Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the hypothalamic level

Glucocorticoids, the end-product of the hypothalamic-pituitary-adrenal (HPA ) axis, suppress gonadotropin release by acting at the level of the pituita ry gland. However, experimental evidence suggests that they may also act at the hypothalamic level to suppress gonadotropin-releasing hormone (GnRH) r elease. The lack of a direct demonstration of this assumption, prompted us to evaluate the effects of glucocorticoids on hypothalamic GnRH release fro m individually-incubated hemi-hypothalami explanted from male rats. Since t estosterone (T), dihydrotestosterone (DHT), and progesterone suppress GnRH release and androgens potentiate the effects of glucocorticoids on GnRH rel ease, we studied also the interaction of these steroids with glucocorticoid s on GnRH release. Corticosterone (B), the main glucocorticoid of the roden ts with greater affinity for the type I glucocorticoid receptor, and dexame thasone (DEX), a synthetic type II glucocorticoid receptor agonist, were ab le to suppress basal GnRH release in a concentration-dependent fashion. DEX induced a more profound suppression of GnRH release. Neither T (0.1 nM) no r DHT (0.01 nM) modulated the suppressive effects of low (10 nM) or high (1 00 nM) concentrations of B on GnRH release. On the other hand, progesterone counteracted the suppressive effect of low concentrations of B (10 nM) on GnRH release, but had no effect on the suppression caused by a higher conce ntration of B (100 nM). The ability of glucocorticoids to inhibit directly GnRH release suggests that these stress-responsive hormones act also at the hypothalamic level to suppress the reproductive function. The suppressive effect of B was not modulated by androgens, but it was neutralized by proge sterone, al least when B was used at low concentrations. We speculate that this steroid "protects" the GnRH-secreting neuron only during basal, but no t stress-induced, HPA axis activity when the concentrations of glucocortico ids are more elevated.