Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.
Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid 5 alpha-reductase (EC 1.3.99.5). The expression of 5 alpha-reductase and the level of 5 alpha-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 5 alpha-reductase, on the expression of 5 alpha-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 5 alpha-reductase enzyme activity. Furthermore, the restoration of prostate growth after castration and the enhancement in 5 alpha-reductase enzyme activity and 5 alpha-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5 alpha-reductase activity or messenger RNA level. These findings indicate that dihydrotestosterone itself controls prostate growth and 5 alpha-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5 alpha-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.
George
F W
FW
Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, Dallas 75235.
Russell
D W
DW
Wilson
J D
JD
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D015152:Blotting, Northern; D013196:Dihydrotestosterone / Q000008:administration & dosage*; D004790:Enzyme Induction / Q000187:drug effects; D018120:Finasteride; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000033:anatomy & histology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase