Available online 15 June 2022, 101010

Anxiety and depression disorders are twice as prevalent in women as in men.

Sex-hormone fluctuations shape the brain and confer female-specific psychiatric risk.

The estrous cycle involves extensive chromatin reorganization in the mouse brain.

Hormone-driven chromatin changes may prime the (epi)genome for psychopathology.

Studies of hormonally-induced risk will reveal sex-specific targets for treatment.

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.

anxiety disorders, depression, estrous cycle

menstrual cycle

estrogen

epigenetics

estrogen receptors

brain structure

hippocampus

chromatin

© 2022 The Author(s). Published by Elsevier Inc.