ACTIVIN AND INHIBIN HAVE OPPOSITE EFFECTS ON STEROID 5-ALPHA-REDUCTASE ACTIVITY IN GENITAL SKIN FIBROBLASTS

The transforming growth factor beta (TGF-beta) superfamily includes several closely related peptides including the activins and inhibins. Since we recently reported that TGF-beta 1 and beta 2 are potent inducers of steroid 5 alpha-reductase (5 alpha R), we have now studied the effects of these other peptides using primary cultures of human scrotal skin fibroblasts. Recombinant human activin A or inhibin A were added to cultured cells (2 x 10(5) cells) for 2 days in a serum free media and 5 alpha R activity was measured by the %-conversion of tracer [H-3]-testosterone to dihydrotestosterone (DHT) over a 4-h period. Activin significantly stimulated 5 alpha R activity in a dose related manner (control 3.0 +/- 0.4%, activin (1.2 x 10(-9) M) 6 +/- 0.7%, P < 0.01, (2.4 x 10(-9) M) 8.5 +/- 0.6%, P < 0.001). In Comparison, androgen (DHT 10(-7) M) induction of 5 alpha R was 4.7 +/- 0.2%, P < 0.05. Combined exposure of fibroblasts to activin (1.2 x 10(-9) M) and androgen (10(-7) M) did not result in additive or synergistic effect on 5 alpha R activity. In contrast, exposure of cells to an androgen (10(-7) M) and TGF-beta (2 x 10(-10) M) led to synergistic effects on 5 alpha R activity (control 1.5 +/- 0.1%, DHT 2.6 +/- 0.2% TGF-beta 1 4.8 +/- 0.5, TGF-beta 1+DHT 9.2 +/- 1.2%). Finasteride, a 4-aza steroid inhibitor of 5 alpha R (10(-8) M) inhibited both activin and TGF-beta-induced 5 alpha R activity suggesting that the type II isoenzyme is induced by these peptides. Activin mediated 5 alpha R activity was abolished by the addition of cycloheximide, consistent with the proposition that enzyme induction requires new protein synthesis. Recombinant human inhibin alone did not alter basal 5 alpha R activity but dose dependently inhibited DHT (10(-7) M)-induced 5 alpha R activity (control 4.1 +/- 0.4%, DHT 7.5 +/- 0.7%, DHT + inhibin (0.6 x 10(-9) M) 5.7 +/- 0.5%, P < 0.05 DHT + inhibin (1.2 x 10(-9) M] 4.3 +/- 0.2%, P < 0.001). The effects of activin or inhibin were not associated with changes in cell number or thymidine uptake. These studies indicate that activin is 100 times more potent on a molar basis than androgen in induction of 5 alpha R activity. Although both activin and TGF-beta 1 induce 5 alpha R activity, the actions of the two peptides differ in the presence of an androgen. In contrast, inhibin significantly inhibits androgen induction of 5 alpha R. Activin and inhibin, two closely related molecules, potentially play opposite roles in DHT formation in sexual tissue.