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Review
. 2022 Jul:66:101010.
doi: 10.1016/j.yfrne.2022.101010. Epub 2022 Jun 15.

Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms

Marija Kundakovic  1 , Devin Rocks  2
Affiliations
Review

Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms

Marija Kundakovic et al. Front Neuroendocrinol. 2022 Jul.

Abstract

Women are at twice the risk for anxiety and depression disorders as men are, although the underlying biological factors and mechanisms are largely unknown. In this review, we address this sex disparity at both the etiological and mechanistic level. We dissect the role of fluctuating sex hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. We provide parallel evidence in humans and rodents that brain structure and function vary with naturally-cycling ovarian hormones. This female-unique brain plasticity and associated vulnerability are primarily driven by estrogen level changes. For the first time, we provide a sex hormone-driven molecular mechanism, namely chromatin organizational changes, that regulates neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. Finally, we map out future directions including experimental and clinical studies that will facilitate novel sex- and gender-informed approaches to treat depression and anxiety disorders.

Keywords: Anxiety disorders; Brain structure; Chromatin; Depression; Epigenetics; Estrogen; Estrogen receptors; Estrous cycle; Hippocampus; Menstrual cycle.

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Conflict of interest statement

Declarations of interest: none

Figures

Figure 1.
Figure 1.. Sex hormone profiles across the menstrual (human) and estrous (mouse) cycle.
Pro, proestrus; Die, diestrus; Est, estrus; Met, metestrus.
Figure 2.
Figure 2.. Sex difference in depression risk and sex hormone levels in females across the life span
(adapted from Deecher et al, 2008).
Figure 3.
Figure 3.. Anxiety-related behavior varies across the estrous cycle and sex in mice.
Die, diestrus (pink); Pro, proestrus (purple); Male, males (blue). (adapted from Jaric et al., 2019b)
Figure 4.
Figure 4.. Comparable changes in hippocampal brain structure across the menstrual cycle in humans and the estrous cycle in mice.
A. In the human hippocampus (red), bilateral fractional anisotropy and left grey matter values are plotted against estrogen levels (in red) across the two menstrual cycles assessed (upper panel; adapted from Barth et al, 2016). In the lower panel, grey matter changes in left hippocampus are displayed with blue voxels corresponding to statistically significant results. B. In the mouse hippocampus (red), we showed structural changes in the ventral hippocampus (black square) as estradiol levels vary across the estrous cycle. In the lower panel, dendritic spine density is shown in the high-estrogenic (Pro, proestrus) phase versus low-estrogenic (Die, diestrus) phase (adapted from Jaric et al, 2019b).
Figure 5.
Figure 5.. Working model of ER signaling mediating chromatin and gene expression changes in vHIP neurons across the estrous cycle.
Estradiol could act through: 1. Nuclear ER that activates transcription by binding to estrogen response elements (ERE); 2. Membrane-bound ER that regulates transcription indirectly, via kinase-dependent activation of Egr1 and other estrogen-dependent transcription factors.
Figure 6.
Figure 6.. Model for epigenetic regulation of anxiety-related behavior by the estrous cycle.
Dlk1 represents an example of a gene whose genetic deletion (knockout, k/o) leads to increased anxiety indices in males (M) but whose expression naturally varies with the estrous cycle in females (F) (A-B). Gene expression is regulated by the accessibility of the regulatory DNA which is packaged into chromatin at the nucleosome level (1D chromatin) or at higher order chromatin organization (3D chromatin) (C). Dlk1 gene changes chromatin organization within putative regulatory regions (dashed rectangles) during the estrous cycle. One of these regions contains an Egr1 binding motif. (D). Other genes such as Pou3f2 (marked by rectangle) show changes in 3D chromatin interactions. Shown are arcs representing differential enhancer-promoter interactions between proestrus and diestrus (left) which are associated with differential gene expression found by RNA-seq (right; TPM, normalized read counts as transcripts per million). All genomic data are derived from triplicates and are depicted here as data merged per group for simplicity (E). Epigenomic changes across the estrous cycle exceed changes in gene expression indicating that they may prime the genome while larger gene expression changes may require another stimulus such as a genetic risk factor or stress exposure (data derived from and figures adapted from Jaric et al, 2019b and Rocks et al, 2022). Die, diestrus (pink); Pro, proestrus (purple); Male, males (blue).
Figure 7.
Figure 7.. Novel model for the sex-biased development of anxiety and depression disorders.
Sex-hormone status in women is added as a third risk factor in addition to the individual’s genetic background and stress exposure. Hormone-driven changes in the epigenome may translate into changes in gene expression, brain structure, and function and contribute to the symptomatology of anxiety and depression disorders and their increased vulnerability in women.
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