Sex differences in response to exogenous corticosterone: a rat model of hypercortisolemia.

: In depressed humans we have noted sex differences in HPA axis regulation and sensitivity to glucocorticoid negative feedback. The present studies were undertaken to develop an animal model of hypercortisolemia and to determine the resistance to suppression of the HPA axis by exogenous glucocorticoids in gonadally intact female rats compared to intact males, as well as the impact of removal of gonadal steroids (ovariectomy) on this resistance. We administered 50% corticosterone pellets, which we and others have previously characterized in male rats, to gonadally intact male and female and ovariectomized (ovx) female rats. While implantation of these pellets increased am plasma corticosterone and decreased pm plasma corticosterone in all groups, the pm plasma corticosterone levels were highest in intact females. Prior to implantation of the pellets, intact females demonstrated a greater ACTH stress response in the am and pm than male rats, which was partially normalized by ovariectomy. Following 50% corticosterone pellet implantation, male rats demonstrate a greatly diminished am and pm ACTH response to restraint stress while intact females demonstrate am and pm ACTH response to restraint stress similar to that observed before implantation. Ovx females were intermediate in the ability of corticosterone to suppress the ACTH stress response. These data suggest that there are differences in male and female rats in their response to exogenous corticosterone, and these differences are partially modulated by circulating gonadal steroids.