Modulation of Leydig cell androgen biosynthesis and cytochrome P-450 levels during estrogen treatment and human chorionic gonadotropin-induced desensitization.

The mechanisms responsible for gonadotropin-induced testicular desensitization were analyzed by direct assay of androgen biosynthetic enzymes and cytochrome P-450 in microsomes and cytosol from testes of adult male rats. Animals were treated with single subcutaneous doses of human chorionic gonadotropin (hCG) (2 and 10 pg) to induce a post-stimulation decrease in testosterone production, previously shown to result from reduced conversion of progesterone to androgen. In addition, the larger dose of hCG caused an earlier biosynthetic defect due to impaired formation of pregnenolone from endogenous precursors. Dose-dependent inhibition of both 17a-hydroxylase and 17,20desmolase activities by 30% and 90% was observed after treatment with 2 and 10 pg of hCG, respectively. In contrast, hCG treatment caused no change in the activities of 3p-hydroxysteroid dehydrogenase and 17p-h~droxysteroid dehydrogenase. The reductions in microsomal enzyme activity were accompanied by a comparable decrease in cytochrome P-450 levels. Similar correlations between the microsomal cytochrome P-450 content and the same enzymatic activities were observed after hypophysectomy. Treatment of hypophysectomized rats with 17/3-estradiol(O.l to 20 pg) reduced testosterone responses to hCG in a dose-dependent manner (by 20 to 60%), and caused further decreases of microsomal enzymatic activities and of the levels of cytochrome P-450, but not of 3fi-hydroxyand 17fl-h~droxysteroid dehydrogenase. The dependence of 17ahydroxylase and 17,2O-desmolase on cytochrome P-450 levels was indicated by the constancy of specific activity of the microsomal enzymes when expressed in terms of cytochrome P-450. The similarity of estrogen-dependent lesions to those produced by hCG treatment further indicates the involvement of endogenous estrogen in the development of the microsomal enzymatic lesions in gonadotropin-induced desensitization of testicular androgen production.