Evidence that testosterone regulates Leydig cell 3 beta-hydroxysteroid dehydrogenase-isomerase activity by a trans-acting factor distal to the androgen receptor.

Leydig cells are a target for their own steroid product, testosterone, and thus could be subject to short-loop feedback regulation by androgens. The authors previously reported that 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta HSD) activity was higher in freshly isolated Leydig cells from C57BL/6J than those from C3H/HeJ inbred mice. To determine whether this strain-related difference in 3 beta HSD activity could be mediated by differential sensitivity to feedback effects of testosterone, Leydig cells from the two strains were cultured in the presence or absence of testosterone, the synthetic androgen receptor agonist, mibolerone, or the nonaromatizable androgen, dihydrotestosterone. After 7 days of treatment, all three androgens significantly decreased 3 beta HSD activity in Leydig cells from C57BL/6J, but not from C3H/HeJ mice. When Leydig cells were cultured with hydroxyflutamide, an androgen receptor antagonist, the effect of testosterone was negated. To determine whether the strain-related difference in sensitivity to testosterone was mediated by a difference in the androgen receptor protein, Leydig cells from reciprocal F1 hybrid lines of mice were cultured in the presence or absence of testosterone. Testosterone treatment inhibited 3 beta HSD activity in both F1 lines to the same extent as observed for Leydig cells from C57BL/6J mice. Thus, there is a strain-related difference in the response to testosterone, but it cannot account for the strain-related difference in Leydig cell 3 beta HSD activity because the high 3 beta HSD strain (C57BL/6J) is the sensitive strain. Although the effect on C57BL/6J Leydig cells is androgen receptor-mediated, the dominant effect of testosterone on both F1 lines rules out a difference in the androgen receptor protein per se. However, the data are consistent with the difference being in a trans-acting factor distal to the androgen receptor.