Most women worldwide experience menopausal symptoms during the menopause transition or postmenopause. Vasomotor symptoms are most pronounced during the first four to seven years but can persist for more than a decade, and genitourinary symptoms tend to be progressive. Although the hallmark symptoms are hot flashes, night sweats, disrupted sleep, and genitourinary discomfort, other common symptoms and conditions are mood fluctuations, cognitive changes, low sexual desire, bone loss, increase in abdominal fat, and adverse changes in metabolic health. These symptoms and signs can occur in any combination or sequence, and the link to menopause may even be elusive. Estrogen based hormonal therapies are the most effective treatments for many of the symptoms and, in the absence of contraindications to treatment, have a generally favorable benefit:risk ratio for women below age 60 and within 10 years of the onset of menopause. Non-hormonal treatment options are also available. Although a symptom driven treatment approach with individualized decision making can improve health and quality of life for midlife women, menopausal symptoms remain substantially undertreated by healthcare providers.

The potential risk for mental health conditions over the menopause transition shapes women's expectations and informs putative physiological mechanisms regulating women's mental health. We review evidence from prospective studies reporting on associations between mental health conditions and the menopause transition. Major depressive disorder and the more prevalent subthreshold depressive symptoms are the most common conditions studied. We reviewed 12 prospective studies reporting depressive symptoms, major depressive disorder, or both over the menopause transition and found no compelling evidence for a universal increased risk for either condition. However, specific subgroups of participants, primarily defined by menopause-related risk factors (ie, vasomotor symptoms that are severe or disturb sleep, a long duration of the transition, or reproductive hormone dynamics) and psychosocial risk factors (eg, stressful life events), were vulnerable to depressive symptoms. The increased risk of major depressive disorder over the menopause transition appears predominantly in individuals with previous major depressive disorder. Greater focus on recognising risk factors in primary care is warranted. On the basis of scarce data, we found no compelling evidence that risk of anxiety, bipolar disorder, or psychosis is universally elevated over the menopause transition. Potential misattribution of psychological distress and psychiatric disorders to menopause could harm women by delaying accurate diagnosis and the initiation of effective psychotropic treatments, and by creating negative expectations for people approaching menopause. A paradigm shift is needed. We conclude with recommendations for the detection and treatment of depressive symptoms or major depressive disorder and strategies to promote good mental health over the menopause transition, while responsibly preparing and supporting those at risk.Copyright © 2024 Elsevier Ltd. All rights reserved.

Menopause is a biological process experienced by all people assigned female at birth. A significant number of women experience mental ill health related to the major brain gonadal hormone shifts that occur in their midlife. There is poor understanding and management of the complex mental ill health issues, with the biological brain hormone changes receiving little formal attention. The current treatment advice is to manage this special type of mental ill health in the same way that all mental ill health is managed. This leads to poor outcomes for women and their families. Many women leave the workforce earlier than expected due to menopause-related depression and anxiety, with subsequent loss of salary and superannuation. Others describe being unable to adequately parent or maintain meaningful relationships - all ending in a poor quality of life. We are a large and diverse group of national and international clinicians, lived experience and social community advocates, all working together to innovate the current approaches available for women with menopausal mental ill health. Above all, true innovation is only possible when the woman with lived experience of menopause is front and centre of this debate.

17Beta-estradiol (E2)-induced neuroprotection is dependent on mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling cascades. We sought to determine whether E2 neuroprotective mechanisms are mediated by a unified signaling cascade activated by estrogen receptor (ER)-PI3K interaction within the same population of neurons or whether E2 activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are independent signaling events in different neuronal populations. Immunoprecipitation of E2-treated cortical neurons was conducted to determine a protein-protein interaction between ER and the PI3K regulatory subunit p85. Subsequently, cortical neurons were treated with E2 alone or in presence of MAPK inhibitors or PI3K inhibitors. Results of these analyses indicated a protein-protein interaction between ER and p85 that was time-dependent and consistent with the temporal profile for generation of Akt (pAkt) and ERK1/2 phosphorylation (pERK1/2). E2-induced phosphorylation of Akt, was first apparent at 10 min and maximal at 30 min. Simultaneously, E2-induced pERK1/2 was first apparent at 5-10 min and maximal at 30 min. Inhibition of PI3K completely blocked E2 activation of pAkt at 10 and 30 min and blocked E2 activation of ERK1/2 at 10 min, which revealed a PI3K-independent activation of ERK at 30 min. Double immunocytochemical labeling for pERK1/2 and pAkt demonstrated that E2 induced both signaling pathways in the same neurons. These results indicate a unified signaling mechanism for rapid E2 action that leads to the coordinated activation of both pERK1/2 and pAkt in the same population of neurons. Implications of these results for understanding estrogen mechanism of action in neurons and therapeutic development are considered.

Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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). Since HPA axis function in women is further modulated by both aging and ovarian steroids, it is possible that a dysregulated HPA axis contributes to the increased risk of PMD.We examined HPA axis function in perimenopausal women with and without depression using the combined dexamethasone-CRH (Dex/CRH) test.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 ACTH and 24-hour urinary free cortisol. 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.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.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 non-reproductive-related depressions.Published by Oxford University Press on behalf of the Endocrine Society 2021.

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.

Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]).Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene.During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

The expression of BDNF in both neuronal and non-neuronal cells is influenced by various stimuli, including prenatal developmental factors and postnatal conditions such as estrogens, dietary habits, and lifestyle factors like obesity, blood pressure, and aging. Central BDNF plays a crucial role in modulating how target tissues respond to these stimuli, influencing the pathogenesis of hypertension, mitigating obesity, and protecting neurons from aging. Thus, BDNF serves as a dynamic mediator of environmental influences, reflecting an individual's unique history of exposure. Estrogens, on the other hand, regulate various processes to maintain overall physiological well-being. Through nuclear estrogen receptors (ERα, ERβ) and the membrane estrogen receptor (GPER1), estrogens modulate transcriptional processes and signaling events that regulate the expression of target genes, such as ERα, components of the renin-angiotensin system (RAS), and hormone-sensitive lipase. Estrogens are instrumental in maintaining the set point for blood pressure and energy balance. BDNF and estrogens work cooperatively to prevent obesity by favoring lipolysis, and counteractively regulate blood pressure to adapt to the environment. Estrogen deficiency leads to menopause in women with low central BDNF level. This review delves into the complex mechanisms involving BDNF and estrogen, especially in the context of hypertension and obesity, particularly among postmenopausal women. The insights gained aim to inform the development of comprehensive therapeutic strategies for these prevalent syndromes affecting approximately 68% of adults.

\n There is a new appreciation of the perimenopause—defined as the early and late menopause transition stages as well as the early postmenopause—as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: (1) epidemiology; (2) clinical presentation; (3) therapeutic effects of antidepressants; (4) effects of hormone therapy; and (5) efficacy of other therapies (\n e.g.\n, psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (\n i.e.\n, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (\n i.e.\n, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.\n

The Menopause-Specific Quality of Life (MENQOL) questionnaire was developed as a validated research tool to measure condition-specific QOL in early postmenopausal women. We conducted a comprehensive scoping review to explore the extent of MENQOL's use in research and clinical practice to assess its value in providing effective, adequate, and comparable participant assessment information.Thirteen biomedical and clinical databases were systematically searched with "menqol" as a search term to find articles using MENQOL or its validated derivative MENQOL-Intervention as investigative or clinical tools from 1996 to November 2014 inclusive. Review articles, conference abstracts, proceedings, dissertations, and incomplete trials were excluded. Additional articles were collected from references within key articles. Three independent reviewers extracted data reflecting study design, intervention, sample characteristics, MENQOL questionnaire version, modifications and language, recall period, and analysis detail. Data analyses included categorization and descriptive statistics.The review included 220 eligible papers of various study designs, covering 39 countries worldwide and using MENQOL translated into more than 25 languages. A variety of modifications to the original questionnaire were identified, including omission or addition of items and alterations to the validated methodological analysis. No papers were found that described MENQOL's use in clinical practice.Our study found an extensive and steadily increasing use of MENQOL in clinical and epidemiological research over 18 years postpublication. Our results stress the importance of proper reporting and validation of translations and variations to ensure outcome comparison and transparency of MENQOL's use. The value of MENQOL in clinical practice remains unknown.

Vasomotor symptoms (VMS) associated with menopause can negatively affect health-related quality of life (HRQoL). The Menopause-Specific Quality of Life (MENQOL) questionnaire has been developed to assess QOL specific to menopause. The objective of the current study was to assess the psychometric properties, sensitivity to change, and clinically meaningful within-patient change of the MENQOL using data from the fezolinetant SKYLIGHT 1 and 2 studies in individuals with VMS.Individuals aged ≥ 40 to ≤ 65 years with moderate-to-severe VMS (≥ seven hot flashes/day) were enrolled. In addition to MENQOL, eight patient-reported outcome (PRO) measures were used for the psychometric evaluation. All PRO assessments were completed at weeks 4 and 12 during the treatment period, and most were completed at baseline. Psychometric analyses included factor analysis and reliability, construct validity, and sensitivity to change assessments. The within-patient threshold for a clinically meaningful change in MENQOL was derived.In total, 1022 individuals were included from SKYLIGHT 1 and 2. Mean MENQOL total score at baseline was 4.30, improving to 3.16 at week 12. The confirmatory factor analysis supported established MENQOL domain structure, including the overall score. The internal consistency of the MENQOL overall and domain scores was supported using Cronbach's alpha and McDonald's omega, and MENQOL construct validity was supported for overall and domain scores. Item-to-item and item-total correlations were generally sufficient, and moderate test-retest reliability was noted. The scales against which construct validity and responsiveness for MENQOL domains were examined were moderately related to the MENQOL domains in general, providing additional support for acceptable measurement properties of MENQOL in this population. A reduction in MENQOL overall score of ≥ 0.9 points was identified as responding to treatment (a clinically important threshold). Thresholds of 2.0 points for the vasomotor domain and 0.9 for the psychosocial domain were estimated, in addition to distribution-based threshold estimates of 0.8 and 1.2 for the physical and sexual domains, respectively.The psychometric properties of the MENQOL overall and domain scores support use of this instrument to capture experiences among individuals with moderate-to-severe VMS associated with menopause and assess related endpoints in clinical trials.ClinicalTrials.gov identifiers NCT04003155 and NCT04003142.© 2024. The Author(s).

We review recent evidence on Illness Anxiety Disorder (IAD), including risk factors and precipitants, diagnostic classification, clinical characteristics of the disorder, and assessment and treatment in both children and adults.

Co-occurrence of thyroid dysfunction, metabolic disturbances, and worsening clinical symptoms in major depressive disorder (MDD) patients with suicidal attempts (SA) are common. However, their relationship in SA patients remains unexplored. We aimed to (1) determine the independent association of thyroid dysfunction, clinical symptoms, and metabolic disturbances with SA; and (2) identify their interactions in SA patients via the network approach.

An association of thyroid function with mood disorders has been widely suggested, but very few studies have examined this association longitudinally.

There is conflicting evidence about the relationship between vitamin D deficiency and depression, and a systematic assessment of the literature has not been available.To determine the relationship, if any, between vitamin D deficiency and depression.A systematic review and meta-analysis of observational studies and randomised controlled trials was conducted.One case-control study, ten cross-sectional studies and three cohort studies with a total of 31 424 participants were analysed. Lower vitamin D levels were found in people with depression compared with controls (SMD = 0.60, 95% CI 0.23-0.97) and there was an increased odds ratio of depression for the lowest v. highest vitamin D categories in the cross-sectional studies (OR = 1.31, 95% CI 1.0-1.71). The cohort studies showed a significantly increased hazard ratio of depression for the lowest v. highest vitamin D categories (HR = 2.21, 95% CI 1.40-3.49).Our analyses are consistent with the hypothesis that low vitamin D concentration is associated with depression, and highlight the need for randomised controlled trials of vitamin D for the prevention and treatment of depression to determine whether this association is causal.

Among midlife and older women, menopause symptoms and menopausal hormone therapy have been linked to mental health disorders and other comorbidities related to suicide. However, the role of hormone therapy as a prognostic factor of suicide risk is largely unknown.To examine associations between menopausal hormone therapy, suicide attempts, and suicide among midlife and older women Veterans.In this longitudinal analysis of national Veterans Health Administration data from women Veterans aged 50 years and above, we used Fine-Gray proportional hazards models to examine associations between menopausal hormone therapy (prescribed in 2012-2013) and incident suicide attempts and suicide (index date-2016).Menopausal hormone therapy and psychoactive medications from pharmacy records; suicide attempts and suicide from national suicide data repositories; demographic variables, medical and psychiatric diagnoses, and substance use disorders from electronic medical record data and International Classification Diagnoses-9-CM codes.In this national sample of 291,709 women Veterans (mean age 60.47, SD 9.81), 6% were prescribed menopausal hormone therapy at baseline. Over an average of 4.5 years, 2673 had an incident suicide attempt (93%) or death by suicide (7%). Adjusting for age, race, and medical diagnoses, menopausal hormone therapy was associated with increased risk of suicide attempt (hazard ratio 1.41; 95% confidence interval, 1.22-1.64) and over 2-fold increased risk of death by suicide (hazard ratio 2.47; 95% confidence interval, 1.58-3.87). Associations with death by suicide remained significant after accounting for psychiatric comorbidity and psychoactive medications.Menopausal hormone therapy may be an important indicator of suicide risk among midlife and older women.Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Objectives: Transcranial electric stimulation (TES) and repetitive transcranial magnetic stimulation (rTMS) have experienced significant development in treating insomnia. This review aims to examine the effectiveness of randomized sham-controlled trials of TES and rTMS in improving insomnia and examine potential moderators associated with the effect of the treatment.

Menopause symptoms significantly impact women’s quality of life, yet existing assessment tools may not fully capture the menopausal experience. The MenoScale is a new digital tool for reporting the number and impact of menopause-associated symptoms.