Evidence That 5α-Reduction of Δ4,3-Ketosteroids May Be More Important for Their Androgenic Than Their Luteinizing Hormone-Inhibiting Activity*

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Abstract
The synthetic anabolic steroid methandrostenolone (M; 17β-hydroxy-17α-methyl-androsta-l:4-dien-3-one) cannot be metabolized to its androgenically more potent 5α-reduced form (17β-hydroxy-17α-methyl-5α-androst-l-ene-3-one). M decreased ventral prostate weight and plasma testosterone (T) concentrations in intact rats and lowered LH concentrations in castrated rats (Steele, R. E., F. Didato, and B. G. Steinetz, Steroids 29: 331,1977). It was postulated that M reduced ventral prostate weight of intact rats by indirectly lowering plasma T via its effect on LH. Because M does have weak androgenic activity, this hypothesis presupposes that the LH-inhibiting activity of M relative to its androgenic activity on the ventral prostate must be greater than that of the endogenous testicular androgens being secreted, predominantly T. The present study was designed to compare the relative LH-inhibiting activity to the androgenic activity of M and T. Male rats were castrated and, 3 days later, injected sc for 4 days with 50, 300, or 450 μg T/100 g BW or 450, 675, 900, or 1350 μg M/100 g BW. Twentyfour hours after the last injection, the rats were anesthetized, bled by cardiac puncture, and killed. The ventral prostates were excised, weighed, dried to a constant weight, and then assayed for their RNA and protein content. The plasma was assayed for LH. These data were used to establish relative potency estimates for M and T on the various indices of androgenic and LHinhibiting activities. M was only 12% as androgenic as T while having 34% the LH-inhibiting activity of T. This same relationship between the LH inhibitory and androgenic activities of M compared to T was also noted when steroid replacement was begun immediately after castration. In these rats, a dose of 400 fig M/100 g BW almost completely prevented the postcastration rise in LH while exhibiting less androgenic activity than a dose of T (50 μg/100 g BW) which was much less effective in preventing the postcastration rise in LH. These findings illustrate the mechaism by which M reduces the ventral prostate weight of intact rats and further suggest that the 5α-reduction of Δ4,3-ketosteroids may be more important for the expression of their androgenic activity on the ventral prostate than their LH-inhibiting activity at the hypothalamic-pituitary axis.