Feed-forward control of prostate growth: Dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5α-reductase

Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid 5α-reductase (EC 1.3.99.5). The expression of 5α-reductase and the level of 5α-reductase messenger RNA in rat ventral prostate are regulated by androgens. To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of finasteride, a potent inhibitor of steroid 5α-reductase, on the expression of 5α-reductase in the prostate. The administration of finasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5α-reductase enzyme activity. Furthermore, the restoration of prostate growth after castration and the enhancement in 5α-reductase enzyme activity and 5α-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5α-reductase activity or messenger RNAlevel. These findings indicate that dihydrotestosterone itself controls prostate growth and 5α-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5α-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade. (.