Response of Rat Ventral Prostate to a New and Novel 5αa-Reductase Inhibitor

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Abstract
17β-N,N-Diethylcarbamoyl-4-methyl-4-aza-5αandrostan-3-one (4-MA) strongly inhibits the 5α-reductase-mediated conversion of testosterone (T) to 5α-dihydrotestosterone [17β-hydroxy-5α-androstan-3-one (DHT)] both in vitro and in vivo. In vitro, 4-MA is a more potent inhibitor than progesterone, androst-4-en-3-one-17β-carboxylic acid (17β), androst-4-en-3-one-17β-carboxylic acid methyl ester (17βME), megestrol acetate (17α-acetoxy-6-dehydro-6-methylprogesterone), medrogestone (6-methyl-6-dehydro-17-methylprogesterone), cyproterone acetate (17α-acetoxy-6-chloro-l,2α-methylene-4,5-pregnadiene-3,20-dione), or flutamide (4′-nitro-3′-trifluoromethylisobutyranilide). The effects of these compounds on prostatic concentrations of T and DHT were determined in young adult intact male rats treated 4 h before sacrifice. Subcutaneous injection of 0.33–10 mg 4-MAȯrat consistently reduced the prostatic concentrationof DHT but increased that of T. At 10 mg/rat, cyproterone acetate, megestrol acetate, and flutamide tended to reduce prostatic levels of both T and DHT, while progesterone, 17βC, 17βME, and medrogestone had little or no effect. Castrate male rats were pretreated with 1 or 10 mg 4-MA and, 2 h later, injected sc with either 200 μg testosterone propionate (TP) or 400 μg dihydrotestosterone propionate (DHTP). They were sacrificed 2 h after receiving exogenous androgen, and prostatic concentrations of T and DHT were determined. The 1-mg dose of 4-MA caused a marked reduction in the prostatic concentration of DHT in rats injected with TP but not in those given DHTP. These results were consistent with the view that 4-MA acts by inhibiting 5α-reductase. However, the 10-mg dose of 4-MA lowered the concentration of DHT in the prostates of animals which had received either TP or DHTP. This indicated that the higher dose of 4-MA may have reduced androgen uptake or retention, an effect not associated with 5α-reductase inhibition. Ventral prostate growth was attenuated by 4-MA in immature castrate male rats injected sc with either TP or T, but 4-MA had much less of an effect in rats given DHTP or DHT. These data further support the hypothesis that 4-MA antagonizes the androgenic action of T by interfering with its conversion to the more active metabolite, DHT.