The Impact of Estradiol Dynamics During the Menopause Transition on Depression Risk: a narrative review of estradiol’s neurobiological mechanisms

Abstract

The menopausal transition (MT) is linked with the development of burdensome symptoms which have substantial adverse impacts on women. Depression risk specifically stands out given its association with adverse impacts on quality of life, higher healthcare utilization, and reduced occupational functioning. Explorations into the pathophysiology of depression risk during the MT have focused largely on the role of estrogen dynamics, and specifically estradiol, the most neuroactive form of estrogen, and whether changes in estradiol across the MT impact brain health. In this narrative review, we describe how estradiol dynamics across the MT modulate neurobiological processes to confer risk for depressive symptoms and perimenopausal onset major depressive episode (PO-MDE). We first examine changing estradiol dynamics characteristic of the MT and what is known about their clinical impacts on brain health, focusing on patterns of estradiol release that underly PO-MDE, as well as how supplementary estradiol treatment informs our understanding of estradiol’s role in the pathogenesis of this illness. Next, we explore potential mechanisms by which estradiol dynamics may impact neurobiological processes to confer risk for depression. This is accomplished through examination of estradiol’s neuromodulatory activity on the following domains: 1) neurotransmitter signaling 2) neuroimmune function 3) brain glucose metabolism, and 4) synaptogenesis. We will also consider how findings may inform treatment and potential future directions in research.

1. Introduction

The menopausal transition (MT) is a high-risk period for neuropsychiatric symptoms and serves as a clinical model of how shifts in reproductive steroid hormones can trigger psychiatric symptomatology. Depression risk increases 14-fold in the two years surrounding menopause (1) and 40–60% of women have clinically significant depressive symptoms during this reproductive transition (2), with 10–20% experiencing a perimenopausal onset major depressive episode or PO-MDE (3,4). In addition to affective symptomatology, neurological symptoms prevalent during the MT include sleep disturbance, experienced by 50–65% of midlife women (5,6) and cognitive disruption or “brain fog,” experienced by 40–60% of women (7). The prevalence of these symptoms highlights the impact of the MT on neurological function and brain health. Moreover, higher menopausal symptom burden has adverse effects on function, quality of life, and healthcare utilization (8,9), in addition to lower socioeconomic output (9). Studies show these effects contribute to an annual loss of $1.8 billion in the United States (8). Depression during the MT is a key contributor to reduced workplace functioning and lower quality of life (10,11), demonstrating its immense societal impacts and the importance of understanding its pathophysiology.

While there are many factors contributing to depression risk during the MT, efforts to understand how specific reproductive hormone dynamics trigger depressive symptoms and PO-MDE have largely focused on the role of estrogen, specifically estradiol (E2)—the most physiologically active form of estrogen—and its neurobiological effects. During the MT, E2 becomes more variable and then declines towards the end of this reproductive transition, which has the potential to impact neurobiological structure and functioning; the effects of E2 trajectories on molecular imaging outcomes have been discussed previously (12). In this review, we consider the impact of E2 dynamics in the MT on risk for depression, the role of E2 in treatment, and describe what is known about potential mechanistic effects of E2 dynamics on: A) neurotransmitter signaling, B) neuroimmune function C) neurometabolism, and D) synaptogenesis. Further, we describe the implications of these E2 effects in conferring risk for PO-MDE, potential for treatment, and possible future directions for research. Beyond estrogen, progesterone (P4) and its metabolites also fluctuate across the MT and emerging research has shown that these changes may have neurobiological implications (13–15). However, this review focuses on the specific patterns and mechanisms linked to estrogen.

2. Defining Menopause

During the MT, women experience alterations in menstrual period frequency, as ovulatory activity and follicular development become infrequent. Perimenopause typically occurs between ages 40–55 (16,17) and spans 5–8 years until one year has passed since the final menstrual period (18,19). For individuals transitioning to menopause naturally, the Stages of Reproductive Aging Workshop + 10 criteria (STRAW +10) define the stages of perimenopause, menopause, and postmenopause based on menstrual cycle changes and corresponding hormonal fluctuations (Table 1) (20–25). Key symptoms of the MT include vasomotor symptoms (VMS, or hot flashes), sleep disturbance, depressive symptoms, cognitive changes, and genitourinary symptoms (3,26–28) which vary greatly in terms of severity and impact on functioning (10). For 30% of women, symptoms persist for 5–10 years into the postmenopause, with some women experiencing symptoms up to 18 years (29). MT symptoms begin earlier, last longer, and are more severe in Black women compared with white women (29–31). Importantly, the MT can also occur due to surgical procedures (oophorectomy), medical conditions (e.g., premature ovarian insufficiency (32)), or in response to medications, such as gonadotropin-releasing hormone (GnRH) agonists/antagonists and cancer treatments.

Table 1.

STRAW Criteria and Corresponding Gonadal Hormone Fluctuations. Adapted from Harlow et al. (2012), (20–25)

Phase	Pre-Menop ause/Reproductive				Perimenopause		Postmenopause
STRAW + 10 Stage	−5	−4	−3b	−3a	−2	−1	+1a	+1b	+1c	+2
Menstrual Cycle Pattern	Variable to regular	Regular	Regular	Subtle changes in flow/length	≥7 days variability in cycle length	≥60 days of amenorrhea	1–2 years since FMP	1–2 years since FMP	>1 year since FMP	>1 year since FMP
Estradiol	E2 rises in the mid-follicular phase, followed by a secondary peak in the mid-luteal, and decreases during late-luteal into early follicular				E2 levels been to rise and fluctuate	High, fluctuating E2 levels	Decreasing E2 levels	Decreasing E2 levels	Low, stable E2 levels	Low, stable E2 levels
Progesterone	P4 rises in the mid-luteal phase, followed by a decrease into low steady levels in the late luteal and follicular				Luteal P4 levels decreasing gradually	Luteal P4 levels decreasing gradually	Luteal P4 levels decreasing gradually	P4 levels remain low, yet detectable	P4 levels remain low, yet detectable	P4 levels remain low, yet detectable

3. Estrogen dynamics across the menopause transition

The MT is marked by increasing fluctuation and eventually withdrawal of ovarian gonadal hormones, namely estrogen and progesterone. Estrogen is predominantly synthesized by the ovaries, though the adrenal glands, fat tissue, and others express the aromatase enzyme needed to convert the precursors of estrogen (33). Starting in the early perimenopause (STRAW Stage −2), estrogen levels rise and become increasingly variable, corresponding with the start of menstrual cycle variability (i.e., menses may be more or less frequent during this stage). In the late perimenopause (STRAW Stage −1), estrogen levels start to decline as ovulatory menstrual cycles become less frequent, and these shifts culminate in the cessation of ovarian estrogen production. Menopause is marked by one year following the last menstrual period (FMP), signifying the start of postmenopause.

The most physiologically active form of estrogen is E2. E2 has a high affinity for intracellular estrogen receptors (ERα and ERβ) and also binds the extracellular G protein-coupled estrogen receptor (GPER) (34). E2 is lipophilic and can cross the blood-brain barrier (BBB) via passive diffusion to modulate neuronal activity and neurotransmitter systems via ERs expressed throughout brain (35). Interactions with ERs facilitate binding to estrogen response elements (EREs) within promoter regions of target genes, thereby regulating transcription (36). Through these mechanisms, E2 regulates a host of neurobiological functions, which has important implications during the MT.

4. Clinical Effects of E2 Dynamics During the MT

Prior naturalistic studies have explored the clinical effects of E2 dynamics during the MT on risk for depression. Most research suggests increased E2 variability during the MT is linked with depression symptom onset, with women who experience the greatest variability having the highest burden of symptoms (37–39). The coupling of E2 variability and mood symptoms is more pronounced in women exposed to stressful life events within the six months preceding assessments, suggesting proximal stress exposure may amplify the effects of E2 variability on mood (37). In contrast, irritability, a prevalent reproductive affective symptom, has been linked with lower E2 variability (40). Thus, different E2 trajectories, rather than E2 levels, may exert different affective effects (41). Beyond changes in E2, a subset of women may also be sensitive to fluctuations in P4 or its metabolites, though less is known about these associations and they are outside of the scope of this review. Moreover, alterations in sleep quality, exposure to stress and a higher burden of menopausal symptoms overall may also contribute to depression risk, underscoring the potentially multifactorial nature of this transition.

5.0. Antidepressant Effects of E2

Several studies have demonstrated that treatment with supplementary E2 reduces depressive symptoms broadly (42–45). E2 may also play a role in preventing PO-MDD, with one study showing that those receiving hormone therapy (HT) had fewer depressive symptoms compared to placebo (46). It is important to note that this study utilized micronized progesterone, which may have fewer negative mood effects than synthetic progestins. In studies where E2 treatment was rapidly withdrawn, this shift precipitated depressive symptoms in perimenopausal women with a preexisting history of reproductive related depression (e.g., perinatal depression), demonstrating that some women are particularly vulnerable to shifts in E2 (45). Importantly, the antidepressant effects of E2 treatment are thought to be independent of its impact on VMS (47). Overall longer duration of exposure to E2 either in the form of medication (e.g., combined oral contraceptive pills) or later onset of perimenopause indicating longer exposure to ovulatory cycles was linked to lower risk of developing depressive symptoms during the MT or post menopause (48), potentially showing protective effects. Further, in women with a history of mood sensitivity to reproductive hormone changes, transdermal E2 increased reward seeking behaviors on a behavioral reward task paradigm (49), showing that E2 can modulate behaviors implicated in depression. These therapeutic benefits suggest that E2 variability, withdrawal, or their combination is linked with the pathogenesis of depression during the MT.

Few studies have examined how E2 treatment impacts neurobiological processes to reduce PO-MDE symptoms. In euthymic women, E2 treatment is associated with brain activation at areas of the hippocampus, cingulate, and putamen (50) and striatum (51). In a population with PO-MDE, an open label trial of supplementary E2 showed that reductions in depressive symptoms correlated with increases in hippocampal volumes (52). E2 treatment also modulates resting state functional connectivity, corresponding with reductions in depressive symptoms (53), and reduced anhedonia in the context of supplementary E2 was associated with less PFC activation (54). These studies suggest that E2 can modulate areas of the brain involved in reward processing and emotion regulation during active depression.

In addition to E2 treatment studies, studies using GnRH agonists to cause E2 suppression have demonstrated that depressive symptoms are triggered by acute E2 suppression (45), which may occur as E2 suppression is associated with reduced activation in the striatum, a key neuroanatomical region involved in reward processing (55). Reduced striatal activation has been linked to increased depression (56) and adding E2 can reverse this (51) providing a mechanistic explanation for how E2 changes may lead to or treat affective symptomatology. Together, these studies point to the antidepressant effects of E2. Below, several mechanisms that may precipitate these effects during the MT are discussed.

6. Mechanisms of E2’s Neurobiological Activity During the MT

E2 changes during the MT have a clear association with risk for adverse affective outcomes as described above, though how these trajectories alter neurobiological processes to confer risk is incompletely understood. E2 exerts potent effects on genomic and non-genomic pathways throughout the body. Highly variable and then decreasing E2 levels and ER density during the MT contribute to changes across neurobiological systems, including those that can have substantial effects on affective outcomes (57). Below, we review several mechanisms of E2’s neurobiological effects during the MT (Table 2) that contribute to structural and functional alterations underlying risk for depressive symptoms according to available pre-clinical and translational evidence (Figure 1).

Table 2.

Summary of E2’s Neurobiological Activity During the MT

		Preclinical			Translational
Domain	Mechanism	Summary	E2 Changes	Citation	Summary	E2 Changes	Citation
Neurotransmitters	Serotonin	↑ TPH-2 transcription → ↑ serotonin; ↓ MAOA; SERT regulation	OVX ↓ serotonin; E2 restores	(59–66)2/10/2026 5:10:00 PM	MAO-A ↑ in perimenopause; mixed SERT findings	Limited effect of E2 on receptor binding	(57,67–69,69–71)
	Dopamine	↑ TH activity; DAT & D2 receptor modulated by E2	OVX ↓ DA markers; E2 restores	(58,72–76)	No D2 change across cycle; HT ↑ DAT	Hormonal contraceptives ↑ DA synthesis	(77–81)
	GABA	E2 reduces GABA inhibition; regulates GABA genes	OVX ↑ GABA receptor density; E2 reverses	(82–88)	MRS: ↓ GABA+ in medial PFC during MT	No correlation with circulating E2	(89–91)
	Glutamate	↑ Glutamatergic transmission; ER-mGluR signaling	OVX ↓ Glu neurons; E2 restores	(58,92–94)	MRS: ↓ Glu in medial PFC during MT	Postmenopause ↓ Glu	(90,95–97)
Neuroimmune	Anti-inflammatory	Suppresses microglia; ↓ cytokines; modulates T cells	OVX ↑ inflammatory mediators; E2 restores	(103–111)	TSPO ↑ with age; E2 mitigates systemic inflammation	Sparse MT-specific data	(112–114)
Neurometabolic	Glucose metabolism	↑ GLUT1/GLUT3; ↑ mitochondrial efficiency	OVX → hypometabolic state; E2 restores	(116–119)	PET: ↓ glucose metabolism postmenopause; HT protective	Greater decline in women vs men	(120–125)2/10/2026 5:10:00 PM
Synaptic Plasticity	Spine density	↑ dendritic spines in hippocampus; cyclic fluctuations	OVX ↓ spine density; E2 restores	(126–131)	MRI: E2 ↑ hippocampal gray matter volume	PET synaptic density studies lacking	(132)

Figure 1:

Summary of the neurobiological impacts of estradiol (E2) during the menopause transition (MT) that may confer risk for depression. Variable and decreasing E2 levels over the course of the MT lead to A) underactive neurotransmitter signaling in key regions of the brain involved in emotion regulation, B) higher levels of neuroinflammation, which are reversed with supplementary E2, C) reduced glucose metabolism and a shift to using less efficient energy sources, and D) less active synaptogenesis. Created with BioRender.com/y6qxjck.

6.1. E2 regulation of neurotransmitter signaling

As noted above, ERs are prevalent across brain regions, including those relevant to emotion regulation, reward processing, and memory. E2’s action on ERs plays a role in modulating several neurotransmitters, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and glutamate (58).

Serotonin

Preclinical Studies

Serotonin has diverse functions in the brain, including regulating mood, sleep, and appetite. Several preclinical studies have established the role of ERs in serotonin synthesis. Female ERβ knockout mice show lower serotonin levels across the brain (59), although this may be region specific and contradictory findings exist (60). E2 binds to ERs (particularly ERβ) to increase transcription of tryptophan hydrolase-2 (TPH-2), the rate-limiting enzyme in serotonin synthesis (58), via an ERE in the TPH2 promotor region. TPH-2 converts tryptophan to 5-hydroxytryptophan (5-HTP), which is the precursor of serotonin and thus affects its production. ERs also influence the breakdown of serotonin through indirect regulation of transcriptional activity of monoamine oxidase A (MAOA; (61)). ERs interact with transcription factors that bind to the MAOA promoter, thereby decreasing mRNA expression (62). TPH-2, MAOA, and serotonin are diminished in mice in the context of estradiol depletion via OVX (61).

E2 may also influence reuptake of 5-HT through interactions with serotonin reuptake transporter (SERT) (62). SERT expression decreases with OVX-mediated E2 depletion and can be restored with exogenous E2 administration in rodents and macaques (63,64); however, differential findings indicate that exogenous E2 administration in OVX rodents could lead to either up- or down-regulation of SERT (65,66). These discrepancies suggest that the effects of E2 on SERT signaling may occur in a context-dependent manner.

Translational Studies

The link between E2 and SERT expression has been less studied in humans, although one study showed SERT binding potential did not differ across menstrual cycle phases (67). In one study of postmenopausal women, E2 levels were not associated with 5HT1A receptor binding potential (68), and exogenous estrogen administration was not shown to significantly alter serotonergic receptor binding (69,70). However, changes in SERT and the impact of E2 during the MT have not been well characterized. One study using PET showed a higher density of MAO-A across brain regions implicated in depression in perimenopausal women, an enzyme linked to higher oxidative stress and apoptosis, which are processes also seen in patients with major depressive disorder without a reproductive component (71). In this study, MAO-A levels were positively associated with depressive symptoms (i.e., tendency to cry), although the sample was not selected for depression diagnosis. Thus, additional work is needed to characterize serotonergic processes implicated in emotion regulation during the MT in humans (57).

Dopamine

Preclinical Studies

Dopamine (DA) has been widely implicated in reward processing and mood regulation. Studies have delineated the tonic and phasic effects of E2 in dopamine synthesis and receptor expression, particularly in the prefrontal cortex and striatum (58,72). Tyrosine hydrolase (TH), a rate limiting enzyme linked to the synthesis of dopamine, can be modulated by E2 through action on both ERα and ERβ (73). Dopamine transporter (DAT) and dopamine receptors are also regulated by E2, and levels are decreased following OVX in rodents (74). Exogenous E2 administration impacts dopamine D2 receptor expression, with potentially conflicting findings across preclinical and clinical studies (58). D2 binding may be rapidly downregulated in OVX female rodents, with chronic E2 being associated with enhanced binding (75,76).

Translational Studies

In humans, although one study showed no change in D2 availability in striatum across menstrual cycle (77), other studies showed that hormonal contraceptive use was associated with greater DA synthesis compared to non-use (78). In the postmenopause, no difference in striatal D2 receptor binding was found between premenopausal and postmenopausal women (79), although exogenous estrogen administration has been associated with increased DAT availability (80). No findings to date have outlined DA synthesis or receptor expression in the context of perimenopause, although one study is underway to examine striatal D2 receptor binding in perimenopausal women with transdiagnostic mood symptoms (81).

GABA

Preclinical Studies

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter implicated in mood disorders. GABAergic function has immense relevance in reproductive mood disorders (82,83), but it is less well characterized in relation to the MT. GABA has been more widely studied as it relates to progesterone and its downstream metabolite allopregnanolone, although preclinical evidence suggests that E2 also plays an important role in regulating GABA. GABAergic neurons have ERs across several brain regions which play a role in how E2 modulates the GABAergic system (84). E2 acts by potentiating sodium potassium chloride cotransporter activity to reduce GABAergic inhibition (85). Further, E2 regulates GABAergic gene expression and GABA throughout regions like hypothalamus, hippocampus, amygdala, and cortex, leading to broad impact on behaviors (86). In rodents, OVX induces increases in GABA receptor binding site density, which is reversed by E2 administration (87). One study in mice found that OVX led to depressive-like symptoms, which were reduced following E2 administration (88). Concurrent administration of GABA_A receptor antagonist decreased this antidepressant-like effect, which suggests that E2 acts in part through GABA_A activation.

Translational Studies

Prior research has characterized changes in GABA levels that correspond to the hormonal changes of the menopause transition using magnetic resonance spectroscopy (MRS). In the medial prefrontal cortex (PFC), GABA+ (a measurement that includes co-edited macromolecules) levels were lower in perimenopause participants compared with those of reproductive age, although this effect became nonsignificant when age was included in the model (89). Interestingly, perimenopausal and reproductive age groups did not differ in GABA+ ratios (referenced to creatine and phosphocreatine) in the dorsolateral PFC in a separate analysis (90), suggesting that sensitivity to the hormonal fluctuations may vary across brain regions, perhaps as a function of ER density. Notably, circulating E2 did not correlate with GABA+ levels in either region. In contrast to null findings in cross-sectional studies, a larger longitudinal study of perimenopausal women tracked GABA levels through the MT (91) and showed that GABA decreased postmenopause.

Glutamate

Preclinical Studies

Glutamate is a key excitatory neurotransmitter implicated in mood regulation and depressive disorders. E2 augments glutamatergic transmission through membrane-mediated pathways and increased presynaptic release and postsynaptic responsiveness (58,92). Using OVX rodent models, previous studies have demonstrated the effects of E2 on long-term potentiation in the hippocampal dentate gyrus (93). Low E2 in the context of OVX contributes to a decrease in glutamatergic neurons alongside decreases in ERα and ERβ expression, which can be reversed by exogenous E2 administration (58). E2 also plays an important role in metabotropic glutamate receptor (mGluR) signaling (94). E2 increases cAMP, response element-binding protein (CREB) phosphorylation, which is regulated through ERα and ERβ activation. Specifically, ERα activation can trigger CREB phosphorylation via mGluR1a, while mGluR2 regulates CREB phosphorylation via both ERα and ERβ functioning. Therefore, both E2 and ERs are important for glutamatergic signaling, which is altered in the context of OVX.

Translational Studies

Similar to GABA, alterations in glutamate (Glu) levels across the MT have been studied in humans using MRS. One such study demonstrated that healthy perimenopausal women had decreased Glu levels in the medial prefrontal cortex compared with women of reproductive age (95), although other work has failed to find significant differences in Glu ratios (referenced to creatine and phosphocreatine) between perimenopausal and reproductive age women (90). In postmenopausal women, glutamate levels have been shown to be lower than in reproductive age women (96). Importantly, declining Glu levels characterize aging outside of the MT, which indicates age and timing of the MT are key factors to consider for interpreting effects (97).

6.2. E2 impact on neuroimmune function

In addition to the widespread neuronal effects outlined above, E2 also modulates the neuroimmune system, which may confer neuroprotective effects (98,99). The MT is associated with systemic increases in inflammation as E2 levels decline (100,101), which are mitigated with exogenous E2 administration (102).

Preclinical Studies

Much of the research examining the link between E2 and neuroinflammation has leveraged preclinical models. E2 suppresses the activation of microglia (103), the brain’s primary immune cells, inhibits pro-inflammatory cytokine expression in astrocytes (104,105), and alters T cell activation and proliferation (106). Additionally, E2 modulates expression of neuroinflammatory genes (107,108). ERα has been posited to be particularly important for inhibiting nuclear factor kappa-B, an inflammatory gene transcription factor, in the context of inflammatory stimuli (109). Reduced E2 levels via OVX are linked to increased mRNA of inflammatory mediators (e.g., tumor necrosis factor alpha, interleukin-1 beta, and macrophage inflammatory protein-2) and heighted responses to inflammatory stimuli (110). Administering E2 in OVX mice increases antigen-specific CD4 T cell responses and interferon gamma producing cells (111).

Translational Studies

Translational research focused on the influence of E2 in neuroimmune pathways is sparse. In one study, age (a potential proxy for menopause status) was correlated with expression of translocator protein (TSPO) in women but not men (112). Although this sample encompassed age ranges inclusive of the MT, reproductive status was not defined. Other work has examined neuroinflammatory changes in the context of Alzheimer’s disease risk (113), which increases in the MT (114). However, more work is needed to characterize the dynamics of E2’s neuroimmune modulation linked to PO-MDE.

6.3. E2 impact on neurometabolic functioning

E2 plays a key role in neural bioenergetic system, including glucose metabolism, glucose transport, and ATP generation (115), through its action on ERα and ERβ. E2 upregulates the expression of glucose transporters (GLUT1 and GLUT3) and increases mitochondrial efficiency, particularly in regions with high energy needs like the hippocampus and cortex (116).

Preclinical Studies

During the MT, an uncoupling between ER network and brain bioenergetic system occurs (117). The result is decreased glucose metabolism, which is also seen in OVX rodent models of menopause (118,119) and can be restored with exogenous E2 (119). E2 depletion with OVX also contributes to depressive like behavior (118). The hypometabolic brain state in OVX triggers a shift to alternative substrates that are less energy efficient and leads to an increased risk for neurodegeneration (116).

Translational Studies

Studies using PET have demonstrated declining glucose metabolism in several brain regions postmenopause, including the prefrontal cortex and posterior cingulate (120), mirroring literature on changes associated with depression outside the MT (121). Exogenous E2 has been shown to protect against decreasing glucose metabolism (120,122). Of note, normal aging is associated with declining glucose metabolism (123), although the effects differ for men and women in line with differing hormonal trajectories for the MT and testosterone decline in men (124). Specifically, the rate of decline is greater for women than men, which may highlight the important role of E2 in regulating bioenergetics (125). However, no studies have combined these lines of inquiry to test whether depression in the MT is linked to alterations in glucose metabolism.

6.4. E2 regulation of synaptic density and dendritic plasticity

Preclinical Studies

Decades of research have established E2 as a key modulator of synaptic plasticity (126,127). These effects are dynamically regulated by hormonal state; a recent in vivo preclinical imaging study showed that dendritic spine density fluctuates across the estrous cycle, peaking when circulating E2 is highest (128). Histological and functional data suggest that these cyclic fluctuations are accompanied by significant changes in synaptic strength, dendritic integration, and neuronal excitability (128). Although most research to date has focused on the hippocampus due to its robust capacity for neuroplasticity, E2’s effects on synaptic plasticity likely extend to other brain regions, including the hypothalamus, amygdala, and frontotemporal cortex (129). Ex-vivo studies of OVX rodents indicate that, in the context of reduced E2, dendritic spine density decreases, which can be restored with exogenous E2 (130,131)

Translational Studies

In a prospective dose-response study, short-term E2 administration in postmenopausal women was found to increase gray matter volume in the posterior hippocampus, particularly at higher doses (132). Notably, this effect was selective to regional subfields and not evident in total hippocampal volume, underscoring the need for high-resolution, region-specific investigations. While such volumetric changes may reflect underlying synaptic remodeling, direct synaptic-level interrogation in humans is still lacking.

6.5. Summary of E2 Neuromodulatory Activity During the MT

Taken together, there is substantial evidence of the many neurobiological pathways that are sensitive to changing E2 during the MT, although much of this work has been done in preclinical models. More research in women across the MT is needed to bolster these findings. Preclinical and existing clinical studies suggest that HT administration may mitigate some of the deleterious effects of decreasing endogenous E2. However, the timing and duration of HT to see these effects, particularly in PO-MDE, requires further investigation.

7.0. Summary and Future Directions

Depression during the MT is prevalent and impairing, making it crucial to understand mechanisms contributing to increased risk. E2 regulates several neurobiological processes reviewed here, and declining E2 levels across the MT contribute to alterations across these systems that have implications for PO-MDE. Existing translational studies underscore the neurobiological changes that are linked to PO-MDE and its treatment with exogenous hormones.

In this review we cover specific E2 dynamics that impact neurobiological pathways and structures to confer risk for PO-MDE. However, there are several challenges to the study of these mechanisms, and we highlight them as potential considerations in designing future research: 1) The prevailing research suggests that E2 variability and not individual levels play a critical role in PO-MDE as discussed above; variability is often best assessed longitudinally and therefore can be challenging to examine. 2) Sensitivity to E2 fluctuations is not universal, underscoring the importance of more work identifying predictors of elevated risk. 3) Estrogen changes coincide and relate directly and indirectly to shifts in other reproductive hormones not considered in this review (e.g., P4, testosterone) which may influence depression risk.

There are other potential mechanistic targets not reviewed here that may interact with E2 dynamics and warrant further investigation, Specifically, kisspeptin, neurokinin B, and dynorphin (KNDy) neurons, other glial cells that contribute to white matter integrity changes, hypothalamic-pituitary-adrenal axis, and blood-brain-barrier integrity. More preclinical and clinical research is needed to examine these pathways and how they interact with E2.

Beyond neurobiological factors, other clinical and environmental exposure likely intersect with E2 dynamics to contribute to PO-MDE risk. Namely, sleep disturbances, psychosocial changes, and stress exposure during the MT are important factors for further exploration. The multitude of these factors highlights the mechanistic complexity of PO-MDE and the need for further investigation.

In summary, existing research highlights the multifactorial impact of E2 and its dynamic impact on biological processes relevant to depression risk during the MT. However, more work leveraging preclinical models and, perhaps more importantly, experimental designs in humans are needed to directly test these mechanisms in the context of PO-MDE, as well depression risk during other reproductive transitions. Understanding the mechanisms underlying depression during this reproductive transition can pave the way for more precise identification, prevention, and treatment efforts.

Abbreviation

5-HTP

5-hydroxytryptophan

BBB

Blood-brain barrier

CREB

cAMP response element-binding protein

DA

Dopamine

DAT

Dopamine transporter

E2

Estradiol

ER

Estrogen receptor

ERE

Estrogen response element

GABA

Gamma-aminobutyric acid

Glu

Glutamate

GLUT

Glucose transporter

GnRH

Gonadotropin-releasing hormone

GPER

G protein-coupled estrogen receptor

HT

Hormone therapy

KNDy

Kisspeptin, neurokinin and dynorphin system

MAOA

Monoamine oxidase A

MRS

Magnetic resonance spectroscopy

MT

Menopause transition

OVX

Ovariectomy

P4

Progesterone

PET

Positron emission tomography

PFC

Prefrontal cortex

PO-MDE

Perimenopausal onset major depressive episode

SERT

Serotonin reuptake transporter

STRAW

Stages of Reproductive Aging Workshop

TH

Tyrosine hydrolase

TPH-2

Tryptophan hydrolase-2

TSPO

Translocator protein

VMS

Vasomotor symptoms