INHIBIN AND ACTIVIN DIFFERENTIALLY REGULATE ANDROGEN PRODUCTION AND 17-ALPHA-HYDROXYLASE EXPRESSION IN HUMAN OVARIAN THECAL-LIKE TUMOR-CELLS

Activin and inhibin are structurally related dimeric glycoproteins bel onging to the transforming growth factor-beta superfamily of proteins which are synthesized and secreted by the granulosa cells of the ovary . Although initially characterized by their ability to influence FSH s ecretion from pituitary cells, paracrine regulatory roles of these fac tors on neighboring ovarian theca interna have been suggested. While i nhibin has been shown to increase and activin to decrease the producti on of androgens, the mechanisms of action are not well defined, partly due to difficulties in obtaining adequate numbers of thecal cells fro m individual patients or animal models. Using a unique human ovarian t hecal-like tumor (HOTT) cell culture model system we investigated the biochemical and molecular mechanisms controlling C19 steroidogenesis a nd the effects of activin and inhibin on the activity and expression o f key ovarian thecal steroidogenic enzymes, cholesterol side-chain cle avage cytochrome P450 (P450scc), 3 beta-hydroxysteroid dehydrogenase ( 3 beta HSD) and 17 alpha-hydroxylase/17,20 lyase cytochrome P450 (P450 c17). Steroid production, level of steroidogenic enzyme mRNA expressio n, and enzyme activity following treatment with forskolin, inhibin-A a nd activin-A were examined. Basal steroid production, enzyme activitie s, and steroidogenic enzyme mRNA levels were not markedly different fo llowing treatment with activin (25 ng/ml) or inhibin (25 ng/ml) alone. Forskolin (10 mu M) markedly increased production of both androstened ione (fivefold) and progesterone (threefold) as well as the activity o f 3 beta HSD (sevenfold), and P450c17 (sevenfold) over basal. Forskoli n stimulated the expression of mRNA for P450scc (fourfold), 3 beta HSD (threefold), and P450c17 (eightfold) over basal.