Sex Differences in Stress Susceptibility as a Key Mechanism Underlying Depression Risk

Abstract

Purpose of review: Although females are at relatively greater risk for a variety of disorders, including depression, the biological mechanisms underlying this striking health disparity remain unclear. To address this issue, we highlight sex differences in stress susceptibility as a key mechanism potentially driving this effect and describe the interacting inflammatory, hormonal, epigenomic, and social-environmental mechanisms involved.

Recent findings: Using the Social Signal Transduction Theory of Depression as a theoretical framework, women's elevated risk for depression may stem from a tight link between life stress, inflammation, and depression in women. Further, research finds hormonal contraceptive use alters cortisol and inflammatory reactivity to acute stress in ways that may increase depression risk in females. Finally, beyond established epigenetic mechanisms, mothers may transfer risk for depression to their female offspring through stressful family environments, which influence stress generation and stress-related gene expression. Together, these findings provide initial, biologically plausible clues that may help explain the relatively greater risk for depression in females vs. males. Looking forward, much more research is needed to address the longstanding underrepresentation of females in biomedical research on the biology of stress and depression.

Keywords: Depression; Intergenerational; Mechanisms; Sex differences; Stress susceptibility; Women’s health.

Fig. 1

Overlapping mechanisms contributing to high rates of female depression. Maternal depression, environmental influences, and hormonal mechanisms interact with each other to contribute to elevated inflammation and dysregulated hypothalamic–pituitary–adrenal (HPA) axis reactivity, which, in turn, contribute to elevated rates of depression for women and girls compared to men and boys