From physiology to psychology: An integrative review of menopausal syndrome

Abstract

This review examines the mechanisms of anxiety and depression in menopausal syndrome from an integrated physiological to psychological perspective. Fluctuations in estrogen and progesterone levels during menopause affect neurotransmitter systems (including serotonin, norepinephrine, and dopamine), hypothalamic-pituitary-adrenal axis function, inflammatory processes, and neurotrophic factor expression, collectively diminishing the resilience of emotional regulation neural circuits. Simultaneously, vasomotor symptoms (such as hot flashes and night sweats), sleep disruption, genetic susceptibility, and epigenetic modifications interact with mood disorders, while psychosocial factors (such as midlife stressors and role transitions) and cognitive factors (including negative schemas about aging, attentional bias toward threats, and difficulties in emotional regulation) further shape women’s experiences of menopausal changes. Clinical practice should adopt a biopsychosocial model, employing personalized multimodal approaches through hormone therapy, antidepressants, psychotherapy, and lifestyle adjustments, while future research should focus on developing biomarkers, utilizing advanced technologies, and developing targeted interventions to support women’s psychological wellbeing during menopause.

Key Words: Menopausal syndrome; Depression and anxiety; Estrogen withdrawal; Neuroendocrine and inflammatory mechanisms; Biopsychosocial model

Core Tip: This integrative review explores how hormonal fluctuations during menopause contribute to anxiety and depression through neuroendocrine, neuroinflammatory, genetic, psychosocial, and cognitive mechanisms. By bridging physiology and psychology, the paper highlights the complexity of menopausal mental health and advocates for a biopsychosocial framework in clinical care. Understanding these interconnected pathways can inform personalized interventions - ranging from hormone therapy to psychotherapy and lifestyle adjustments - and guide future research on biomarkers and targeted treatments to support emotional wellbeing in midlife women.

INTRODUCTION

Menopausal syndrome represents a complex constellation of symptoms occurring during the female reproductive aging process, characterized by the permanent cessation of menstruation due to loss of ovarian follicular activity. This transition typically occurs between the ages of 45 and 55 years and is marked by significant hormonal, physiological, and psychological changes that can substantially impact a woman’s quality of life[1,2]. In the spectrum of menopausal manifestations, mood disturbances particularly anxiety and depression stand as especially common and disruptive elements. Epidemiological data demonstrates that women transitioning through menopause face a 2-3-fold elevated risk of experiencing major depressive episodes compared to their premenopausal counterparts. Despite their considerable toll, the psychological facets of menopausal syndrome have traditionally been overshadowed by vasomotor complaints in both scientific investigation and medical management[3,4].

How changing hormones affect feelings during the change of life offers special insight into how our brains and bodies work together. Parts of the brain that control emotions, handle stress, and help us think - like the fear center, memory area, and thinking region - have lots of spots where female hormones attach. When a woman’s body makes much less of these hormones during middle age, it throws off these carefully balanced systems. This can lead to mixed-up brain chemicals, changes in how brain cells connect, and body inflammation, all working together to cause mood problems[5,6]. These physical weak spots become even more important when we think about what’s happening in a woman’s life during these years - often dealing with many different pressures, changing roles in family and work, and questions about who she is becoming. We don’t completely know all the ways that body processes, thoughts, feelings, and life situations work together to make women more likely to have emotional troubles during this time[7].

Looking back at old ideas about middle-aged women’s changes shows how our thinking about their emotional struggles has grown. Years ago, doctors mostly saw this time as a “missing hormone problem”, but today’s studies show women go through very different experiences based on their background, community values, and personal lives. When researchers look at women in different countries and cultures, they find big differences in what bothers them and how upset they get, which tells us that body changes mix with social beliefs to affect how women feel and think about getting older[8]. Studying worry and sadness during these years helps connect women’s body doctors with mind doctors, who usually work without talking to each other. This split often means a woman might see one doctor for hot flashes while getting help for feeling down somewhere else or maybe not getting that help at all. All this shows why simple explanations don’t work, and why we need approaches that bring everything together to truly understand what women face during these challenging years[9].

This paper looks at the many reasons why women often feel worried or sad during their middle years. We bring together ideas from different fields - how female body changes affect hormones, brain science, how stress affects both mind and body, family traits, and mental health experts’ views - to better explain what connects body changes with feelings. Knowing these connections helps us find better ways to spot problems early, prevent them when possible, and treat them when needed, so women can stay emotionally healthy during this big life change. Our work also helps explain why, throughout life, women tend to have twice as many problems with worry and sadness as men do. These differences start showing up during teen years and continue through the child-bearing years - suggesting that sex hormones strongly affect mood. The dramatic hormone drops of middle age give researchers a natural way to study why women might be more likely to have these troubles. So while we focus on middle-aged women’s emotional health, we also connect it to women’s mental wellbeing during other life stages, seeing both what makes this time special and how it relates to other phases when hormones change[10,11].

OVERVIEW OF MENOPAUSAL TRANSITION

The menopausal transition represents a dynamic biological process rather than a singular event. According to the Stages of Reproductive Aging Workshop criteria, this transition begins with variations in menstrual cycle length in the late reproductive stage and progresses through the early and late menopausal transition - characterized by increased variability in cycle length, elevated follicle-stimulating hormone levels, and increasing episodes of amenorrhea - until reaching postmenopause, defined as 12 months after the final menstrual period[12,13].

The progression through these stages is driven by fundamental changes in ovarian function. As women age, the number and quality of ovarian follicles progressively decline, resulting in reduced ovarian responsiveness to gonadotropins and diminished production of estradiol and inhibin B. This decline triggers a compensatory increase in follicle-stimulating hormone and luteinizing hormone levels due to reduced negative feedback at the hypothalamic-pituitary level. The result is a complex pattern of hormonal fluctuations rather than a simple decline, with estrogen levels that may initially increase or fluctuate dramatically before eventually declining permanently in late postmenopause.

Body hormone changes explain the many different problems women face during their middle years. About three-quarters of women get sudden feelings of heat and nighttime sweating, which happen because lower female hormones confuse the body’s temperature control center in the brain. Many women up to 60% also have trouble sleeping, either because of night sweats or for other reasons. Problems “down below” like dryness, needing to rush to the bathroom, and getting infections more easily happen because these sensitive areas depend on female hormones to stay healthy.

While considerable research has focused on the pathological aspects of menopause, emerging evidence reveals that many women experience positive outcomes during this transition, challenging deficit-focused narratives. Psychological resilience, defined as the capacity to adapt successfully in the face of adversity, represents a critical protective factor that modulates menopausal experiences. Studies demonstrate that women with higher baseline resilience scores report significantly fewer depressive symptoms and better overall quality of life during perimenopause, independent of hormone levels or vasomotor symptom severity[14].

Psychological flexibility the ability to remain present-focused and adaptively respond to changing circumstances emerges as a particularly important protective mechanism. Research utilizing the Acceptance and Action Questionnaire has shown that women with greater psychological flexibility demonstrate reduced catastrophic thinking about menopausal symptoms and enhanced emotional regulation capabilities[15]. This cognitive adaptability appears to buffer against the development of anxiety disorders during hormonal transitions, with effect sizes comparable to those observed in pharmacological interventions.

How long these middle-age changes last and what they feel like varies greatly from woman to woman. Though most women have their final period around age 51, the whole process can take anywhere from 7 to 14 years. Things that affect this timing include family traits, racial background, weight, whether someone smokes, money situation, and overall health. Just like body symptoms differ between women, emotional changes also range widely some women hardly notice any mood changes while others struggle with serious feelings of sadness or worry that might continue for years during and after this time of life[16,17]. Knowing how these body changes work helps explain why women might feel worried or down during middle age. It’s not just about having less female hormones when these changes happen, how long they last, and their up and down patterns might matter just as much for mood problems as the actual amount of hormones in the body[18].

Although average risk for mood disturbances increases during the menopause transition[2,7], individual trajectories vary substantially. Some women develop clinically significant depression, whereas others remain psychologically resilient despite comparable endocrine changes. Potential moderators span biological and psychosocial domains[6,9,15]. Early-life stress can leave enduring “epigenetic scars” on stress-regulatory genes such as glucocorticoid receptor gene and FK506 binding protein 5 gene via DNA methylation and histone modifications, sensitizing the hypothalamic-pituitary-adrenal (HPA) axis and limbic circuits to later-life estradiol fluctuations (epigenetic priming). Biomarkers such as anti-Mullerian hormone levels, antral follicle count, and menstrual cycle length variability not only predict menopause timing but may also reflect neuroendocrine sensitivity to hormonal volatility. Protective psychosocial factors - including robust social support networks, good sleep quality, and psychological flexibility - can buffer the impact of hormonal fluctuations on mood regulation, potentially offsetting biological risk factors. Recognition of these moderators underscores the importance of precision risk stratification in menopausal mental health, guiding targeted prevention and individualized intervention strategies[7,12].

While the transition into menopause has been associated with increased vulnerability to mood disturbances[5], it is important to recognize that many women demonstrate remarkable psychological resilience during this life stage. Factors such as psychological flexibility, robust social capital, and supportive interpersonal networks have been shown to buffer the emotional impact of hormonal and life stressors. Incorporating resilience research into the biopsychosocial framework not only balances the narrative but also highlights potential targets for preventive and strength-based interventions in midlife mental health care[7,9].

Beyond risk factors, many women exhibit psychological resilience during the menopause transition. Protective mechanisms - including psychological flexibility, perceived control, social capital, and supportive work–family environments - can buffer the emotional impact of hormonal volatility and midlife stressors[5]. Conversely, structural stressors such as workplace discrimination or economic precarity may amplify symptom burden via heightened threat appraisal, sleep disruption, and increased allostatic load. Integrating these psychosocial mechanisms into the biopsychosocial framework provides a more balanced account and highlights modifiable targets for preventive, strengths-based care[7].

EPIDEMIOLOGY OF ANXIETY AND DEPRESSION IN MENOPAUSE

The middle-years change puts women at greater risk for feeling sad or worried. Big health studies keep finding more cases of both mild and serious mood problems during this time. The Women’s Health Across the Nation Study, which followed many women from different backgrounds for years, showed they were 2-4 times more likely to have sad feelings during these changes than before, with about one in four reporting serious enough symptoms to matter medically. In the same way, the Penn Ovarian Aging Study found women had about two-and-a-half times higher chance of scoring high on depression tests during these body changes[19].

The prevalence of anxiety symptoms and disorders during menopause has been less extensively studied compared to depression, yet available evidence suggests similarly elevated rates. In the SWAN study, approximately 51% of women reported irritability, nervousness, or frequent mood changes during the menopausal transition[20]. Systematic reviews have found that anxiety symptoms are reported by 23%-51% of women during perimenopause, with higher rates observed in clinic-based samples compared to community samples.

Several risk factors have been identified that increase vulnerability to anxiety and depression during menopause. A consistent finding across studies is that prior history of depression or anxiety represents one of the strongest predictors of mood symptoms during the menopausal transition[21]. This suggests that menopause may trigger recurrence or exacerbation of existing psychological vulnerabilities rather than necessarily causing new-onset disorders in all women[21].

Additional risk factors include severe vasomotor symptoms (VMS), sleep disturbances, chronic health conditions, surgical menopause, early onset of menopause, psychosocial stressors (e.g., caregiving responsibilities, relationship problems), low socioeconomic status, and limited social support. Interestingly, the Harvard Study of Moods and Cycles found that women with no history of depression who experienced rapid changes in reproductive hormones during the early perimenopausal transition were particularly vulnerable to developing first-onset depression[22].

Longitudinal studies have revealed temporal patterns in the presentation of mood symptoms across the menopausal transition[23]. The risk of depression appears to peak during late perimenopause and early postmenopause periods characterized by significant hormonal fluctuations and may diminish in late postmenopause when hormonal levels have stabilized. This pattern supports the “window of vulnerability” hypothesis, suggesting that it is the instability in hormone levels rather than low estrogen levels per se that confers risk for mood disturbances[24].

Comorbidity between mood symptoms and other menopausal complaints is common and clinically significant. Women experiencing moderate to severe hot flashes are more likely to report depressive symptoms, with some studies suggesting a bidirectional relationship. Similarly, sleep disruption is both a symptom of menopause and a risk factor for mood disorders, potentially serving as a mediating mechanism. This clustering of symptoms suggests shared underlying mechanisms and highlights the need for integrated approaches to assessment and treatment[25].

The predominant focus on estrogen withdrawal in menopausal mood research has overshadowed the contribution of multiple concurrent biological changes that characterize midlife. Thyroid dysfunction represents a particularly significant confounding factor, with subclinical hypothyroidism affecting 15%-20% of women over 50 years. The symptom overlap between thyroid dysfunction and depression - including fatigue, cognitive impairment, mood liability, and sleep disturbances creates diagnostic challenges and may lead to misattribution of symptoms to estrogen deficiency alone. Prospective studies indicate that thyroid-stimulating hormone levels within the upper normal range predict increased depressive symptoms during perimenopause, independent of reproductive hormone levels[26].

EXAMINES NEUROENDOCRINE MECHANISMS CONNECTING HORMONAL CHANGES TO MOOD DISORDERS

The dramatic fluctuations and eventual decline in ovarian hormone production during menopause have profound implications for brain function, particularly in systems regulating mood and anxiety. Estrogen, beyond its reproductive functions, acts as a neuroactive steroid with widespread effects on neurotransmitter systems implicated in affective regulation[27]. Estrogen modulates serotonergic function through multiple mechanisms, including upregulation of 5-hydroxytryptamine (5-HT) synthesis, inhibition of 5-HT reuptake, downregulation of 5-HT receptor 1A autoreceptors, and increased postsynaptic 5-HT receptor 2A receptor density. During the menopausal transition, fluctuations and eventual decline in estrogen levels may therefore result in serotonergic dysregulation, potentially contributing to mood disturbances. This relationship is supported by evidence that selective serotonin reuptake inhibitors demonstrate efficacy for both depression and VMS in perimenopausal women[28].

Similarly, estrogen enhances noradrenergic and dopaminergic transmission through increased synthesis, reduced degradation, and modulation of receptor sensitivity. The noradrenergic system is particularly relevant given its role in both mood regulation and vasomotor symptom generation, potentially explaining the frequent co-occurrence of these symptoms. Estrogen also potentiates dopaminergic activity in the mesolimbic pathway, associated with motivation and reward processing, and in the prefrontal cortex, involved in executive function and emotional regulation[29,30].

The distribution of estrogen receptors (ER) throughout the brain provides anatomical specificity to these effects. ERα and ERβ are abundantly expressed in brain regions central to emotion processing and stress response, including the amygdala, hippocampus, hypothalamus, and prefrontal cortex. ERβ is particularly relevant to mood regulation, as demonstrated by preclinical studies showing that ERβ agonists exert anxiolytic and antidepressant-like effects, whereas ERβ knockout mice exhibit increased anxiety and depressive behaviors[31].

While numerous observational studies have documented temporal associations between estradiol fluctuations and mood disturbances, such correlations do not, in themselves, establish causality. Longitudinal cohort data and experimental manipulations - such as gonadotropin-releasing hormone agonist models that induce a reversible hypogonadal state - offer stronger inferential leverage[12,15,17]. Findings from these paradigms suggest that estradiol withdrawal can precipitate mood symptoms in susceptible individuals, yet the magnitude of this effect is moderated by pre-existing biological and psychosocial factors[12,15,17].

Although estrogen’s neuromodulatory properties are well-supported by both preclinical and clinical studies[18,23], evidence from large-scale randomized trials such as the Women’s Health Initiative found no significant antidepressant benefit of hormone therapy (HT) in postmenopausal women[21]. These discrepancies may be partly explained by the type and dosage of estrogen used, the inclusion of progestogens with potentially adverse mood effects, variability in blood-brain barrier permeability, and differences in baseline mood disorder risk. Integrating such contradictory findings underscores the importance of considering hormonal effects in the broader context of neurobiological, psychosocial, and vascular factors influencing mood during midlife.

The dysregulation of the HPA axis constitutes a pivotal neuroendocrine pathway through which menopause influences mood regulation. Under normal physiological conditions, estrogen serves as a key regulator of stress response systems by strengthening the negative feedback mechanisms that operate through glucocorticoid receptors located within hypothalamic and pituitary structures. During the menopausal transition, the progressive decline in circulating estrogen compromises these regulatory mechanisms, leading to impaired feedback control and consequent overactivation of the stress response system, characterized by sustained elevation in cortisol secretion. Clinical investigations have demonstrated that women navigating the perimenopausal period display amplified stress reactivity when exposed to psychological challenges, contrasting markedly with the more contained responses observed in their premenopausal counterparts. This exaggerated stress sensitivity creates a neurobiological environment conducive to mood disturbances, particularly when considered alongside the cascade of other menopausal manifestations. The relationship between HPA axis dysfunction and mood vulnerability becomes particularly pronounced through its synergistic interactions with concurrent menopausal symptoms. Sleep fragmentation, a common consequence of nocturnal vasomotor episodes, further compromises stress recovery mechanisms and perpetuates cortisol dysregulation. This creates a self-reinforcing cycle wherein sleep disruption exacerbates HPA axis dysfunction, which in turn impairs sleep quality and emotional regulation, ultimately amplifying susceptibility to anxiety and depressive disorders during this transitional period[32].

It is important to distinguish between direct neuromodulatory effects of estradiol on corticotropin-releasing hormone neurons and glucocorticoid receptor sensitivity[29], and secondary dysregulation of the HPA axis arising from chronic psychosocial stress or sleep disruption. Experimental studies using hormone suppression and add-back designs indicate that while estradiol can acutely modulate HPA axis reactivity, the persistence of dysregulation often reflects an interaction with non-hormonal stressors, emphasizing the multifactorial nature of menopausal mood disturbances[30,31].

Neurosteroids derived from progesterone, particularly allopregnanolone, exert potent anxiolytic effects through positive allosteric modulation of gamma-aminobutyric acid (GABA)-A receptors. During the menopausal transition, fluctuations in progesterone and consequently in allopregnanolone levels may contribute to anxiety symptoms and heightened stress sensitivity. This mechanism may be particularly relevant for women with histories of premenstrual dysphoric disorder or postpartum depression, conditions associated with sensitivity to reproductive hormone fluctuations and altered GABA-ergic function[33]. The complex interplay between these neuroendocrine systems contributes to the diverse manifestations of mood symptoms during menopause. Importantly, individual differences in sensitivity to hormone fluctuations, rather than absolute hormone levels, may better explain the variability in psychological vulnerability during this transition.

Neuroinflammatory mechanisms

Emerging evidence suggests that neuroinflammatory processes may represent an important mechanism linking menopausal status to mood disturbances[34]. Estrogen exerts potent anti-inflammatory effects through inhibition of pro-inflammatory cytokine production, suppression of microglial activation, and reduction of oxidative stress. Consequently, the decline in estrogen levels during menopause may result in an enhanced pro-inflammatory state that contributes to neuropsychiatric symptoms[35].

Several studies have documented elevated levels of pro-inflammatory cytokines, including interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, in postmenopausal compared to premenopausal women[36]. Importantly, these inflammatory markers have been independently associated with depression and anxiety in the general population, and some evidence suggests this association may be particularly robust during the menopausal transition. In the SWAN study, higher levels of inflammatory markers were associated with greater depressive symptoms during the menopausal transition, even after controlling for age, body mass index, and other health factors[37,38].

Mechanistically, pro-inflammatory cytokines can impact neurotransmitter metabolism through multiple pathways. They activate the enzyme indoleamine 2,3-dioxygenase, which metabolizes tryptophan away from serotonin synthesis and toward production of potentially neurotoxic kynurenine metabolites. Additionally, pro-inflammatory cytokines can increase the activity of the serotonin transporter, thereby reducing serotonin availability at the synapse. They also stimulate microglia to release glutamate and reduce astrocytic glutamate reuptake, potentially leading to excitotoxicity in mood-regulating brain regions[39-41].

The relationship between inflammation and VMS may represent another pathway linking inflammation to mood disorders during menopause. Hot flashes have been associated with elevated levels of inflammatory markers, and both hot flashes and inflammatory processes activate similar brain regions involved in interoception and emotional processing, including the insula and anterior cingulate cortex. This shared neural circuitry may partially explain the frequent co-occurrence of vasomotor and mood symptoms[42].

Oxidative stress, often accompanying inflammatory processes, increases during menopause due to reduced antioxidant effects of estrogen. Markers of oxidative damage have been associated with depressive symptoms in menopausal women, suggesting that oxidative stress may represent a complementary mechanism linking menopause to mood disorders. Estrogen’s antioxidant properties include upregulation of antioxidant enzymes, direct free radical scavenging, and reduction of reactive oxygen species production, all of which may be compromised during the menopausal transition[43,44].

The dynamic interplay between neuroendocrine and inflammatory systems is further complicated by their bidirectional relationship. HPA axis hyperactivity can promote inflammation, while pro-inflammatory cytokines stimulate cortisol release, potentially creating a self-reinforcing cycle that maintains both systemic inflammation and stress dysregulation during menopause. Similarly, sleep disruption resulting from VMS can enhance inflammatory responses, creating another pathway through which menopausal symptoms may interact to increase the risk of mood disorders[45].

Neurotrophic and neuroplasticity factors

Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), play crucial roles in neuronal survival, synaptic plasticity, and neurogenesis - processes fundamental to mood regulation and cognitive function. Estrogen exerts significant modulatory effects on BDNF expression and signaling, suggesting that alterations in neurotrophic support during menopause may contribute to mood disturbances. Estrogen enhances BDNF expression in the hippocampus, prefrontal cortex, and amygdala through direct genomic effects via estrogen response elements in the BDNF gene promoter and through indirect mechanisms involving cAMP response element-binding protein activation. Preclinical studies demonstrate that estrogen withdrawal is associated with reduced BDNF levels in these regions, and these reductions correlate with depressive-like behaviors[46-48]. In humans, lower serum BDNF levels have been observed in postmenopausal compared to premenopausal women, and these lower levels correlate with depressive symptoms[49]. Beyond BDNF, estrogen influences other neurotrophic factors, including nerve growth factor, insulin-like growth factor-1, and vascular endothelial growth factor, which collectively support neuronal health and function. The coordinated reduction in these trophic factors during menopause may compromise neural resilience, particularly in brain regions sensitive to stress and involved in emotion regulation[50].

Hippocampal neurogenesis represents a key mechanism through which estrogen and neurotrophic factors maintain mood regulation. Estrogen promotes the proliferation and survival of neural progenitor cells in the dentate gyrus, an effect mediated in part through increased BDNF signaling. Reduced hippocampal neurogenesis following estrogen withdrawal may contribute to depression vulnerability, as suggested by preclinical models where inhibition of hippocampal neurogenesis blocks the behavioral effects of antidepressants. In menopausal women, reduced hippocampal volume has been associated with both depressive symptoms and cognitive complaints.

Synaptic plasticity, the ability of synapses to strengthen or weaken in response to activity, is another estrogen-sensitive process relevant to mood regulation. Estrogen enhances dendritic spine density in hippocampal CA1 neurons and prefrontal cortical neurons, increases long-term potentiation, and modulates glutamatergic and GABA-ergic transmission to favor excitatory signaling. The loss of these estrogen effects during menopause may impair neural circuit function in regions critical for emotional processing and stress responsivity.

Neuroimaging studies provide evidence for structural and functional connectivity changes during the menopausal transition[51]. Reduced gray matter volume in emotion-regulating regions, including the hippocampus, amygdala, and prefrontal cortex, has been observed in postmenopausal compared to premenopausal women. Functional connectivity studies demonstrate altered patterns of activation and connectivity in emotional processing networks in response to negative stimuli among women during the menopausal transition, particularly those reporting depressive symptoms. These alterations in brain structure and function may reflect the cumulative impact of changes in neurotrophic support and neuroplasticity[52].

Importantly, the effects of HT on neurotrophic factors and neuroplasticity suggest a potential mechanism for its mood-enhancing effects in some perimenopausal women. Estrogen therapy increases BDNF levels, enhances hippocampal neurogenesis, and restores synaptic plasticity in preclinical models of menopause. The timing of intervention appears critical, with greater benefits observed when initiated during perimenopause rather than after an extended period of hormone deprivation, consistent with the “critical window hypothesis” for HT effects on brain function (Figure 1).

Figure 1 Epidemiology of anxiety and depression in menopause. This figure presents the prevalence rates, risk factors, comorbidity patterns, and temporal vulnerability patterns of mood disorders during the menopausal transition. Depression prevalence reaches 23% in menopausal women (2.4-fold higher than premenopausal women), while anxiety prevalence ranges from 23% to 51%. The “window of vulnerability” concept illustrates peak risk periods during late perimenopause and early postmenopause, with sleep disruption serving as a key mediating factor in the bidirectional relationships between vasomotor symptoms and mood disorders.

Beyond estrogen-related pathways, midlife women often experience other physiological changes that can influence mood, such as thyroid dysfunction and metabolic syndrome[49,51]. Hypothyroidism and subclinical thyroid disorders have been linked to depressive symptoms through altered monoaminergic neurotransmission and dysregulated hypothalamic-pituitary-thyroid axis activity[53]. Metabolic syndrome - characterized by insulin resistance, central adiposity, and low-grade inflammation - can further exacerbate mood disturbances via vascular and neuroinflammatory pathways. Recognizing these common comorbidities as potential confounders is critical for accurate diagnosis, comprehensive risk assessment, and tailoring of treatment strategies in menopausal women.

VMS AND MOOD DISORDERS

VMS - primarily hot flashes and night sweats - represent the hallmark symptoms of menopause, affecting approximately 75%-80% of women during the menopausal transition. A substantial body of evidence indicates a robust association between VMS and mood disturbances, though the directionality and mechanisms underlying this relationship remain subjects of ongoing investigation[53].

Epidemiological studies consistently demonstrate that women with moderate to severe VMS are more likely to experience depressive symptoms and clinical depression compared to those with mild or no VMS[54]. In the SWAN study, women with VMS had a 1.5-2-fold increased risk of depression, with the strongest associations observed among women with the most frequent and bothersome symptoms. Similarly, anxiety symptoms and disorders show increased prevalence among women reporting significant VMS.

Two primary models have been proposed to explain the relationship between VMS and mood disorders. The “domino hypothesis” suggests that VMS influence mood indirectly through their disruptive effects on sleep, with chronic sleep deprivation subsequently leading to daytime fatigue, irritability, and mood disturbances. Supporting this model, studies using objective measures of sleep (polysomnography and actigraphy) demonstrate that nocturnal VMS are associated with sleep fragmentation, reduced sleep efficiency, and increased wake time after sleep onset[55].

The “shared vulnerability hypothesis”, in contrast, proposes that VMS and mood symptoms arise from common underlying neurobiological mechanisms, particularly the dysregulation of central monoaminergic and neuroendocrine systems following estrogen withdrawal. This model is supported by evidence that estrogen therapy and certain antidepressants (particularly serotonin-norepinephrine reuptake inhibitors and some selective serotonin reuptake inhibitors) effectively reduce both VMS and depressive symptoms, suggesting shared pathophysiological pathways.

These hypotheses are not mutually exclusive, and accumulating evidence suggests a complex, bidirectional relationship between VMS and mood. Neuroimaging studies provide insights into shared neural circuits that may mediate this relationship[56]. Functional MRI studies demonstrate that hot flashes activate brain regions involved in interoception and emotional processing, including the insula, anterior cingulate cortex, and prefrontal cortex - regions also implicated in depression and anxiety disorders. This overlapping neural circuitry may represent a substrate through which VMS and mood symptoms influence each other.

Thermoregulatory neural circuits in the hypothalamus, particularly the median preoptic area, are directly modulated by estrogen and may represent another shared pathway. Estrogen withdrawal leads to a narrowing of the thermoneutral zone, increasing sensitivity to small changes in core body temperature that trigger hot flashes. This same hypothalamic region contains dense projections to limbic structures involved in mood regulation and stress responsivity, potentially facilitating bidirectional interactions between thermoregulatory and emotional systems[57].

Individual differences in sensitivity to estrogen fluctuations may partly explain why some women experience both severe VMS and mood disturbances while others report minimal symptoms in either domain. The concept of “neurohormonal sensitivity” proposes that certain women possess increased sensitivity to normal hormone fluctuations, manifesting as both reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, perimenopausal depression) and heightened VMS.

Clinical implications of the VMS-mood relationship include the importance of comprehensive symptom assessment and integration of treatments targeting both symptom domains. Given the potential mediating role of sleep disruption, interventions specifically addressing sleep problems may represent an important component of treatment for mood disorders during menopause. Additionally, the effectiveness of certain antidepressants for both VMS and mood symptoms provides pharmacological options that can simultaneously address multiple symptom domains (Figure 2).

Figure 2 Estrogen effects on neurotrophic factors and neuroplasticity. This diagram illustrates how estrogen regulates neurotrophic factors and neuroplasticity in the brain, showing how declining estrogen levels during menopause lead to reduced brain-derived neurotrophic factor and other neurotrophic factors, subsequently affecting hippocampal neurogenesis, dendritic spine density, and synaptic plasticity, ultimately increasing depression risk. Additionally, the diagram demonstrates how hormone replacement therapy can have positive effects through restoring brain-derived neurotrophic factor levels and enhancing neuroplasticity when administered within the “critical window” of intervention. BDNF: Brain-derived neurotrophic factor; NGF: Nerve growth factor; IGF-1: Insulin-like growth factor-1; VEGF: Vascular endothelial growth factor.

GENETIC AND PSYCHOSOCIAL MECHANISMS

Genetic and epigenetic mechanisms

Genetic factors contribute significantly to the risk of experiencing mood disturbances during the menopausal transition, with heritability estimates for depression during this period ranging from 40%-50%. Research exploring specific genetic polymorphisms has focused primarily on genes involved in estrogen signaling, neurotransmitter systems, and stress response pathways[58].

Variations in ER genes have been associated with differential vulnerability to mood symptoms during menopause. Polymorphisms in ESR1 (encoding ERα), particularly the PvuII and XbaI variants, have been linked to increased depressive symptoms during the menopausal transition, potentially by altering receptor sensitivity to declining estrogen levels. Similarly, variations in ESR2 (encoding ERβ) have been associated with increased anxiety and depressive symptoms in postmenopausal women. Genetic variations in estrogen-metabolizing enzymes, including catechol-O-methyltransferase and cytochrome P450 enzymes (CYP1B1, CYP3A4), may further influence susceptibility by affecting estrogen bioavailability and metabolism.

Polymorphisms in serotonin system genes have also been implicated in menopause-related mood disorders. The short (S) allele of the serotonin transporter promoter polymorphism, associated with reduced transcriptional efficiency and serotonin reuptake, has been linked to increased depressive symptoms during the menopausal transition, particularly among women experiencing significant life stress. This finding aligns with the broader literature on gene-environment interactions in depression vulnerability. Variations in serotonin receptor genes, including HTR1A and HTR2A, have similarly been associated with differential risk for depression and anxiety during menopause[59].

Genetic variations influencing stress response systems may also contribute to psychological vulnerability during menopause. Polymorphisms in the glucocorticoid receptor gene and FK506 binding protein 5 gene, which modulates glucocorticoid receptor sensitivity, have been associated with heightened cortisol responses to stress and increased depressive symptoms during reproductive transitions. These variations may render women more susceptible to the effects of estrogen withdrawal on HPA axis regulation[60]. Beyond single-gene effects, genome-wide association studies and polygenic approaches suggest that menopause-related mood disorders likely involve complex interactions among multiple genetic variants, each contributing small effects to overall risk. This polygenic architecture may explain why studies of individual candidate genes have often yielded inconsistent results[61].

Epigenetic mechanisms - heritable changes in gene expression without alterations in DNA sequence - represent another level at which reproductive hormones may influence mood regulation during menopause. Estrogen regulates gene expression not only through classical genomic pathways involving estrogen response elements but also through epigenetic modifications, including DNA methylation, histone modifications, and microRNA expression[62]. During the menopausal transition, changing estrogen levels may alter the epigenetic landscape in brain regions relevant to mood regulation[63]. For instance, estrogen withdrawal has been associated with increased DNA methylation in the promoter regions of BDNF and ESR1 in animal models, corresponding with reduced expression of these genes and increased anxiety-like behaviors. Such epigenetic changes may persist beyond the acute hormonal fluctuations, potentially explaining the prolonged vulnerability to mood disorders observed in some women (Table 1).

Table 1 Neuroinflammatory mechanisms linking menopause to mood disorders.

Mechanism	Description	Effects	Relevance to mood disorders
Reduction in estrogen’s anti-inflammatory effects[46]	Estrogen normally inhibits pro-inflammatory cytokine production, suppresses microglial activation, and reduces oxidative stress	Decline in estrogen during menopause leads to enhanced pro-inflammatory state	Creates neurobiological environment conducive to mood disturbances
Elevated pro-inflammatory cytokines[47]	Increased levels of IL-6, TNF-α, and CRP in postmenopausal women	Impact neurotransmitter metabolism and neural function	Associated with depression and anxiety, particularly robust during menopausal transition (SWAN study)
Altered tryptophan metabolism[48]	Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase	Metabolizes tryptophan away from serotonin synthesis toward neurotoxic kynurenine metabolites	Reduces serotonin availability, contributing to mood disorders
Serotonin transporter activity	Pro-inflammatory cytokines increase serotonin transporter activity	Reduces serotonin availability at the synapse	Contributes to serotonergic dysfunction in mood regulation
Glutamate dysregulation	Pro-inflammatory cytokines stimulate microglial glutamate release and reduce astrocytic glutamate reuptake	Potential excitotoxicity in mood-regulating brain regions	Disrupts normal brain function in regions critical for emotional processing
Vasomotor symptoms and inflammation	Hot flashes associated with elevated inflammatory markers	Activate similar brain regions involved in interoception and emotional processing (insula, anterior cingulate cortex)	Shared neural circuitry may explain co-occurrence of vasomotor and mood symptoms
Oxidative stress	Reduced antioxidant effects of estrogen during menopause	Increased markers of oxidative damage	Associated with depressive symptoms in menopausal women
HPA axis-inflammation interaction	Bidirectional relationship between HPA axis and inflammatory systems	HPA hyperactivity promotes inflammation; pro-inflammatory cytokines stimulate cortisol release	Creates self-reinforcing cycle maintaining both inflammation and stress dysregulation

IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; CRP: C-reactive protein; HPA: Hypothalamic-pituitary-adrenal.

Life experiences and environmental factors interact with genetic predispositions through epigenetic mechanisms to influence psychological vulnerability during menopause. Chronic stress, trauma exposure, and adverse childhood experiences have been associated with lasting epigenetic modifications in stress response genes, potentially sensitizing neural circuits to the effects of hormonal fluctuations during menopause. This gene-environment interplay may partially explain why psychosocial factors so strongly predict mood disorders during this transition[64].

Clinical implications of genetic and epigenetic research include the potential for developing biomarkers to identify women at heightened risk for menopause-related mood disorders, enabling targeted preventive interventions. Additionally, pharmacogenetic approaches may help predict individual responses to hormonal and non-hormonal treatments, advancing personalized medicine for menopausal symptoms[65].

Psychosocial mechanisms

While biological mechanisms provide a foundation for understanding mood disturbances during menopause, psychosocial factors profoundly influence how women experience and respond to this transition. Stress-diathesis models offer a framework for conceptualizing menopause-related mood disorders as arising from interactions between underlying neurobiological vulnerabilities (diathesis) and psychosocial stressors that often coincide with midlife[66].

The menopausal transition frequently overlaps with significant life stressors and role transitions that may tax coping resources and increase vulnerability to mood disorders. These midlife stressors may include caring for aging parents, launching adult children, relationship changes (including divorce or widowhood), career transitions, emerging health problems, and confronting issues of aging and mortality. The SWAN study found that the number and perceived impact of recent negative life events significantly predicted depressive symptoms during the menopausal transition, independent of hormone levels or VMS[67-69].

The “role overload” commonly experienced by midlife women may be particularly relevant to psychological vulnerability. Many women in this life stage face competing demands from multiple roles - professional, parental, spousal, and caregiving - creating chronic stress that can deplete psychological resources. The “sandwich generation” phenomenon, wherein women simultaneously care for both children and aging parents, exemplifies this role strain and has been associated with increased psychological distress during midlife[70,71].

Social support functions as a critical moderating factor that can buffer the impact of both biological and psychosocial stressors during menopause. Women with strong social connections and emotional support report fewer depressive symptoms and better overall adjustment to menopausal changes. Conversely, relationship dissatisfaction, particularly in marital or partnership relationships, predicts greater psychological distress during this transition. The quality of social relationships may be particularly important during menopause because women often rely on female peers for normalizing information about menopausal experiences[72].

Cultural and societal attitudes toward menopause and aging women significantly influence psychological experiences during this transition. In Western societies, where youth and fertility are often overvalued, negative stereotypes about menopause and aging may contribute to psychological distress. Women who internalize these negative attitudes may experience greater shame, loss of self-esteem, and concerns about attractiveness and sexuality. Cross-cultural studies reveal considerable variation in the prevalence and expression of psychological symptoms during menopause, with some non-Western cultures reporting lower rates of depression and anxiety, potentially reflecting more positive cultural narratives about this life transition[73,74].

Money and social standing work together with other life factors to affect how likely women are to feel down during middle age changes. Those with less schooling, money worries, and trouble getting medical care report more sad feelings during this time. These everyday hardships create problems in several ways - such women face more ongoing stress, have fewer ways to handle problems, and can’t easily get treatments that might help with their body changes[75-78].

Bad experiences from the past, especially being hurt as a child or by a partner, greatly affect how women feel during their middle years. Women who suffered such troubles tend to start their change earlier, get worse hot flashes, and more often feel worried or sad during this time. These connections might happen because old hurts change how the body handles stress and inflammation for many years, and these changes react badly with the natural hormone shifts of middle age, making emotional problems more likely[79].

Clinically, addressing psychosocial mechanisms requires integrated approaches that combine biomedical interventions with psychosocial supports[80,81]. Cognitive-behavioral therapy (CBT), interpersonal therapy, and mindfulness-based interventions have demonstrated efficacy for menopause-related mood symptoms, particularly when adapted to address the specific psychosocial challenges of this life stage. Community-based interventions and support groups may further enhance women’s resources for coping with this transition by providing social connection, normalizing information, and countering negative cultural narratives about menopause[82].

Cognitive mechanisms

Cognitive factors play a significant role in shaping emotional responses to menopausal changes and may contribute to vulnerability for anxiety and depression during this transition. Negative cognitive schemas regarding aging, femininity, and bodily changes can influence how women interpret and respond to menopausal symptoms, potentially amplifying distress and contributing to mood disorders[83-85]. Negative thought patterns - the fixed ways some women understand their experiences can become a problem during this life change, especially for those who strongly tie being a woman to staying young, having babies, or looking pretty. These women might see normal aging signs as meaning they’re losing who they are or becoming less attractive, which leads to bad feelings about themselves and sad thinking. The Thinking Model of Bad Views of Middle Age suggests that women who believe more negative things about this time will feel worse mentally, no matter how mild or severe their physical problems actually are[86-89].

Specific cognitive distortions common during menopause include catastrophizing (exaggerating the negative consequences of symptoms), personalization (attributing symptoms to personal inadequacy rather than normal biological processes), and dichotomous thinking (viewing menopausal transition as either completely positive or completely negative). These cognitive patterns can transform normal menopausal experiences into sources of significant distress. For example, a woman catastrophizing about occasional memory lapses might interpret them as evidence of permanent cognitive decline or early dementia rather than as temporary, stress-related cognitive inefficiencies[90-92].

Attentional biases toward threat and negative information represent another cognitive mechanism potentially contributing to anxiety during menopause. Women with anxiety disorders typically demonstrate selective attention to threat-relevant stimuli, and this attentional bias may become more pronounced during perimenopause, possibly due to estrogen effects on fear processing in the amygdala. This heightened threat sensitivity may lead women to over-attend to bodily sensations (such as the onset of hot flashes) and interpret ambiguous sensations as threatening, maintaining anxiety in a self-reinforcing cycle[93-96].

Impaired emotional regulation abilities may further contribute to mood disturbances during menopause. Emotional regulation refers to processes that influence which emotions arise, when they occur, and how they are experienced and expressed. Neuroimaging studies suggest that estrogen modulates activity in brain regions critical for emotional regulation, including the prefrontal cortex and amygdala[97]. As estrogen levels fluctuate and decline during menopause, women may experience greater difficulty with emotional regulation strategies such as cognitive reappraisal and distress tolerance, potentially increasing vulnerability to mood disturbances[98-100].

Cognitive changes commonly reported during menopause, particularly difficulties with verbal memory, working memory, and attention, may interact with emotional processing to influence mood. These cognitive inefficiencies can impair problem-solving abilities and reduce cognitive flexibility, potentially limiting women’s capacity to cope with stress during this transition. Additionally, subjective cognitive complaints, regardless of objective performance, have been associated with greater depressive symptoms during menopause, suggesting that women’s perceptions of cognitive difficulties may contribute to psychological distress[101-103].

CBT approaches targeting these cognitive mechanisms have demonstrated efficacy for both VMS and mood disturbances during menopause. CBT interventions typically focus on identifying and challenging negative thoughts about menopause, developing adaptive coping strategies for symptoms, addressing sleep problems, and enhancing stress management skills. Randomized controlled trials have found that CBT significantly reduces hot flash problem ratings and depressive symptoms compared to waitlist control conditions, with improvements maintained at six-month follow-up[104-107].

Mindfulness-based interventions represent another cognitive approach with growing evidence for managing menopausal symptoms. These interventions foster non-judgmental awareness of present-moment experiences, potentially reducing reactivity to physical symptoms and negative thoughts. By cultivating a more accepting stance toward menopausal changes, mindfulness practices may help women navigate this transition with greater psychological flexibility and reduced distress[108-110].

CONCLUSION

Based on these findings, the research emphasizes the need for integrated treatment approaches that combine pharmacological interventions, psychotherapy, and social support. Personalized treatment plans tailored to each woman’s specific circumstances are essential for effectively addressing psychological health challenges during the menopausal transition.