INHIBITION OF PLACENTAL 3β-HYDROXY-STEROID DEHYDROGENASE BY NATURALLY OCCURRING STEROIDS. A POTENTIAL MECHANISM REGULATING OESTROGEN SYNTHESIS FROM UNCONJUGATED PRECURSORS

Abstract

ABSTRACT We have proposed that inhibition of placental steroid 3-sulphatase by endogenous steroids may regulate oestrogen synthesis during human pregnancy. The possibility that an additional regulatory mechanism, involving the placental 3β-hydroxy-steroid dehydrogenase (SDH), may also be operative has now been examined. Inhibitory effects of naturally occurring steroids on SDH activity were determined from the reduction in initial rate of conversion of 3H-dehydroepiandrosterone to non-digitonin precipitable products by 10 000 × g supernatant from homogenates of human term placentae. The apparent Km for dehydroepiandrosterone was 0.33 × 10−6 m. Δ4-3-Oxo products of SDH action (4-androstene-3,17-dione, app. Ki = 0.60 × 10−6 m; progesterone, app. Ki = 1.5 × 10−6 m) were the most potent inhibitors and appeared to act non-competitively. Δ5-3β-Hydroxy alternative substrates were less inhibitory and in the case of pregnenolone (app. Ki = 4.5 × 10−6 m) behaved competitively. 11β-, 16α-, 17α- or 21-hydroxylation and epimerization of 3β- or 17β-hydroxyl functions of inhibitors decreased their activity. It is concluded that inhibition of both sulphatase and SDH by endogenous steroids may provide complementary methods of regulating placental oestrogen synthesis in vivo. The SDH mechanism may regulate oestrogen synthesis from unconjugated precursors, either formed within the placenta or derived from the circulation. The major potential inhibitors appear to be Δ4-3-ketones, acting non-competitively, and formed within the placenta. In the sulphatase mechanism alternative substrates of extraplacenta origin, acting competitively, are the major potential inhibitors controlling utilization of conjugated precursors.