Mechanism by which GnRH inhibits androgen synthesis directly in ovarian interstitial cells

The mechanism by which GnRH acts on ovarian interstitial cells to inhibit androgen synthesis was studied in primary cultures of ovarian cells from hypophysectomized immature rats. Interstitial cells cultured in defined medium with LH showed a 200-fold increase in steroid production, of which androsterone was the principal metabolite (88% of the total steroid content). Treatment with GnRH (10(-8) M) inhibited LH-stimulated androsterone production by 92%. This inhibitory effect of GnRH was not due to changes in cell number, cell viability, or 125-I-hCG binding capacity. Prostaglandin E2, cholera toxin and 8-Br-cyclic AMP mimicked the LH effect on androsterone synthesis and these increases were also inhibited by GnRH. Metabolic studies of GnRH-treated cultures revealed that LH-stimulated androsterone and 5 alpha-androstane-3 alpha, 17 beta-diol were decreased by 90%; androstenedione, testosterone and DHEA were decreased by 70%; 17 alpha-hydroxypregnenolone and 17 alpha-hydroxyprogesterone were decreased by 50%; pregnenolone was unchanged; and progesterone was increased 40%. Collectively, these results suggest that GnRH directly inhibits androgen synthesis in ovarian interstitial cells by selectively inhibiting the 17 alpha-hydroxylase and C17-20 desmolase activities.