REGULATION OF HUMAN PLACENTAL 17-BETA-HYDROXYSTEROID OXIDOREDUCTASE - MECHANISM OF STIMULATION OF 17-BETA-ESTRADIOL FORMATION FROM ESTRONE BY 5-ALPHA-DIHYDROTESTOSTERONE IN HOMOGENATES AND VILLI INVITRO

The mechanism of stimulation of 17-beta-estradiol (E2) formation from estrone (E1) by 5-alpha-dihydrotestosterone (5-alpha-DHT) in placental villi was investigated by examining; (1) if dehydroepiandrosterone (DHA) was stimulatory, (2) if NAD(P)H-generating, non-steroidal substrates stimulated E2 formation, (3) the subcellular localization of the effect, (4) if NAD(P) or NAD(P)H was required and (5) rates of 5-alpha-DHT oxidation by villi and microsomes. Although 5-alpha-DHT and DHA both inhibited the E2 to E1 reaction in villi and microsomes, only 5-alpha-DHT stimulated the conversion of E1 to E2. Glucose and lactate were slightly stimulatory when compared with 5-alpha-DHT. Stimulation of E2 formation was observed with microsomes but not with cytosol, and NAD or NADP was required. The results indicate that neither inhibition of the back reaction, E2 to E1, nor NADH or NADPH formation via the 3-beta-hydroxysteroid dehydrogenase/5-ene-3-ketosteroid isomerase reaction can account for the stimulation. It is proposed that the mechanism of stimulation involves one or more forms of membrane-bound 17-beta-hydroxysteroid oxidoreductase with NADH or NADPH formed as a product of 5-alpha-DHT oxidation being used as the cofactor for E1 reduction. This may involve a direct transfer of reduced pyridine nucleotide between enzyme molecules without equilibration with intracellular coenzyme pools.