Self-Suppression of Corticosteroidogenesis: Evidence for a Role of Adrenal 5α-Reductase*

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Abstract
Exogenous corticosterone (B), the natural glucocorticoid product of rats, suppressed endogenous B production of isolated rat adrenocortical cells induced by .alpha.ACTH-(1-24), [9-tryptophan (O-nitrophenylsulfenyl)]ACTH-(1-24) ([Trp (Nps)9]ACTH-(1-24)), and cAMP as well as pregnenolone supported-steroidogenesis. This self-suppression occurred within 2 h. It was dependent on the concentration of exogenous B. Self-suppression did not alter the 1/2 maximal steroidogenic concentration (ED50) of each steroidogenic agent. In addition, exogenous B did not suppress ACTH-induced cAMP production or gross protein synthesis, as measured by Leu incorporation into bulk cellular proteins. These results with isolated cells suggested at least 2 mechanisms for self-suppression: exogenous B inhibited steroidogenic steps in a noncompetitive manner, and/or exogenous B induced B degradation. In this study the effect of exogenous B on the degradation of B was studied. Accordingly, the adrenal 5.alpha.-reductase activity (5.alpha.RA) of cell homogenates prepared from treated cells was measured. Isolated adrenocortical cells were incubated for 2 h with .alpha.ACTH-(1-24), ovine PRL (oPRL), and B. They were then homogenized and assayed for 5.alpha.RA, as indicated by the disappearance of exogenous B, as shown by RIA [radioimmunoassay]. The percentage of exogenous tritium-labeled B ([3H]B) converted to 5.alpha.-dihydrocorticosterone (DHB), the principal reduced metabolite of B, was determined by TLC. Isolated adrenocortical cells from intact rats showed insignificant 5.alpha.RA and DHB formation when incubated with or without .alpha.ACTH-(1-24) and with or without oPRL. With exogenous B, there was significant 5.alpha.RA and DHB formation, oPRL plus B decreased DHB formation. The effects of B and oPRL were more demonstrable with cells from hypophysectomized rats. These cells exhibited high 5.alpha.RA and DHB formation; exogenous B increased these values, whereas oPRL acutely reversed the effects of hypophysectomy and exogenous B. In other work avoiding cell homogenization, exogenous B suppressed ACTH-induced B accumulation and increased DHB formation in intact cell suspensions from intact rats and intact male domestic fowl. Exogenous B increased the conversion of [3H]pregnenolone to DHB in intact cell suspensions from intact rats, showing that B synthesized de novo as well as exogenous B can be degraded during self-suppression. These data indicate that acute self-suppression of coticosteroidogenesis is at least partly mediated by an increase in 5.alpha.RA.