Androgen Biosynthesis in Leydig Cells after Testicular Desensitization by Luteinizing Hormone-Releasing ormone and Human Chorionic Gonadotropin

Abstract

LHRH-induced elevation of endogenous LH in adult male rats was followed by dose-dependent loss of testicular LH receptors and cAMP responses to hCG stimulation in vitro. Leydig cells from animals treated with 10-100 jtxg LHRH to induce over 50% receptor loss showed reduced testosterone responses to hCG, dibutyryl cAMP, and choleragen. However, prognenolone formation (measured in the presence of 17β-hydroxy- 4,4,17-trimethyl-3-oxoandrost-5-ene-2a-carbonitrile and spironolactone) was normal or increased after LHRH treatment. When LHRH-desensitized cells were stimulated with hCG in vitro, the marked decrease in testosterone production was accompanied by accumulation of 17a-hydroxyprogesterone, either alone or with progesterone. These findings localized the major steroidogenic block in LHRH-desensitized cells at the site of conversion of the 17a-hydroxylated steroid to androgen, similar to the lesion observed in Leydig cells from animals treated with iv hCG. In the latter, the steroidogenic defects were more marked, with prominent increases of 17a-hydroxyprogesterone and progesterone during in vitro cell incubations and significant accumulation of these precursors in the blood In contrast, sc treatment with hCG doses that induced comparable receptor loss caused no reduction in the maximum testosterone response to gonadotropin, only minor changes in enzyme activity, and a reduction in the ED50 for hCG of 20- to 40-fold. This suggested that the steroidogenic block was not simply related to receptor depletion but was also related to the more acute stimulus by iv (vs. sc) hCG and LHRH stimulation. After LHRH treatment that caused minor receptor loss (<50%), Leydig cells showed enhanced steroid biosynthetic capacity, with increases of all steroid intermediates from 2- to 10-fold, and no apparent inhibition of distal steroidogenic enzymes. This effect is consistent with the trophic action of the hormone during initial receptor occupancy and with a positive action on steroidogenic enzymes at the expense of a small loss or utilization of LH receptor sites. These results demonstrate that a partial defect in testicular 17,20-desmolase is mainly responsible for the impaired testosterone re reponse of rat Leydig cells desensitized by LHRH or iv hCG. Such findings have obvious implications in the therapeutic use of LHRH or hCG to stimulate the gonads, and they emphasize the ability of appropriate doses of LHRH treatment to inhibit gonadal function.