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Learning Objectives: After participating in this activity, learners should be better able to:• Outline the clinical recommendations for menopausal hormone treatment related to cognitive concerns• Debate and discuss the various research pieces on the use of menopausal hormone therapy cognitive decline, dysfunction, and dementia., Abstract: Menopause has been associated with subjective cognitive dysfunction and elevated rates of depression. While menopausal hormone therapy (MHT) is Food and Drug Administration-approved for the treatment of vasomotor symptoms related to menopause, a potential role for MHT in treating and preventing cognitive decline, dysfunction, and dementia has remained unclear and a topic of continued interest and debate across decades of research. Increasing numbers of patients are seeking help for subjective cognitive decline, and those with poorer mental health are substantially more likely to perceive themselves to be at high risk of developing dementia; thus, mental health professionals are likely to encounter such patients and may be asked to provide advice concerning MHT, cognition, and indications for MHT use. Here, we synthesize the neurobiological effects of MHT, make recommendations for its use in current clinical practice in the contexts of cognitive dysfunction associated with major depressive disorder, cognitive decline, and Alzheimer's disease, and discuss the frontiers being explored by ongoing research on this topic. We conclude that MHT to improve cognitive functioning has only a few scenarios where it would be recommended and that particular caution may be warranted for carriers of the APOE ε4 allele., (Copyright © 2022 President and Fellows of Harvard College.)

Background and Purpose: Emerging work has linked menopausal vasomotor symptoms (VMS) to subclinical cardiovascular disease (CVD) among women. However, VMS are dynamic over time. No studies have considered how temporal patterns of VMS may relate to subclinical CVD. We tested how temporal patterns of VMS assessed over 13 years were related to carotid intima media thickness (IMT) among midlife women., Methods: The Study of Women's Health Across the Nation is a longitudinal cohort study of midlife women. Eight hundred and eleven white, black, Hispanic, and Chinese participants with a well-characterized final menstrual period completed measures of VMS, a blood draw, and physical measures approximately annually for 13 years. Women underwent a carotid artery ultrasound at study visit 12., Results: Four trajectories of VMS were identified by trajectory analysis (consistently high, early-onset, late-onset, persistently low VMS) and tested in relation to carotid indices in linear regression models. Results indicated that women with early-onset VMS had both greater mean IMT (beta, b [standard error, SE]=0.03 [0.01], P=0.03) and greater maximal IMT (b [SE]=0.04 [0.01], P=0.008) than women with consistently low VMS, adjusting for demographics and CVD risk factors., Conclusions: This is the first study to test trajectories of VMS in relation to subclinical CVD. Women with VMS early in the menopause transition had higher mean IMT and maximal IMT than those with consistently low VMS across the transition. Associations were not accounted for by demographic factors nor by CVD risk factors. Results can signal to women in need of early CVD risk reduction., (© 2015 American Heart Association, Inc.)

Objective: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials., Methods: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time., Results: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements., Conclusion: These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).

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: To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes., Methods: In 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., Results: Participants 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., Conclusion: Overall 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 Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209., Level of Evidence: I.

Objective: To examine whether mood symptoms increased more for women in the years after hysterectomy with or without bilateral oophorectomy relative to natural menopause., Methods: Using data from the Study of Women's Health Across the Nation (n=1,970), depression and anxiety symptoms were assessed annually for up to 10 years with the Center for Epidemiological Studies Depression Index and four anxiety questions, respectively. Piece-wise hierarchical growth models were used to relate natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy to trajectories of mood symptoms before and after the final menstrual period or surgery. Covariates included educational attainment, race, menopausal status, age the year before final menstrual period or surgery, and time-varying body mass index, self-rated health, hormone therapy, and antidepressant use., Results: By the tenth annual visit, 1,793 (90.9%) women reached natural menopause, 76 (3.9%) reported hysterectomy with ovarian conservation, and 101 (5.2%) reported hysterectomy with bilateral oophorectomy. For all women, depressive and anxiety symptoms decreased in the years after final menstrual period or surgery. These trajectories did not significantly differ by hysterectomy or oophorectomy status. The Center for Epidemiological Studies Depression Index means were 0.72 standard deviations lower and anxiety symptoms were 0.67 standard deviations lower 5 years after final menstrual period or surgery., Conclusion: In this study, mood symptoms continued to improve after the final menstrual period or hysterectomy for all women. Women who undergo a hysterectomy with or without bilateral oophorectomy in midlife do not experience more negative mood symptoms in the years after surgery., Level of Evidence: II.

Objective: To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle-stimulating hormone., Methods: Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A-1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle-stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones., Results: Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: β [standard error]=1.48 [0.47], P<.01; 6 days or more: β [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: β [standard error]=0.30 [0.18]; 6 days or more: β [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: β [standard error]=0.92 [0.47], P<.10; 6 days or more: β [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: β [standard error]=1.41 [0.41], P<.001; 6 days or more: β [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41-4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women., Conclusion: Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk., Level of Evidence: II.

The lifetime risk for major depression in women is well known to be twice the risk in men and is especially high during the reproductive years between menarche and menopause. A subset of reproductive-age women experience depressive episodes that are triggered by hormonal fluctuations. Such "reproductive depressions" involve episodes of depression that occur specifically during the premenstrual, postpartum, and perimenopausal phases in women. These reproductive subtypes of depression can be conceptualized as a specific biological response to the effects of hormonal fluctuations in the brain. The different types of reproductive depressions are associated with each other, have unique risk factors that are distinct from nonreproductive depression episodes, and respond to both hormonal and nonhormonal interventions. This review uses a PubMed search of relevant literature to discuss clinical, animal, and genetic evidence for reproductive depression as a specific subtype of major depression. Unique treatment options, such as hormonal interventions, are also discussed, and hypotheses regarding the underlying biology of reproductive depression-including interactions between the serotonergic system and estrogen, as well as specific effects on neurosteroids-are explored. This review will provide evidence supporting reproductive depression as a distinct clinical entity with specific treatment approaches and a unique biology that is separate from nonreproductive depression.