Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.

Abstract

Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid Sa-reductase (EC 1.3.99.5). The expression of 5a-reductase and the level of 5a-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 rmasteride, a potent inhibitor of steroid 5a-reductase, on the expression of 5a-reductase in the prostate. The administration of rmasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5a-reductase enzyme activity. Furthermore, the restoration ofprostate growth after castration and the enhancement in 5a-reductase enzyme activity and 5a-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5a-reductase activity or messengerRNAlevel. Thesefindingsindicatethatdihydrotestosterone itself controls prostate growth and Sa-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5a-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.Both the differentiation of the prostate gland during male embryogenesis (1) and the subsequent growth of the tissue during postnatal life (2) are controlled by androgenic hormones synthesized in the testes. Some androgen actions, such as the promotion of spermatogenesis and the enhancement of muscle growth, are believed to be mediated by the testicular androgen testosterone (2). In other target tissues, including the prostate, testosterone is converted to dihydrotestosterone by the enzyme steroid Sa-reductase (EC 1.3.99.5) (3, 4). Dihydrotestosterone is a more potent androgen than testosterone in some bioassay systems (5), and dihydrotestosterone formation is believed to be essential for many androgen actions. For example, studies of subjects with hereditary steroid Sa-reductase deficiency (6) and investigations of the effects of inhibitors of steroid Sareductase (7-11) indicate that dihydrotestosterone formation is necessary for both the embryonic differentiation and the postnatal growth of the prostate. Furthermore, unregulated dihydrotestosterone action is believed to cause hyperplastic prostate growth in aging dogs and men (12).In addition to the role in the control of differentiation and growth, androgens also control the expression of a number of genes in the prostate, including the gene for steroid 5a-reductase (13). In the ventral prostate of the rat both the steady-state level and the recovery of 5a-reductase after castration are regulated by androgens (13), and this regulation is mediated at the level of transcription of Sa-reductase mRNA (14).To determine whether testosterone or dihydrotestosterone is responsible for...

Cell-type-specific expression of rat steroid 5 alpha-reductase isozymes.

“…This apparent sensitivity problem was overcome by examining the expression of the type 1 mRNA in the regenerating ventral prostate. Previous studies have shown that the steady-state levels of the type 1 and type 2 mRNAs are markedly induced in the regenerating gland (18,19). In a typical experiment of this type, animals were castrated and their prostates were allowed to regress for 7 days.…”

“…Furthermore, both Sa-reductase genes in the rat are regulated by DHT, the product of the encoded enzyme, via a form of feed-forward regulation. This regulatory mechanism is common among developmentally important genes (19). In the current study, we have used in situ mRNA hybridization and immunohistochemical analysis to determine the cell-type-specific expression patterns of the Sareductase isozymes in the regenerating rat ventral prostate, epididymis, and liver.…”

Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

“…Studies have shown that the 5␣-reductase gene is differentially regulated by testosterone in androgen-responsive vs. nonresponsive tissue. Moreover, the response of the 5␣-reductase genes to DHT represents a feed-forward regulation in which the product of the enzyme was positively affecting the expression of its gene (19).…”

5α-reductases=physiology and pathology

“…Par contre l'association de finast~ride h la testost6rone bloque compl~tement cette a u g m e n t a t i o n alors qu'elle est sans effet sur l'action de la DHT ce qui est normal puisqu'il s'agit d'un inhibiteur comp6titif [6].…”

“…La 5a-r~ductase repr~sente donc dans la prostate, comme dans la peau pubienne, un syst~me d'amplification de l'action des androg~nes [6].…”