The effect of exogenous estrogen on depressive mood in women: A systematic review and meta-analysis of randomized controlled trials

Zhang, Jianzhao; Yin, Jie; Song, Xiaodong; Lai, Shunkai; Zhong, Shuming; Jia, Yanbin

doi:10.1016/j.jpsychires.2023.04.002

Cited by 12 publications

(6 citation statements)

References 59 publications

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“…58 Prior studies have consistently shown lower oestrogen levels in women with SMI, recently supported by randomized-controlled trials that show administering exogenous oestrogen is effective in treating SMI. 59,60 A possible explanation for our results could be that our MR analysis lacked sufficient power. The instruments for oestrogen contained only two to four SNPs stratified on menopausal status, up to a maximum of eight not stratified, and showed heterogeneity.…”

Section: Discussionmentioning

confidence: 92%

The role of sex hormones in severe mental illness: a genetic exploration

Veeneman,

Verweij,

Sommer

et al. 2024

Preprint

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IntroductionDespite advances in psychotherapies and pharmacological treatments, the burden of severe mental illness (SMI) remains high. Prominent sex differences exist in SMI, with increasing evidence pointing towards a pivotal role for sex hormones. Elucidation of these hormonal influences is crucial to tailor sex-specific prevention and treatment.MethodsTo investigate potential shared genetics and bi-directional causal effects between sex hormone traits and SMI, we computed genetic correlations using linkage disequilibrium score regression and bi-directional summary-level Mendelian Randomization (MR). A range of sensitivity methods was applied and potential mediators were investigated using multivariable MR. Sex-stratified data from genome-wide association studies (GWAS)s were used, further stratified on menopausal status when available. The main analysis focused on depressive disorder (N women=23,618 and N men=17,336), bipolar disorder (N women=26,573 and N men=22,381), schizophrenia (N women=54,513 and N men=68,287) as SMIs, and oestrogen (N women=229,966 and N men=206,927) and testosterone (N women=230,454 and N men=194,453) as the primary sex hormone traits. Exploratory analyses included other sex hormone traits (progesterone, sex hormone-binding globulin, prolactin, age of menarche, age of menopause). Potential mediators examined included levels of cortisol and CRP, smoking initiation, alcohol dependence, alcohol intake, BMI and body fat distribution. Only individuals of European ancestry were included.ResultsWe found a widespread pattern of significant genetic correlations between oestrogen/testosterone levels and depressive disorder/schizophrenia, in both positive and negative directions in both sexes (ranging between -0.22 and 0.13). There was no significant genetic correlation for bipolar disorder. In the MR analyses, evidence for causal effects was largely lacking; however, there was consistent evidence for a causal, increasing effect of testosterone levels on schizophrenia risk in men, completely mediated by CRP. Conversely, there was evidence for a causal, increasing effect of liability to schizophrenia on testosterone levels in both sexes.ConclusionThis study offers new insights into the complex aetiology of SMI by comprehensively mapping genetic associations with sex hormone traits, emphasizing the need to further investigate sex hormones’ impact on SMI using larger and more precisely phenotyped samples to identify individuals particularly vulnerable to hormonal disturbances.

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Section: Discussionmentioning

confidence: 92%

The role of sex hormones in severe mental illness: a genetic exploration

Veeneman,

Verweij,

Sommer

et al. 2024

Preprint

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“…As in migraine, there is a relationship between low sex hormone levels and increased prevalence of depression [260]. Furthermore, the administration of exogenous estrogens has antidepressant effects in depressed women, with the effect more significant if administered during perimenopause, in the form of a transdermal patch, or the postpartum period [261][262][263]. However, there is controversy, as other studies have shown that estrogens did not improve mood in postmenopausal women or even increase the risk of cognitive impairment and stroke [264][265][266].…”

Section: Estrogensmentioning

confidence: 99%

Understanding the Biological Relationship between Migraine and Depression

Viudez-Martínez,

Torregrosa,

Navarrete

et al. 2024

Biomolecules

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Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities.

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“…Research reveals that puberty-related hormonal changes contribute to sex-based disparities in depression prevalence ( Morssinkhof et al, 2020 ). Notably, females who experience early onset of puberty face an elevated vulnerability to depression compared with their peers ( MacSweeney et al, 2023 ), and women in the perimenopausal and postmenopausal stages exhibit a significant association with depressive disorders ( Zhang J. et al, 2023 ), which may arise from the fact that depressive symptoms during these phases are more closely linked to fluctuations in estrogen levels. Significantly, administering exogenous estrogen can alleviate the severe hormonal fluctuations experienced by women during perimenopause and postmenopause.…”

Section: Sex Differences In Depressionmentioning

confidence: 99%

“…Significantly, administering exogenous estrogen can alleviate the severe hormonal fluctuations experienced by women during perimenopause and postmenopause. Intriguingly, the effectiveness of exogenous estrogen in mitigating the adverse effects of estrogen fluctuations depends more on the age of the women rather than the dosage of the administered estrogen ( Zhang J. et al, 2023 ). Overall, a relative fluctuation in estrogen appears to correspond with heightened depressive symptoms ( Morssinkhof et al, 2020 ), and these findings contribute to the partial elucidation of the sex differences in depression prevalence.…”

Section: Sex Differences In Depressionmentioning

confidence: 99%

“…Sex hormones not only contribute to the pathogenesis of depression but also serve as one of essential approach in its treatment, and to be specific, both estrogens in women and androgens in men have been implicated in the treatment of depression. Estradiol therapies have demonstrated effectiveness in alleviating depressive symptoms, especially in women experiencing significant fluctuations or reductions in ovarian hormones, such as during the perimenopause and postpartum periods ( Zhang J. et al, 2023 ). Likewise, testosterone therapies have shown efficacy in alleviating depression in men with hypogonadism ( Eid et al, 2019 ).…”

Section: Sex Differences In Depressionmentioning

confidence: 99%

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Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

Chen,

Wang,

Liu

et al. 2024

Front. Aging Neurosci.

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Depression and Alzheimer’s disease (AD) are prevalent neuropsychiatric disorders with intriguing epidemiological overlaps. Their interrelation has recently garnered widespread attention. Empirical evidence indicates that depressive disorders significantly contribute to AD risk, and approximately a quarter of AD patients have comorbid major depressive disorder, which underscores the bidirectional link between AD and depression. A growing body of evidence substantiates pervasive sex differences in both AD and depression: both conditions exhibit a higher incidence among women than among men. However, the available literature on this topic is somewhat fragmented, with no comprehensive review that delineates sex disparities in the depression–AD correlation. In this review, we bridge these gaps by summarizing recent progress in understanding sex-based differences in mechanisms, genetics, and therapeutic prospects for depression and AD. Additionally, we outline key challenges in the field, holding potential for improving treatment precision and efficacy tailored to male and female patients’ distinct needs.

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The effect of exogenous estrogen on depressive mood in women: A systematic review and meta-analysis of randomized controlled trials

Cited by 12 publications

References 59 publications

The role of sex hormones in severe mental illness: a genetic exploration

The role of sex hormones in severe mental illness: a genetic exploration

Understanding the Biological Relationship between Migraine and Depression

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

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