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Review
. 2023 Feb;75(1):32-43.
doi: 10.1007/s43440-022-00444-2. Epub 2023 Jan 14.

Estrogen fluctuations during the menopausal transition are a risk factor for depressive disorders

Affiliations
Review

Estrogen fluctuations during the menopausal transition are a risk factor for depressive disorders

Justyna Turek et al. Pharmacol Rep. 2023 Feb.

Abstract

Women are significantly more likely to develop depression than men. Fluctuations in the ovarian estrogen hormone levels are closely linked with women's well-being. This narrative review discusses the available knowledge on the role of estrogen in modulating brain function and the correlation between changes in estrogen levels and the development of depression. Equally discussed are the possible mechanisms underlying these effects, including the role of estrogen in modulating brain-derived neurotrophic factor activity, serotonin neurotransmission, as well as the induction of inflammatory response and changes in metabolic activity, are discussed.

Keywords: Depression; Estrogen receptors; Menopause.

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Conflict of interest statement

The authors declare that they have no competing interests to disclose.

Figures

Fig. 1
Fig. 1
Stages of aging of the reproductive system in women. STRAW (Stages of Reproductive Aging Workshop) comprises ten stages beginning with the onset of menstrual cycles: reproductive age (− 5: early; − 4: peak fertility; − 3b − 3a: late reproductive stage), perimenopause (− 2 − 1: early and late menopausal transition), and postmenopause (+ 1a + 1b + 1c:early stages and + 2 late stage). With the onset of menopause, ovaries with fewer follicles induce a decrease in AMH (anti-Müllerian hormone), estradiol, and inhibin B production. The lack of ovarian responsiveness to FSH (follicle-stimulating hormone) and LH (luteinizing hormone) contributes to a negative feedback loop for estradiol and inhibin B resulting in the increased hypothalamic–pituitary release of GnRH (gonadotropin-releasing hormone) and FSH, and LH. Elevated FSH levels are particularly characteristic of the post-menopausal period. Note. The data are from Executive Summary of the Stages of Reproductive Aging Workshop 10: Addressing the Unfinished Agenda of Staging Reproductive Aging, by Harlow et al. [50]
Fig. 2
Fig. 2
Hormonal changes occurring in the perimenopausal period are responsible for many ailments and adversely affect the quality of life of women. The substrate of these disorders changes ovarian function [decreased maturation of Graff follicles, insufficiency of corpus luteum, deficiency of progesterone, estrogen, ovarian inhibin, and increased concentration of the FSH (follicle-stimulating hormone)]
Fig. 3
Fig. 3
ER (estrogen receptors) in the brain. Most receptors are located in the Cb (cerebellum), PFC (prefrontal cortex), Hip (hippocampus), and Amy (amygdala). ERα is located in the Amy and hypothalamus, whereas ERβ is found mainly in the Hip. In the Cb and thalamus, both receptors are expressed simultaneously. Created with BioRender.com
Fig. 4
Fig. 4
Simplified model showing estrogen receptor signaling in the Hip (hippocampus). E2 (estradiol) influences CNS (Central Nervous System) function through modulation of gene transcription (3) and rapid membrane signaling (1, 2). E2 by binding to the membrane ER (estrogen receptors) (4), rapidly activates signaling cascades involved in synaptic plasticity processes, thereby affecting memory processes. Membrane receptors ERα and ERβ lack the intrinsic ability to activate secondary messenger systems but bind to other membrane receptors mGluR (the metabotropic glutamate receptors). In Hip neurons, membrane receptor ERα activates mGluR5 and subsequently increases activation of the cellular transcription factor CREB (cAMP response element-binding protein) (2). Estrogens also activate membrane receptor subtypes: GPER-1 (G protein-coupled estrogen receptor), Gq-mER (Gq-coupled membrane estrogen receptor), and ER-X (1). Membrane receptors initiate Ca2+ signaling and activate PLC (phospholipase C) and AC (adenylyl cyclase), followed by the activation of multiple kinases: PI3K (phosphoinositide 3-kinase), ERK, AKT (protein kinase B), PKA (protein kinase A), PKC protein kinase C (5) which in turn can rapidly affect neuronal physiology by phosphorylation of transcription factors such as CREB or ERα to induce gene transcription. The relationship between serotonin and BDNF (brain-derived neurotrophic factor) TrkB (tropomyosin receptor kinase B) signaling is regulated by ERβ signaling in the hippocampus. Decreased ERβ receptor activity (4) decreases BDNF levels (5) and increases 5-HT2A and MAO (monoamine oxidase) levels (7). Aging is associated with altered brain bioenergetics, leading to reduced ATP (adenosine triphosphate) levels, decreased antioxidant defense, and increased ROS production and mtDNA (mitochondrial DNA) damage (8). Estrogen deficiency exacerbates immune dysfunction by activating the pro-inflammatory cytokines IL-1, IL-6, and IL-18 (6). Depressive disorders are caused by neuroanatomical changes involving the limbic system, including the Hip. Changes in synaptic transmission due to decreased estrogen production and neurotransmitter transmission contribute to reduced synaptic plasticity. Synaptic loss and deficits in functional connectivity include alterations in the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor and NMDA (N-methyl-d-aspartate) receptor function, changes in glutamate release, and structural alterations of dendritic spines (9). Created with BioRender.com

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