Glucocorticoid cascade hypothesis revisited: Role of gonadal steroids

Sex differences in HPA axis regulation have been documented in other species, particularly in rats, where estrogen regulates cortisosteroid binding globulin (CBG). Given that depression is more common in women, gonadal steroids may impact upon the HPA axis dysregulation often seen in depression. A number of our studies comparing HPA axis dysregulation in depressed men and women suggest that there are differences. We suggest that gonadal steroids may play a modulatory role in premenopansal depressed women. In particular, estrogen increases the level of CBG providing a greater buffering capacity against hypercortisolemia. In addition, progesterone can function as a glucocorticoid antagonist, thus blocking some of the negative sequellae of hypercortisolemia. Following menopause, the incidence of resistance to dexamethasone suppression increases to almost 100%, suggesting that loss of gonadal steroids is an important aspect of the age-HPA axis interaction. Depression 3:20–27 (1995). © 1995 Wiley-Liss, Inc.