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Published in final edited form as: Psychiatry Res. 2024 Oct 28;345:116239. doi: 10.1016/j.psychres.2024.116239

Follicle-stimulating hormone: More than a marker for menopause FSH as a frontier for women’s mental health

Julie Spicer a,b,c,*, Dolores Malaspina a,b, Stephanie V Blank c, Ki A Goosens a,b
PMCID: PMC12094525  NIHMSID: NIHMS2068116  PMID: 39892305

Abstract

The average current life expectancy entails that women will spend over one-third of their lives in menopause. Follicle-stimulating hormone (FSH) levels in women begin to increase roughly six years before the final menstrual period, reaching a menopausal plateau that is nearly 14 times the level of FSH observed in men, a profound sex-specific difference. A promising new body of work examines whether these age-associated increases in FSH contribute to multiple menopause-related conditions, including psychiatric morbidities. This paper highlights research advances showing the potential role of FSH and its underlying mechanisms in mental health conditions for women in menopause and makes the call for more research.

Keywords: Menopause, FSH, Mood symptoms, Depression, Anxiety, Oophorectomy, Aging

1. Menopause: a significant part of the life span

Menopause marks the cessation of women’s natural reproductive capacity and is an inevitable consequence of age-related declines in ovarian follicular functioning. The postmenopausal span is a significant proportion of a woman’s life: in the United States, those with an average age of menopause onset of 51.6 years (Greendale et al., 2012) and an average age of death of 80.2 years (Kochanek et al., 2024) will spend over one-third of their lives in this stage. Additionally, the postmenopausal span may define an even larger proportion of a woman’s life given that a substantial proportion of women at increased genetic risk for cancer are undergoing bilateral salpingo-oophorectomy in their 30s and 40s, or surgical menopause, as a risk reducing measure (Metcalfe et al., 2019). Indeed, over half of the oophorectomies in the United States are estimated to occur before the median age of natural menopause (Wild, 2007). This expansive timeline suggests that the peri/postmenopausal period may represent an important window of opportunity in mid-life for intervention and optimization toward better health.

2. Risk of depressive and anxiety symptoms in the menopause transition

Aging alone increases the prevalence of chronic health conditions in men and women, however aging women show additional risks for mood disorders (Centers for Disease Control and Prevention and National Association of Chronic Disease Directors, 2008). Overall, estimates suggest up to a three-fold increase in the risk of peri/postmenopausal depression and anxiety (relative to premenopausal women) based on large cohort studies of natural menopause and mood outcomes from the United States, Australia and Asia (de Kruif et al., 2016; Freeman, 2010; Kravitz et al., 2022; Mulhall et al., 2018), and this risk may be even higher for women with a history of depression (Freeman et al., 2014). The elevated psychiatric risk is tied to the menopause transition itself: even women with no history of a psychiatric disorder demonstrate increasing depressive and anxiety symptoms in both the peri- and postmenopause (Cohen et al., 2006; Freeman et al., 2006; Mulhall et al., 2018), with risks either similar to or exceeding overall estimates. Studies also show that surgical menopause may lead to the greatest risk for mood symptoms (Brauner et al., 2022; Hickey et al., 2021; Lin et al., 2020; Rocca et al., 2018) as these studies demonstrate one to three-fold increases relative to control groups who do not undergo surgical menopause.

3. FSH as a potential neurobiological pathway

This sex-specific age-associated health disparity suggests that biological aging has sex-specific underpinnings that are important to understand. Although much research on women’s health has focused on the impact of age-related decreases in the ovarian hormone estradiol, a promising new body of work is examining whether the age-associated increases in follicle-stimulating hormone (FSH) and its extra-gonadal actions could contribute to menopause-related conditions (Lizneva et al., 2019; Zaidi et al., 2023). Here, we highlight research conducted on FSH and mood symptom changes during the menopause transition. Prompted by these recent findings on extra-gonadal actions of FSH, we propose FSH as a potential mediating neurobiological pathway underlying mood symptom changes in menopause.

FSH is a gonadotropin with well-characterized roles in sexual development and reproduction in both men and women (Casarini and Crépieux, 2019). It is released by the anterior pituitary gland in response to hypothalamic gonadotropin-releasing hormone (Casarini and Crépieux, 2019) and inhibited by a negative feedback loop from either ovarian estradiol in women (Shaw et al., 2010) or inhibin B secreted by Sertoli cells in men (Meachem et al., 2001). Though adult women and men both have circulating FSH, aging is associated with a robust female-specific increase in FSH levels. In healthy men, FSH generally increases by roughly 3% each year between ages 40 and 80 (Feldman et al., 2002), yielding a physiological range that is comparable to that observed in menstruating women (Fig. 1, blue versus orange). However, in women, FSH levels begin to increase roughly six years before the final menstrual period (FMP) (Randolph et al., 2011), well before estradiol decreases are first detected at approximately two years prior to the FMP (Randolph et al., 2011), reaching a menopausal plateau that is nearly 14 times the level of FSH observed in men (Fig. 1, 64.3 versus 4.5 mIU/mL). Elevated FSH values (> 25 mIU/mL), in addition to an amenorrhea interval of ≥ 60 days, are two consensus criteria for defining late perimenopause (Harlow et al., 2012).

Fig. 1.

Fig. 1.

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Women experience a far greater age-related increase in FSH levels than men. Data depicts the median ± 95% confidence intervals for FSH reference ranges from Siemen’s ADVIA Centaur FSH Assay (Rev. U, 2020–06).

Notably, an increased risk of depressive and anxiety symptoms emerges before the FMP (Bromberger et al., 2007; Freeman et al., 2014, 2008). This is consistent with the idea that FSH is a sensitive measure of menopausal status in the pre- and perimenopause (Randolph et al., 2003), but also raises an important and underexplored question: could the increase in FSH contribute to the psychiatric morbidity of menopause whose emergence pre-dates the FMP?

4. Studies of FSH and mood in the menopause transition

We searched the literature for studies that presented findings on FSH in association with mood outcomes in the menopause transition, yielding reports from population-based cohort studies and studies with select samples as reviewed below and summarized in Table 1. The representative and population-based Penn Ovarian Aging Study (POAS) enrolled premenopausal women and followed them through the menopause transition. The POAS examined the association between hormones and depression severity by self-reported symptoms utilizing the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff, 1977) and diagnosis of major depressive disorder by diagnostic criteria. For non-cycling women, hormones were assayed at two consecutive monthly time points per assessment period (8 month to 1 year intervals), while for cycling women, hormones were assayed in the early follicular phase of two consecutive menstrual cycles. Three major findings on FSH emerge from this cohort study.

Table 1. Studies Correlating FSH or Estradiol with Mood in the Menopause Transition.

Studies on the menopause transition and mood reviewed for this article were first identified from the literature based on a search with key term, ’follicle-stimulating hormone’, and were further identified from reference lists found within those articles first identified. Of the studies reviewed, two were excluded from this table with negative findings for both FSH and estradiol (Bromberger et al., 2010; Schmidt et al., 2002), one was excluded as it reported correlations among hormones and mood at baseline, but without including p-values (Willi et al., 2021), and one was excluded as estradiol was measured, but not FSH (Gallicchio et al., 2007). For those studies that are included in this table, only results from fully adjusted models are shown when they are available. When they are not available, unadjusted results are shown.

 
Source, year (sample size; age in years) Study Design Pre;Peri;Post-Menopausal % FSH Estradiol Mood FSH Estradiol Adjusted Depression History
Direction Direction Direction Statistic (95% CI) Relating FSH to Mood Statistic (95% CI) Relating Estradiol to Mood
Natural Menopause
Daly et al., 2003 (N=110; 40-55) L Peri only subgroup with ≥ 50% decrease in FSH level in 6 weeks (n=23) ? outcome: decrease in CES-D in 6 weeks Paired t = 2.2 (df = 22), p = .03 mc exhibiting depression at enrollment
outcome: decrease in FSH level in 6 weeks ? subgroup with ≥ 50% decrease in CES-D in 6 weeks (n=18) Paired t = 2.6 (df = 17), p = .02 mc
Freeman et al., 2004 (N=332; 38-52) L 73;24;3% more rapid increase in FSH level (quadratic trend) nsa reduced odds of CES-D ≥ 16 in 4 years OR = 0.50 (0.34-0.73), p < .001 cov cov
Freeman et al., 2006 (N=231; 35-47b) L 57;43;0% FSH mean level increase ns increased odds of CES-D ≥ 16 in 8 years OR = 4.58 (2.03-10.35), p < .001 cov excluded
FSH variability (SD) increase estradiol variability (SD) increase increased odds of CES-D ≥ 16 in 8 years OR = 2.09 (1.70-3.41), p < .001 OR = 1.36 (1.02-1.80), p = .03 cov excluded
FSH mean level increase ns increased odds of depression Dx in 8 years OR = 9.33 (2.55-3.41), p < .001 cov excluded
FSH variability (SD) increase estradiol variability (SD) increase increased odds of depression Dx in 8 years OR = 1.81 (1.33-3.09), p = .006 OR = 2.45 (1.54-3.89), p < .001 cov excluded
Ryan et al., 2009 (N=138; 56-67) L Post only large increase in FSH level in 2 years (≥ 9 IU/L) decrease in estradiol level in 2 years (>0 pmol/L) increased odds of CES-D ≥ 10 (short form) OR = 2.57 (1.00-6.69), p = .05 OR = 3.49 (1.23-9.95), p = .019 cov cov
Bromberger et al., 2011 (N=221; 42-52b) L 0;41;59% increase in FSH levelc ns increased odds of depression Dx in 10 years OR = 1.25 (0.97–1.62), p = .08 no mixed
Freeman et al., 2014 (N=203; 42-58d) L Post only increase in FSH level rate of change, in 4 years preceding FMP (for each 1 SD increase in FSH level slope) ns reduced odds CES-D ≥ 16 after FMP (≥ 2 years relative to < 2 years) OR = 0.65 (0.46-0.91), p = .01 cov cov
Rajewska & Rybakowski, 2003 (N=90; 38-46) C Pre only increase in FSH level in depression Dx group (n=60) ns increase in BDI in depression Dx group (n=60) Pearson r = .37, p < .05 mc onset after age 38 in depression Dx group
Berent-Spillson et al., 2017 (N=54; 42-61) C 28;20;52% increase in FSH level ns increase in POMS negative mood Pearson r = .36, p = .009 no psychiatric illness
increase in FSH levelc ns increase in BDI Pearson r = .21, p = .093 no excludede
Surgical Menopause
Hickey et al., 2021 (N=194; 24-53b) L Pre onlyb ? ? CES-D ≥ 16 ? mixed
? ? GAD-7 ≥ 10 ? mixed
Brauner et al., 2022 (N=25,188; ≥ 45b) L ? ? ? Incident depression Dx or ? excluded
? ? filled Rx for antidepressants ? excluded
Page et al., 2023 (N=1,971; 35-65) C 30;17;37% ? ? CES-D ≥ 16 ? ?
16% surgical ? ? GAD-7 ≥ 10 ? ?
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Orange highlight indicates measures that are significantly increased. Blue highlight indicates measures that are significantly decreased. Gray highlight indicates measures that were either not obtained or not reported. No highlight indicates measures that are not significant. Using this color scheme, it is apparent that estradiol is not significantly correlated with depressive symptoms, while the majority of studies support a positive correlation between FSH and depressive symptoms. It is also clear that FSH and estradiol are both understudied with respect to mood symptoms in women with surgical menopause (e.g. Brauner et al., 2022; Hickey et al., 2021; Page et al., 2023).

a

= significant finding in the report, but not in final model.

b

= at baseline.

c

= marginal significance: p > .05 & < 0.10

d

= at final menstrual period.

e

= psychiatric illness reported as study exclusion criterion, but not indicated whether current or past.

BDI = Beck Depression Inventory; C = cross-sectional; CES-D = Center for Epidemiologic Studies Depression Scale; CI = confidence interval; cov = covariate(s) included in analysis; df = degrees of freedom; Dx = diagnosis; excluded = depression history as exclusion criterion; FMP = final menstrual period; FSH = follicle-stimulating hormone; GAD-7 = Generalized Anxiety Disorder 7-item scale; L = longitudinal; mc = adjusted for multiple comparisons; mixed = a mix of participants included with and without depression history; ns = not significant; OR = odds ratio; POMS = Profile of Mood States; Rx = prescription; SD = standard deviation; ? = measure not obtained or not reported.

In an initial report, when some women had transitioned from the premenopausal to the perimenopausal phase over 4 years of the study, results showed lower odds of clinically meaningful elevations of depressive symptoms (CES-D ≥ 16) with more rapidly increasing FSH and estradiol levels (quadratic profiles), although only FSH emerged with an overall significance of the risk factor (Freeman et al., 2004). In a subsequent report that doubled the number of women in the perimenopausal phase across 8 years of the study, but only focused on the subset of women with no prior depression diagnosis, those with CES-D ≥ 16 were 4.58 times more likely to have elevated FSH mean levels at the time of the high symptoms score, and more likely to have higher FSH (OR = 2.09) and estradiol (OR = 1.36) variability (Freeman et al., 2006). In the subset who met diagnostic criteria for a depressive disorder, there was more than a 9-fold likelihood of elevated mean level FSH and increased odds of FSH (OR = 1.81) and estradiol (OR = 2.45) variability. In a later study across 14 years of the cohort, when all women had reached the FMP and measures from postmenopausal timepoints had been collected, results showed lower odds of high depressive symptoms 2 years or more since the FMP (relative to the first 2 years post-FMP) with greater rate of change in FSH levels in the 4 years prior to the FMP (FSH slope), but not with pre-FMP estradiol rate of change (Freeman et al., 2014).

In a study of postmenopausal women from the population-based Melbourne Women’s Midlife Health Project, who on average were 5.9 – 7.0 years since menopause and relatively older than other studies presented here (56–67 years), large increases in FSH (≥ 9 IU/L) and decreases in estradiol (> 0 pmol/L) over 2 years associated with increased depressive symptoms (Ryan et al., 2009). However, neither FSH nor estradiol levels associated with depressive symptoms in the population-based Study of Women across the Nation which included 8 annual assessments through the menopause transition (Bromberger et al., 2010), although increased FSH levels showed a marginally significant association with diagnosis of major depressive disorder over 10 years, but only in univariate analysis (Bromberger et al., 2011).

In a longitudinal study of 110 perimenopausal women recruited from a menopause clinic and who exhibited depression at enrollment, for 23 participants who showed a large decrease (≥ 50%) in plasma FSH level in 6 weeks, CES-D scores decreased, and for the 18 participants who showed a large decrease (≥ 50%) in CES-D scores in 6 weeks, FSH levels decreased (Daly et al., 2003). However, the study did not show that women increasing in FSH levels also increased CES-D scores or that those increasing in CES-D scores also increased their FSH levels, though the number of women exhibiting these increases was relatively smaller than women with decreases. Estradiol was not presented in the study.

Two relatively small cross-sectional studies report a positive correlation of FSH, but no correlation of estradiol, with depressive symptoms in a group of premenopausal women diagnosed with major depression (Rajewska and Rybakowski, 2003) and negative mood in a sample of pre-, peri- and postmenopausal women recruited from a population-based longitudinal study of the menopause transition (Berent-Spillson et al., 2017). However, one study did not include details on cycling history (Rajewska and Rybakowski, 2003) and the other did not provide the correlation result with a correction for multiple comparisons (Berent-Spillson et al., 2017).

Animal studies furthermore link FSH and depressive behaviors. Stressed ovariectomized rats, for example, showed higher levels of FSH and depressive behaviors than controls (Gu et al., 2018). In stressed rats both with and without ovariectomy, FSH and monoamines (dopamine and serotonin) are inversely correlated, whereas FSH and stress hormones (norepinephrine, ACTH, corticosterone) are positively correlated (Gu et al., 2018). These findings are consistent with studies that causally link the monoaminergic system and stress hormone levels with depression-like behaviors in rodents (Cryan et al., 2005; Sturm et al., 2015; Yohn et al., 2016), so it is notable that both are associated with FSH. Collectively, both human and animal studies point to the hypothesis that changes in FSH may underlie mood changes in the peri- and postmenopause.

5. Underlying mechanism of the FSH and mood association: role of FSHR in inflammatory and neural processes

Research suggests a role for inflammatory mediators in the effects of elevated FSH. FSH receptors (FSHRs) are expressed in monocytes (Robinson et al., 2010) and stimulate production of proinflammatory cytokines, including interleukin 6, tumor necrosis factor alpha (Cannon et al., 2011; Iqbal et al., 2006) and interleukin 1 beta (Han et al., 2023). Inflammatory hypotheses for mood disorders, rheumatoid arthritis and Alzheimer’s disease, all diseases with a greater prevalence in aged women compared to aged men (Alzheimer’s Association, 2023; Centers for Disease Control and Prevention and National Association of Chronic Disease Directors, 2008; Crowson et al., 2011), are well-documented (Miller and Raison, 2016; Shrivastava and Pandey, 2013; Uddin et al., 2022). This suggests that FSH-driven proinflammatory processes may contribute to disease risk in peri- and postmenopausal women.

Recently published work reveals extensive expression of FSHRs throughout the brain, including many regions with no links to fertility or reproductive behavior (Ryu et al., 2022), supporting a far more robust role for FSH than has been appreciated. Notably, FSHR was detected in multiple brain regions that regulate mood and depressive behavior, including the nucleus accumbens, insula, cingulate cortex, hippocampus, amygdala, and lateral and dorsomedial hypothalamus (Pandya et al., 2012; Price and Drevets, 2012; Russo and Nestler, 2013).

Exactly which aspects of FSH are important for mood changes may be suggested by Table 1. Here an overall pattern indicates that increased levels of FSH or increased variability in FSH is related to increased mood symptoms, however reports from the POAS also show that a more rapid change in FSH relates to fewer mood symptoms (Freeman et al., 2014, 2004). As noted above, the POAS collected measurements in approximately two consecutive months per assessment period, and studies with additional consecutive measurements may be necessary to provide further support for the hypothesis that a rapid change in FSH is protective, and to make meaningful hypotheses about an underlying mechanism for protection. For example, these effects may be FSHR-mediated, and we know remarkably little about how FSHR changes with age, especially in the brain. Additional research should reveal the extent to which serum FSH levels and FSHR are linked. For example, some evidence shows that among perimenopausal patients without detectable levels of FSHR in ovarian tissue, serum FSH levels are higher compared to patients with detectable levels, suggesting a loss of FSH signaling in ovarian tissue despite high levels of ligand (Vihko et al., 1996); perhaps this pattern extends to other tissues.

6. More evidence for neural actions of FSH

FSH remains elevated beyond the menopause transition into postmenopause (Randolph et al., 2011; Zaidi et al., 2018). Rates of Alzheimer’s disease among women are greater than men (Alzheimer’s Association, 2023), and some studies show increased gonadotropin levels in patients with Alzheimer’s disease (Bowen et al., 2000; Short et al., 2001). A causal role of FSH is being established for Alzheimer’s disease; Xiong et al. (2022) found that an anti-FSHβ antibody reversed neuronal and behavioral phenotypes of Alzheimer’s disease in mice, specifically blocking the acceleration of amyloid-β and tau deposition in hippocampal and cortical regions, as well as cognitive impairments. Human studies utilizing the FSH-blocking antibody may soon be underway (Rojekar et al., 2023).

7. Roles of FSH and estradiol variability in mood outcomes of the menopause transition

Beyond these newly suggested direct actions of FSH in inflammatory and neural processes to produce changes in mood, an additional explanation is suggested by the estradiol variability hypothesis (for review, Gordon and Sander, 2021). This model posits that extreme FSH fluctuations, predominantly occurring in ovulatory cycles of the early perimenopause, co-occur with estradiol fluctuations, and that sensitivities to estradiol increases, decreases or change may explain changes in mood symptoms. Furthermore, estradiol fluctuation remains possible in late perimenopause, when anovulatory cycles are more common, and early postmenopause, possibly a time when ovarian senescence has not yet been completed, though notably overall estradiol levels in these stages are significantly reduced, while FSH levels remain elevated.

For example, in one randomized clinical trial, postmenopausal women with previous perimenopausal depression and postmenopausal women with no perimenopausal depression history (controls) were administered transdermal estradiol (Schmidt et al., 2015). After 3 weeks, some were randomized to continue estradiol and some were switched to placebo for another 3 weeks. The women with perimenopausal depression history who switched to placebo experienced depressive symptoms increase relative to the estradiol-only depression history group and controls. Also, an observational study found that week-to-week increases in estradiol over 4 weeks linked to increased negative mood in perimenopausal depressed women (Gordon et al., 2016). The estradiol variability hypothesis applies to mood disturbances in other reproductive stages such as premenstrual dysphoric disorder (Schmidt et al., 2017), premenstrual exacerbation of depressive symptoms (Eisenlohr-Moul et al., 2022) and postpartum depression (Bloch et al., 2003).

Progesterone, another ovarian hormone, is less well-studied in the perimenopause, although overall, it does not appear to show fluctuations like estradiol in the early perimenopause but rather declines in the late perimenopause (see Gordon and Sander, 2021). In one study of perimenopausal women with mild to moderate depressive symptoms at baseline, decreased progesterone levels and increased estradiol variability associated with increased depressive symptoms over 8 weekly measurements (Joffe et al., 2020).

8. The surgical menopause model

Extant data show broad perimenopausal changes in mood and FSH (de Kruif et al., 2016; Randolph et al., 2011), but published studies using cohorts of women undergoing natural menopause demonstrate several important limitations which may contribute to the mixed findings relating mood and FSH (Freeman, 2015). First, the onset of natural perimenopause has a range of more than ten years across individuals, and the duration of the menopausal transition can span over nine years, with a median of 4.37 years for those in the oldest quartile at age-of-onset and 8.57 years for those in the youngest quartile at age-of-onset, by adjusted estimations (Paramsothy et al., 2017). Thus, longitudinal studies taking measurements at set intervals may not obtain study measurements at equivalent time points across all individuals. Second, large cohort studies typically obtain measurements of hormones at sampling points that span years because of the impracticality and cost of obtaining more frequent measurements. This low temporal resolution may impair the ability to accurately assess rates of changes in FSH or to detect changes in FSH that precede changes in mood. Additionally, definitions of the menopause transition may vary with studies employing consensus criteria from the Stages of Reproductive Aging Workshop+10 (Harlow et al., 2012) or FMP time (Greendale et al., 2012) and others, an issue that may be particularly important when determining study enrollment criteria (Streicher, 2023). Differences in identification of the menopausal transition may contribute to cross-study variability.

Studying women who require oophorectomy would overcome some of the limitations described above because the exact date of menopause is precisely known (the date of surgery) and sampling of hormones and mood symptoms could be obtained at identical time points across participants. Moreover, FSH rises dramatically by three months post-surgery (nearly seven times higher than baseline) and remains elevated in subsequent months (Gumussoy et al., 2020). This temporal compression of menopause and its associated hormonal shifts mean that longitudinal studies using this model can capture study measurements at more similar time points across individuals, and also in a relatively short timeframe, in contrast to the necessarily lengthy studies of natural menopause. This reduced variability may enhance the ability to detect relationships between hormonal changes and other measures of interest, such as mood symptoms, especially in studies seeking to understand how changes in FSH are related to menopausal changes in health (Freeman et al., 2014, 2004). Although one potential limitation of this research is that its findings may not generalize to all women undergoing natural menopause, the knowledge gained would nonetheless be useful given that a substantial number of women seek the procedure for risk-reducing reasons. Additionally, generalizability to natural menopause cannot be known, unless it is studied.

9. FSH hypothesis

Several research questions remain on the role of FSH in mood symptom changes over the menopause transition. First, although FSH and estradiol fluctuations may be correlated, it appears rise in FSH level should be further explored as the sheer rise in FSH may trigger separate or additional pathways than a fluctuation hypothesis posits. For example, in new onset cases, mean FSH level elevations associate with high depressive symptoms scores and increased odds of a depression diagnosis (along with FSH and estradiol variability) (Freeman et al., 2006); and a faster rate of FSH change four years prior to the FMP, a time covering the late perimenopause, associates with reduced depressive symptoms in the two or more years following FMP (Freeman et al., 2014). Second, while estradiol variability is commonly found in ovulatory cycles of the early perimenopause, how much this mechanism underlies mood changes of the late perimenopause when anovulatory cycles more commonly occur, is less clear (for review, Gordon and Sander, 2021). Also, additional research shows that increased mood symptoms may be a feature of the postmenopause relative to premenopause (Kravitz et al., 2022; Mulhall et al., 2018), in particular for those with pre-FMP symptoms (Kravitz et al., 2022), again at a time when mean level estradiol is significantly reduced.

Third, when receiving transdermal estradiol, women with prior perimenopausal depression showed lower FSH in addition to higher estradiol relative to women with such history receiving placebo (Schmidt et al., 2015), likely due to the known negative feedback of estradiol on FSH. Although neither change in plasma level FSH nor estradiol from transdermal estradiol administration to placebo correlated with symptoms change or maximum symptoms score during placebo, the influence of FSH could be further explored. Fourth, it is unclear whether separate mechanisms underlie the development of perimenopausal mood symptoms in those with a previous history of depression versus those without this history. For individuals who experienced a reproductive stage mood disruption, such as those tied to the menstrual cycle or parturition, it could be that estradiol sensitivity is an underlying mechanism of perimenopausal depression. It also could be that estradiol sensitivity and separate mechanisms triggered by FSH rise combine or interact to produce greater mood disturbance. Finally, it could be that for those who do not have a history of estradiol sensitivity, rising FSH may trigger perimenopausal mood disruption. Future research is needed to address these open questions.

10. Conclusion

Taken together, several studies support an association between FSH and depressive symptoms in the natural menopause transition, and it is also clear that hormonal associations with mood symptoms are understudied in women with surgical menopause. There already are important gains in knowledge on the role of FSH in other conditions of aging in women, such as osteoporosis (Gera et al., 2022; Shieh et al., 2019; Wang et al., 2015) and atherosclerosis (El Khoudary et al., 2016; Han et al., 2023; Khoudary et al., 2012), and an exciting expansion of knowledge of FSHR in the brain, including FSHR in hippocampus and cortex (Ryu et al., 2022). Depression (Freeman, 2015; Hickey et al., 2021; Mulhall et al., 2018), anxiety (Hickey et al., 2021; Mulhall et al., 2018), psychosis (Culbert et al., 2022) and dementia (Hao et al., 2023) have known changes with the perimenopause and menopause, and the full picture of underlying mechanisms is still unknown. For women, who have been historically underrepresented in medical research (Beery and Zucker, 2011; Yoon et al., 2014), a deeper understanding of the molecular changes that accompany menopause is a critical first step towards understanding the changes in disease risk that follow it.

Funding

This research was supported by a grant from the National Institute of Mental Health (R01MH135079–01 to JS).

Footnotes

CRediT authorship contribution statement

Julie Spicer: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Dolores Malaspina: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Stephanie V. Blank: Writing – review & editing, Conceptualization. Ki A. Goosens: Writing – review & editing, Writing – original draft, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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