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Abstract Objective Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the United States. Cardiometabolic risk further increases with psychosocial stress exposure and during menopausal transition in women. Because disease risk and stress burden are associated with aberrant immune signaling, we hypothesized that responses of interleukin-6 (IL-6) to psychosocial stress may predict longitudinal cardiometabolic outcomes in perimenopausal women. Methods We conducted post hoc analyses in 151 perimenopausal or early postmenopausal women participants in a previously completed study. At study onset, participants underwent the Trier Social Stress Test (TSST), and plasma IL-6 was measured repeatedly before and during the 1 hour post-TSST. Subsequently, participants were randomly assigned to either hormonal treatment (HT) or placebo and followed for 12 months to determine longitudinal changes in cardiometabolic biomarkers. Results Greater IL-6 reactivity to stress, measured with baseline-adjusted area under the curve, predicted 12-month decrease in flow-mediated dilatation of the brachial artery (P = 0.0005), a measure of endothelial-dependent vascular function, but not in endothelial-independent function measured with nitroglycerin-mediated dilatation (P = 0.17). Greater baseline IL-6 levels predicted 12-month increase in insulin resistance based on the homeostatic model assessment of insulin resistance score (P = 0.0045) and in the number of criteria met for metabolic syndrome (P = 0.0008). These predictions were not moderated by HT. Conclusions Greater baseline IL-6 levels as well as its reactivity to stress may predict worsening in distinct cardiometabolic biomarkers as women transition to menopause. Interleukin-6 reactivity predicts decline in endothelial-dependent vascular function, whereas baseline IL-6 presages accumulation of metabolic risk.

Abstract Context Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated. Objective To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology. Design and Intervention Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models. Setting Academic medical center. Patients Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3). Main Outcome Measure Depressive symptoms (MADRS score). Results During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = −2.62 [95% CI, −4.52 to −0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events. Conclusions Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.

Abstract Background The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease. Methods Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12. Results Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing. Conclusions TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Abstract Context Menopause, the permanent cessation of menses, reflects oocyte depletion and loss of gonadal steroids. It is preceded by a transition state, the perimenopause, which is characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns. The goal of this mini-review is to discuss the basic pathophysiology of the menopausal transition and the hormonal and nonhormonal management of clinicopathology attributed to it. Evidence Acquisition A Medline search of epidemiologic, population-based studies, and studies of reproductive physiology was conducted. A total of 758 publications were screened. Evidence Synthesis The reproductive hormonal milieu of the menopausal transition precipitates bothersome vasomotor symptoms, mood disruption, temporary cognitive dysfunction, genitourinary symptoms, and other disease processes that reduce the quality of life of affected women. The endocrine tumult of the menopause transition also exposes racial and socioeconomic disparities in the onset, severity, and frequency of symptoms. Hormone therapy (HT) treatment can be effective for perimenopausal symptoms but its use has been stymied by concerns about health risks observed in postmenopausal HT users who are older than 60 and/or women who have been postmenopausal for greater than 10 years. Conclusions The menopause transition is a disruptive process that can last for over a decade and causes symptoms in a majority of women. It is important for clinicians to recognize early signs and symptoms of the transition and be prepared to offer treatment to mitigate these symptoms. Many safe and effective options, including HT, are available.

Aims To explore the efficacy of Femoston plus escitalopram for perimenopausal women with chronic insomnia and the relevant biomarkers. Methods A total of 166 patients randomly received: escitalopram plus placebo (Escitalopram Group), Femoston plus placebo (Hormone Group), and Femoston plus escitalopram (Combined Group) for 3 months and followed for 2, 4, 8, and 12 weeks. The primary efficacy endpoint was changes in Pittsburgh Sleep Quality Index Scale (PSQI), Insomnia Severity Index Scale (ISI), and Epworth Sleepiness Scale (ESS) scores at week 12 from baseline. Secondary endpoints included changes in the Modified Kupperman Menopausal Index Scale (KMI) scores, blood 5‐HT neurotransmitters and their receptor, and blood sex hormone levels during the treatment. Results Compared with baseline levels, all groups displayed increased serum 5‐HT levels and decreased serum FSH levels, with more significant changes in the combined group. Compared with the other two groups, the combined group reported a gradual increase in serum E2 levels and a gradual decrease in serum LH levels, and the lowest KMI, ESS, ISI, and PSQI scores at weeks 4 and 12. The PSQI score was negatively correlated with serum 5‐HT and E2 and positively correlated with serum FSH and LH levels, respectively. Conclusion Femoston plus escitalopram improves chronic insomnia in perimenopausal women. Serum levels of 5‐HT, E2, FSH, and LH may objectively indicate the clinical severity of chronic insomnia in this population. Compared with hormone or escitalopram alone, a combined therapy of Femoston with escitalopram may be more effective in the treatment of perimenopausal chronic insomnia. Serum levels of 5‐HT, E2, FSH, and LH may serve as objective indicators to assess the disease severity in perimenopausal women.

Abstract Context Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of depression, and studies have documented the role of stress and stressful life events in the ontogeny of perimenopausal depressions (PMD). Because HPA axis function in women is further modulated both by aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD. Objective We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone–corticotropin-releasing hormone (Dex/CRH) test. Methods Dex/CRH tests were performed on 20 women with PMD and 20 women who were also perimenopausal but without current or past depression (control women). Main outcome measures were plasma levels of cortisol and adrenocorticotropin (ACTH) and 24-hour urinary free cortisol (UFC). Five women took chronic stable medications, otherwise all women were medically healthy, and both groups were comparable with respect to reproductive stage and age. Standardized symptom rating scales were administered to each woman prior to Dex/CRH testing. Results No group differences were present in either baseline or stimulated ACTH and cortisol secretion. Baseline plasma measures of estradiol, progesterone, and 24-hour UFC levels similarly did not differ in PMD and control women. Conclusion Despite reports of increased stress responsiveness in PMD, we observed no abnormalities of HPA axis activity associated with PMD compared with women without depression. These findings suggest that PMD is not uniformly associated with HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from women with nonreproductive-related depressions.

Key Points The clinical definition of perimenopause focuses on functional changes in the reproductive system; however, the symptoms of the perimenopause are largely neurological in nature Most women transition through perimenopause without long-term adverse effects; however, a substantial proportion of women emerge from this transition with an increased risk of neurological decline Estrogen functions as a master regulator to ensure the brain responds appropriately to coordinate signalling and transcriptional pathways that regulate energy metabolism The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and a hypometabolic state associated with neurological dysfunction emerges In neurological transition states, indicators of dysfunction at the limits of those normally seen can signal tipping points for neurological diseases The presence, variability, intensity and duration of neurological perimenopausal symptoms could be warning signs for increased risk of neurodegenerative diseases later in life All women, regardless of ethnicity, geographic location or culture will transition through perimenopause. Many of the neurological symptoms that emerge during this transition are the result of estrogen depletion in the brain. In this Review, the authors discuss the neurological symptoms associated with perimenopause in the context of estrogen-mediated processes in the brain. Perimenopause is a midlife transition state experienced by women that occurs in the context of a fully functioning neurological system and results in reproductive senescence. Although primarily viewed as a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in the context of their relationship to the network of estrogen receptors that control metabolism in the brain.

Purpose of Review To review recent research regarding cognitive problems during perimenopause, including which menopause-related symptoms, demographic variables, stress exposures, and neural biomarkers are associated with cognitive problems and which interventions demonstrate efficacy at improving cognitive performance. Recent Findings Cognitive problems are common during perimenopause and have a significant impact on a substantial proportion of women. Evidence continues to indicate that verbal learning and verbal memory are the cognitive functions that are most negatively affected during perimenopause, and new research suggests that perimenopause may also be associated with deficits in processing speed, attention, and working memory. Recent research suggests that the cognitive profiles of women transitioning through perimenopause are heterogenous – with some showing strengths and others demonstrating weaknesses in particular cognitive domains. Depression, sleep problems, and vasomotor symptoms in perimenopause may be associated with cognitive difficulties. Recent neuroimaging studies are identifying changes in activity patterns within brain regions that correlate with cognitive performance in perimenopause, but future causal studies are needed to understand the neural mechanisms of cognitive problems during this time. Although clinical treatment studies for cognitive concerns have historically focused on postmenopause, some small trials in perimenopausal samples have been conducted recently but are frequently underpowered. Current guidelines from the North American Menopause Society do not support the use of hormone therapy at any age for cognitive problems. Animal research demonstrates that estradiol and levonorgestrel combined may alleviate working memory problems. Summary Much progress has been made in understanding how perimenopause impacts cognition, and more research is needed to better identify who is at highest risk and how to meaningfully prevent and alleviate cognitive problems during this reproductive stage. Larger-scale randomized intervention trials specifically during perimenopause are urgently needed to address cognitive concerns in this population of women. More consistent reproductive staging, inclusion of covariates, and analyses examining perimenopause specifically would improve study quality and the ability to draw clear conclusions from this research.

BackgroundKnowledge of the impact of perimenopause on women with attention-deficit/hyperactivity disorder (ADHD) is lacking. We compared levels of perimenopausal symptoms and prevalence of severe perimenopausal symptoms among women with and without ADHD across age groups.MethodsIn this cohort study, we used data from the population-based Stress-and-Gene-Analysis cohort study. ADHD diagnosis was self-reported at baseline and 5-year follow-up. At follow-up, we assessed ADHD symptoms using the Adult ADHD Self-Report Scale, perimenopausal symptoms (psychological, somatic, and urogenital) using Menopause Rating Scale (MRS), and general physical symptoms using Patient Health Questionnaire. We described mean scores and mean difference on MRS among women with and without ADHD with linear regression models and contrasted the prevalence of severe perimenopausal symptoms among women with and without ADHD, calculating prevalence ratios (PRs) with 95% confidence intervals (CIs) using modified Poisson regression models.ResultsWomen with ADHD (n = 535) had higher total perimenopausal symptom scores (18.0 vs. 13.0, p < 0.01) than women without ADHD (n = 4,857). The difference was most pronounced among women aged 35–39 years (19.0 vs. 12.5, p < 0.01). The prevalence of severe perimenopausal symptoms was significantly higher among women with ADHD compared to those without, both overall (54.2% vs. 30.1%, PR = 1.80, 95% CI = 1.64–1.98) and on all subdimensions (psychological: 58.6% vs. 36.0%, PR = 1.63, 95% CI = 1.51–1.76; somatic: 30.4% vs. 13.9%, PR = 2.20, 95% CI = 1.88–2.57; uro-genital: 43.2% vs. 27.5%, PR = 1.57, 95% CI = 1.40–1.77).ConclusionWomen with ADHD have higher prevalence of severe perimenopausal symptoms. These symptoms present at an earlier age than among women without ADHD, indicating an earlier onset age of perimenopause in ADHD.