Steroid biosynthetic lesions in gonadotropin-desensitized Leydig cells

Abstract

Administration of exogenous gonadotropins to rats causes loss of LH receptors and a decrease in the maximum steroidogenic response when Leydig cells are subsequently stimulated by LH or hCG. The impaired testosterone response of desensitized Leydig cells is more evident after intravenous than after subcutaneous treatment with hCG, and is due to a partial defect in testicular 17,20 lyase activity. The enzyme defect is present in Leydig cells from animals given intravenous hCG to produce about 70% loss of LH receptors, yet is relatively small after treatment with subcutaneous hCG to produce the same degree of receptor loss, suggesting that the steroidogenic block is not only due to receptor depletion. Acute elevations of endogenous LH by single doses of LHRH caused the same changes as exogenous hCG, with marked receptor loss and reduction in testosterone responses to hCG, dibutyryl cyclic AMP and choleragen. However, pregnenolone formation (measured in the presence of cyanoketone and spironolactone to inhibit pregnenolone metabolism) was normal or increased in desensitized Leydig cells from LHRH-treated animals. Accumulation of progesterone and 170H-progesterone occurred in serum and incubated Leydig cells of desensitized animals, localizing the major steroidogenic block to the conversion of 170H-steroids to androgens. In cultures of normal rat and murine tumor Leydig cells, 17–20 lyase and 17α-hydroxylase were markedly decreased when LH receptors were lost, suggesting coordinate regulation of receptors and steroidogenic enzymes in vitro. However, the in vivo development of the steroid block was not coincident with the loss and return of LH receptors. A role of oestradiol in the gonadotropin-induced enzyme defect was suggested by acute elevations of testicular oestradiol 30 min after intravenous hCG (whereas more gradual increases occurred 4–8 h after subcutaneous hCG), and by the ability of an oestrogen antagonist (Tamoxifen) to prevent the reduction of testosterone responses caused by intravenous hCG. These results indicate that acute elevation of oestradiol production is a contributory factor in the steroidogenic lesions of LHRH- and hCG-desensitized Leydig cells in the rat testis.