EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA AND EPIDERMAL GROWTH-FACTOR ON STEROID 5-ALPHA-REDUCTASE ACTIVITY IN GENITAL SKIN FIBROBLASTS

Regulation of steroid 5 alpha-reductase (5 alpha R) activity and dihydrotestosterone (DHT) formation is central to prostate and sexual skin (hair) growth and cell function. Transforming growth factor-beta(1) (TGF-beta(1)> is a ubiquitous peptide present in skin and scrotal tissue and its receptor is universally expressed. We have explored the role of TGF-beta(1) and -beta(2) on androgen formation in skin. Rat or human sexual skin fibroblasts were grown in primary cultures (passage 3-7). 5 alpha-Reductase activity was measured by the %-conversion of tracer H-3-testosterone to dihydrotestosterone over a 4 h period. Incubation of scrotal fibroblasts (2 x 10(5) cells) in serum and growth factor free media with androgen, such as DHT for two days significantly stimulates 5 alpha R in these cells (1.6-fold, p < 0.05 vs control). TGF-beta(1) alone at picomolar concentrations (2 X 10(-11) M to 2 X 10(-10) M) was a potent inducer of 5 alpha R activity in both rat (1.8-fold and 2.8-fold, respectively, p < 0.001 vs control at both doses) and human cells (TGF-beta(1) 2 X 10(-10) M 3.3-fold, p < 0.001 vs control). Combined exposure of these fibroblasts to TGF-beta(1) (2 x 10(-10) M) and androgen (10(-7) M) further potentiated 5 alpha R activity (rat cells 6.5-fold, human cells 6.4-fold, p < 0.001 vs DHT or TGF-beta(1) alone). TGF-beta(2) (2 X 10(-10) M), a closely related peptide produced similar effects on 5 alpha R activity in human cells (DHT 1.5-fold, TGF-beta(2) 2-fold, TGF-beta(2) + DHT 5.5-fold), again synergism was noted with DHT. These effects were not associated with changes in cell number or increased H-3-thymidine incorporation. In contrast, epidermal growth factor (EGF, 5 x 10(-9) M) which has a sequence homology with transforming growth factor-alpha (TGF-alpha) and interacts with the TGF-alpha type receptor did not significantly induce basal 5 alpha R or in combination with an androgen. These studies indicate that TGF-beta is much more potent than an androgen and is synergistic with androgen in inducing 5 alpha R activity and DHT formation. EGF (TGF-alpha) has no significant effects on these events. TGF-beta may play a role in androgen formation in sexual tissue.