Pharmacological Induction of 5<i>α</i>-Reductase Deficiency in the Rat: Separation of Testosterone-Mediated and 5<i>α</i>-Dihydrotestosterone-Mediated Effects*

Abstract

(5 alpha, 20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5 alpha-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles,and preputial glands, but had no effect on growth of the levator ani muscle. (5 alpha-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5 alpha-dihydrotestosterone (5 alpha-DHT). The inhibitor thus produced a pure 5 alpha-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5 alpha-reductase-deficient human male: reduction of 5 alpha-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5 alpha-DHT. Evidence is presented which indicates that the testes are the source of circulating 5 alpha-DHT in the immature rat.