Stress-induced sex differences: Adaptations mediated by the glucocorticoid receptor

This article is part of a Special Issue “Neuroendocrine-Immune Axis in Health and Disease.”Clinical evidence has indicated that women are more susceptible to stress-related and autoimmune disorders than men. Although females may be more susceptible to some disease states, males do not escape unscathed and are more susceptible to metabolic dysfunction. The hypothalamic–pituitary-axis plays a pivotal role in the sexually dimorphic effects of chronic stress through alterations in negative feedback. Recent evidence has implicated the glucocorticoid receptor and its co-chaperones in the etiology of psychiatric and somatic diseases. Gonadal hormones heavily interact with both glucocorticoid receptor expression and glucocorticoid receptor action either through direct or indirect effects on proteins in the chaperone and co-chaperone complex. Diverse systems including the hypothalamic–pituitary-axis, the immune system, and metabolism are affected differently in males and females, possibly through the glucocorticoid receptor system. New considerations of glucocorticoid regulation through the co-chaperone complex in the brain will be vital to the development of treatment strategies for men and women afflicted by neuropsychiatric and somatic disorders.

► Men and women differ in susceptibility to anxiety, immune, and metabolic disorders.
► The glucocorticoid receptor system plays a critical role in these disorders.
► Gonadal hormones may mediate, at least in part, these sex differences through GR.