Steroid Hormone Signaling Pathways and Sex Differences in Neuroendocrine and Behavioral Responses to Stress

The hypothalamo-pituitary-adrenal (HPA) axis responds to stress by redirecting the physiology and behavior of an organism toward survival and maintenance of homeostasis using a coordinated and well-orchestrated activation of the neuroendocrine and autonomic nervous systems. A plethora of studies have demonstrated the existence of sex differences in the components of the HPA axis and its response to stress, with the females reacting more rapidly and robustly compared with males. Gonadal steroid hormones mediate these sex differences, not only by organizing the HPA axis during development, but also by modulating HPA function in adulthood, with estrogens enhancing and androgens inhibiting HPA axis activity. Part of this involves interactions with circulating glucocorticoids, which exert negative feedback actions on HPA function. Cellular and molecular evidence indicates that androgens, estrogens, and glucocorticoids can interact to affect stress responses through intracellular, membrane-associated, or extranuclear receptors in the central nervous system.