11-BETA-HYDROXYSTEROID DEHYDROGENASE ALLEVIATES GLUCOCORTICOID-MEDIATED INHIBITION OF STEROIDOGENESIS IN RAT LEYDIG-CELLS

Leydig cells from mature rat testes contain high levels of 11 beta-hyd roxysteroid dehydrogenase (11HSD), an enzyme that oxidatively inactiva tes glucocorticoids. We have proposed that the 11HSD of Leydig cells p rotects the testis from the effects of high levels of glucocorticoids, as may occur in stress and Cushing's disease. In this paper we invest igate whether testicular 11HSD by inactivating glucocorticoids diminis hes their ability to inhibit testosterone (T) production. Corticostero ne (B) and dexamethasone (DEX) inhibited T production by purified Leyd ig cells in a dose-dependent manner. Activity was diminished by 50% wi th 1.5 nM DEX us. 0.4 mu M B. The shapes of the inhibition curves were consistent with a saturable process; inhibition by both steroids was overcome with the glucocorticoid receptor antagonist RU486. We conclud ed that the effect was mediated by glucocorticoid receptors. Aldostero ne, 11 beta-hydroxyprogesterone, and 11-deoxycorticosterone did not de crease T production. The greater potency of DEX compared to B may be d ue to its resistance to oxidative inactivation by 11HSD. As 11-dehydro corticosterone, the product of the oxidation of B by 11HSD, did not in hibit T production, it was predicted that inactivation of 11HSD should enhance the inhibitory effect of B. Consistent with this prediction, inhibition by B was increased by carbenoxolone, an inhibitor of 11HSD, becoming more similar to that by DEX. Suppression of T production by DEX (which is not a substrate of 11HSD) was unaffected by carbenoxolon e. We conclude that through reduction of the levels of inhibitory gluc ocorticoids, 11HSD has a novel role among Leydig cell steroid-metaboli zing enzymes in the regulation of T production.