Effects of transforming growth factor β and epidermal growth factor on steroid 5α-reductase activity in genital skin fibroblasts

Abstract

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