Sex Differences in the Hypothalamic–Pituitary–Adrenal Axis’ Response to Stress: An Important Role for Gonadal Hormones

The document reviews the influence of gonadal hormones on the sex differences in the hypothalamic-pituitary-adrenal (HPA) axis response to stress. It highlights that female rodents show a greater acute HPA response to stress compared to males, with this difference being modulated by testosterone and estradiol from the hypothalamic-pituitary-gonadal (HPG) axis. The review also notes that sex differences in the human HPA axis are less pronounced and vary with the type of stress. It discusses the necessity of glucocorticoid receptors (GR) in HPA regulation, which is less consequential for females, and higher levels of corticosteroid-binding globulin (CBG) in females, which may enhance their HPA axis activity. The roles of estrogen receptors (ERα and ERβ) and androgen receptors (AR) in mediating the effects of gonadal hormones on the HPA axis are also explored. The document emphasizes the organizational effects of gonadal hormones during critical developmental periods, such as the perinatal period and puberty, on HPA axis function. It suggests that early exposure to gonadal hormones influences gene expression related to HPA activation and glucocorticoid feedback mechanisms, with puberty being a critical period for the organizational actions of these hormones. The review raises questions about the direct effects of sex chromosomes on the HPA axis and the need for more research on the HPA response to chronic stress, especially in the context of sex differences and the potential for better coping skills in females when faced with novel stressors. It concludes that understanding these sex differences is crucial due to the higher risk of stress-related diseases in women and the therapeutic implications for both sexes.