Mechanism of glucocorticoid-induced suppression of testicular androgen biosynthesis in vitro.
The mechanism whereby glucocorticoids directly inhibit gonadotropin-stimulated testosterone production was studied by using primary cultures of testicular cells from adult hypophysectomized rats. Testicular cells were maintained in serum-free media with hormone treatments administered on Day 8 and media collected 48 h later for steroid and cAMP measurement. Highly purified human chorionic gonadotropin (hCG) increased testosterone production relative to controls. Concomitant administration of either natural (cortisone greater than deoxycorticosterone = aldosterone) or synthetic (dexamethasone greater than or equal to prednisolone) corticosteroids inhibited hCG-stimulated testosterone production in a dose-dependent manner. Dexamethasone at 10(-7) M decreased testosterone production by approximately 50-60% and this inhibitory effect was reversible upon removal of the glucocorticoid. In the presence or absence of a phosphodiesterase inhibitor, dexamethasone decreased hCG-stimulated cAMP production by approximately 60%. Dexamethasone also decreased testosterone production induced by cholera toxin and (Bu)2 cAMP by 43 and 63%, respectively. The dexamethasone suppression of testosterone production was accompanied by marked decreases in androstenedione (80% decrease) and 17 alpha-hydroxyprogesterone (57%) production, with a lesser effect on progesterone production (28% decrease) and no effect on pregnenolone production. Exogenous progesterone and 17 alpha-hydroxyprogesterone augmented hCG-stimulated testosterone production. Dexamethasone reduced the conversion of exogenous progesterone to testosterone by 33% but did not affect the conversion of 17 alpha-hydroxyprogesterone to androstenedione and testosterone, suggesting a specific inhibition of 17 alpha-hydroxylase. These results suggest that glucocorticoids directly suppress Leydig cell steroidogenesis by decreasing gonadotropin stimulation of cAMP production and the activity of 17 alpha-hydroxylase.
D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis
D000728:Androgens; D006063:Chorionic Gonadotropin; D005938:Glucocorticoids; D013739:Testosterone; D011374:Progesterone; D003994:Bucladesine; D003907:Dexamethasone; D002772:Cholera Toxin; D000242:Cyclic AMP