agents for improving menopause-related quality of life in healthy women with VMS.

The United States Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture (MOF) is at least 9.3% using the Fracture Risk Assessment Tool. In postmenopausal women age 50-64 years old, it is uncertain how the USPSTF screening strategy compares with the Osteoporosis Self-Assessment Tool and the Simple Calculated Osteoporosis Risk Estimate (SCORE) in discriminating women who will and will not experience MOF.This study aimed to assess the sensitivity, specificity, and area under the receiver operating characteristic curve of the three strategies for discrimination of incident MOF over 10 years of follow-up among postmenopausal women age 50-64 years.This was a prospective study conducted between 1993-2008 at 40 US Centers.We analyzed data from participants of the Women's Health Initiative Observational Study and Clinical Trials, age 50-64 years, not taking osteoporosis medication (n = 62 492).The main outcome was 10-year (observed) incidence of MOF.For identifying women with incident MOF, sensitivity of the strategies ranged from 25.8-39.8%, specificity ranged from 60.7-65.8%, and AUC values ranged from 0.52-0.56. The sensitivity of the USPSTF strategy for identifying incident MOF ranged from 4.7% (3.3-6.0) among women age 50-54 years to 37.3% (35.4-39.1) for women age 60-64 years. Adjusting the thresholds to improve sensitivity resulted in decreased specificity.Our findings do not support use of the USPSTF strategy, Osteoporosis Self-Assessment Tool, or SCORE to identify younger postmenopausal women who are at higher risk of fracture. Our findings suggest that fracture prediction in younger postmenopausal women requires assessment of risk factors not included in currently available strategies.

Knowledge regarding association of dietary branched-chain amino acid (BCAA) and type 2 diabetes (T2D), and the contribution of BCAA from meat to the risk of T2D are scarce. We evaluated associations between dietary BCAA intake, meat intake, interaction between BCAA and meat intake and risk of T2D. Data analyses were performed for 74 155 participants aged 50−79 years at baseline from the Women’s Health Initiative for up to 15 years of follow-up. We excluded from analysis participants with treated T2D, and factors potentially associated with T2D or missing covariate data. The BCAA and total meat intake was estimated from FFQ. Using Cox proportional hazards models, we assessed the relationship between BCAA intake, meat intake, and T2D, adjusting for confounders. A 20 % increment in total BCAA intake (g/d and %energy) was associated with a 7 % higher risk for T2D (hazard ratio (HR) 1·07; 95 % CI 1·05, 1·09). For total meat intake, a 20 % increment was associated with a 4 % higher risk of T2D (HR 1·04; 95 % CI 1·03, 1·05). The associations between BCAA intake and T2D were attenuated but remained significant after adjustment for total meat intake. These relations did not materially differ with or without adjustment for BMI. Our results suggest that dietary BCAA and meat intake are positively associated with T2D among postmenopausal women. The association of BCAA and diabetes risk was attenuated but remained positive after adjustment for meat intake suggesting that BCAA intake in part but not in full is contributing to the association of meat with T2D risk.

The objective of this study was to determine whether consumption of 100% fruit juice as compared to whole fruit is associated with increased risk of hypertension or diabetes. We analyzed postmenopausal women in the United States enrolled in the Women’s Health Initiative between 1993 and 1998. Whole fruit and 100% fruit juice intake were assessed by baseline food frequency questionnaire. Standardized questionnaires assessed outcomes every 6–12 months during a mean 7.8 years of follow-up. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for incident hypertension (n= 36,314 incident cases/80,539 total participants) and diabetes (n=11,488 incident cases/114,219 total participants). In multivariable analyses there was no significant association comparing the highest to lowest quintiles of 100% fruit juice consumption (8 ounces/day compared to none) and incident hypertension (HR 1.00, 95% CI 0.97–1.03) or diabetes (HR 0.96, 95% CI 0.90–1.03). There was also no significant association between whole fruit consumption (2.4 servings/day compared to 0.3 servings/day) and incident hypertension (HR 1.02, 95% CI 0.98–1.05) or diabetes (HR 1.03, 95% CI 0.96–1.10). Consuming moderate amounts of 100% fruit juice or whole fruit was not significantly associated with risk of hypertension or diabetes among postmenopausal US women.

Objective This study aims to determine the positive and negative predictive values of self-reported diabetes during the Women's Health Initiative (WHI) clinical trials. Methods All WHI trial participants from four field centers who self-reported diabetes at baseline or during follow-up, as well as a random sample of women who did not self-report diabetes, were identified. Women were surveyed regarding diagnosis and treatment. Medical records were obtained and reviewed for documented treatment with antidiabetes medications or for physician diagnosis of diabetes supported by laboratory measurements of glucose. Results We identified 1,275 eligible participants; 732 consented and provided survey data. Medical records were obtained for 715 women (prevalent diabetes, 207; incident diabetes, 325; no diabetes, 183). Records confirmed 91.8% (95% CI, 87.0-95.0) of self-reported prevalent diabetes cases and 82.2% (95% CI, 77.5-86.1) of incident diabetes cases. Among those who never self-reported diabetes, there was no medical record or laboratory evidence for diabetes in 94.5% (95% CI, 89.9-97.2). Women with higher body mass index were more likely to accurately self-report incident diabetes. In a subgroup of participants enrolled in fee-for-service Medicare, a claims algorithm correctly classified nearly all diabetes cases and noncases. Conclusions Among WHI clinical trial participants, there are high positive predictive values of self-reported prevalent diabetes (91.8%) and incident diabetes (82.2%) and a high negative predictive value (94.5%) when diabetes is not reported. For participants enrolled in fee-for-service Medicare, a claims algorithm has high positive and negative predictive values.

Author(s): Reed, Susan D; Mitchell, Caroline M; Joffe, Hadine; Cohen, Lee; Shifren, Jan L; Newton, Katherine M; Freeman, Ellen W; Larson, Joseph C; Manson, JoAnn E; LaCroix, Andrea Z; Guthrie, Katherine A | Abstract: ObjectiveTo evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes.MethodsIn an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between 0.5 mg oral estradiol per day or 75 mg venlafaxine per day (both compared with a placebo). Measures included composite and six domain scores from the Female Sexual Function Index and sexually related personal distress.ResultsParticipants were aged 54.6 years (standard deviation [SD] 3.8) years, 59% white, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean Female Sexual Function Index change from baseline to week 8 was 1.4 (95% confidence interval [CI] -0.4 to 3.2) for estradiol, 1.1 (95% CI -0.5 to 2.7) for venlafaxine, and -0.3 (95% CI -1.6 to 1.0) for placebo. Composite Female Sexual Function Index and sexually related distress change from baseline did not differ between estradiol and placebo (P=.38, P=.30) or venlafaxine and placebo (P=.79, P=.48). Among sexually active women, Female Sexual Function Index domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0-0.6) for estradiol, -0.6 (95% CI -1.2 to 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2-1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction.ConclusionOverall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8 weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although a subtle increase in desire (estradiol) and decreases in orgasm and pain (venlafaxine) may exist.Clinical trial registrationClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209.Level of evidenceI.

The US Preventive Services Task Force (USPSTF) recommends osteoporosis screening for women younger than 65 years whose 10-year predicted risk of major osteoporotic fracture is ≥ 9.3%. For identifying screening candidates among women aged 50 to 64 years, it is uncertain how the USPSTF strategy compares with the Osteoporosis Self-Assessment Tool (OST) and the Simple Calculated Osteoporosis Risk Estimate (SCORE). We examined data (1994 to 2012) from 5165 Women's Health Initiative participants aged 50 to 64 years. For the USPSTF (Fracture Risk Assessment Tool [FRAX] major fracture risk ≥ 9.3% calculated without bone mineral density [BMD]), OST (score 7) strategies, we assessed sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) to discriminate between those with and without femoral neck (FN) T-score ≤-2.5. Sensitivity, specificity, and AUC for identifying FN T-score ≤-2.5 were 34.1%, 85.8%, and 0.60 for USPSTF (FRAX); 74.0%, 70.8%, and 0.72 for SCORE; and 79.8%, 66.3%, and 0.73 for OST. The USPSTF strategy identified about one-third of women aged 50 to 64 years with FN T-scores ≤-2.5. Among women aged 50 to 64 years, the USPSTF strategy was modestly better than chance alone and inferior to conventional SCORE and OST strategies in discriminating between women with and without FN T-score ≤-2.5.

Author(s): Orchard, Tonya S; Larson, Joseph C; Alghothani, Nora; Bout-Tabaku, Sharon; Cauley, Jane A; Chen, Zhao; LaCroix, Andrea Z; Wactawski-Wende, Jean; Jackson, Rebecca D | Abstract: BackgroundMagnesium is a necessary component of bone, but its relation to osteoporotic fractures is unclear.ObjectiveWe examined magnesium intake as a risk factor for osteoporotic fractures and altered bone mineral density (BMD).DesignThis prospective cohort study included 73,684 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Total daily magnesium intake was estimated from baseline food-frequency questionnaires plus supplements. Hip fractures were confirmed by a medical record review; other fractures were identified by self-report. A baseline BMD analysis was performed in 4778 participants.ResultsBaseline hip BMD was 3% higher (P l 0.001), and whole-body BMD was 2% higher (P l 0.001), in women who consumed g422.5 compared with l206.5 mg Mg/d. However, the incidence and RR of hip and total fractures did not differ across quintiles of magnesium. In contrast, risk of lower-arm or wrist fractures increased with higher magnesium intake [multivariate-adjusted HRs of 1.15 (95% CI: 1.01, 1.32) and 1.23 (95% CI: 1.07, 1.42) for quintiles 4 and 5, respectively, compared with quintile 1; P-trend = 0.002]. In addition, women with the highest magnesium intakes were more physically active and at increased risk of falls [HR for quintile 4: 1.11 (95% CI: 1.06, 1.16); HR for quintile 5: 1.15 (95% CI: 1.10, 1.20); P-trend l 0.001].ConclusionsLower magnesium intake is associated with lower BMD of the hip and whole body, but this result does not translate into increased risk of fractures. A magnesium consumption slightly greater than the Recommended Dietary Allowance is associated with increased lower-arm and wrist fractures that are possibly related to more physical activity and falls.

Objective This study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms. Methods Late perimenopausal and postmenopausal sedentary women with frequent vasomotor symptoms (VMS) participated in a randomized controlled trial conducted in three sites: 106 women randomized to exercise and 142 women randomized to usual activity. The exercise intervention consisted of individual facility-based aerobic exercise training three times per week for 12 weeks. VMS frequency and bother were recorded on daily diaries at baseline and on weeks 6 and 12. Intent-to-treat analyses compared between-group differences in changes in VMS frequency and bother, sleep symptoms (Insomnia Severity Index and Pittsburgh Sleep Quality Index), and mood (Patient Health Questionnaire-8 and Generalized Anxiety Disorder-7 questionnaire). Results At the end of week 12, changes in VMS frequency in the exercise group (mean change, -2.4 VMS/d; 95% CI, -3.0 to -1.7) and VMS bother (mean change on a four-point scale, -0.5; 95% CI, -0.6 to -0.4) were not significantly different from those in the control group (-2.6 VMS/d; 95% CI, -3.2 to -2.0; P = 0.43; -0.5 points; 95% CI, -0.6 to -0.4; P = 0.75). The exercise group reported greater improvement in insomnia symptoms (P = 0.03), subjective sleep quality (P = 0.01), and depressive symptoms (P = 0.04), but differences were small and not statistically significant when P values were adjusted for multiple comparisons. Results were similar when considering treatment-adherent women only. Conclusions These findings provide strong evidence that 12 weeks of moderate-intensity aerobic exercise do not alleviate VMS but may result in small improvements in sleep quality, insomnia, and depression in midlife sedentary women.