Abstract

The stress response is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, which is activated in response to both physical and psychological stressors. Prolonged activation of this axis contributes to sex-specific patterns of stress-induced hormonal imbalance, with significant implications for mental health. Recent studies, primarily conducted in mice but increasingly complemented by human data, have sought to elucidate the biological mechanisms underlying sex-dependent differences in HPA axis responses to stress. Central to these differences is the adrenal gland, a key component of the HPA axis that exhibits pronounced sexual dimorphism. Dimorphic traits of the adrenal cortex, spanning from tissue physiology, metabolism, and steroidogenesis to tissue turnover, progenitor recruitment, and the local microenvironment, shape the gland's adaptive capacity and hormonal output under stress. This review summarizes current knowledge on the sexually dimorphic hormonal response of the adrenal gland and the HPA axis, highlighting adrenocortical traits that underlie sex-differential steroidogenic responses to stress.