Inhibition of Leydig Cell Function Through Hormonal Regulatory Mechanisms

Abstract

The regulation of testicular endocrine function by hormonal mechanisms depends upon the integrated actions of gonadotropins (LH, FSH and prolactin) and steroids (estrogen and androgen) upon the Leydig cell. Withdrawal of gonadotropic support by hypophysectomy causes partial loss of LH receptors and testosterone responses, whereas cyclic AMP responses are normal or increased. Thus, the major effects of hypophysectomy are on processes beyond receptor activation and cyclic AMP formation. Treatment with FSH increases LH receptors and testosterone responses to hCG, and reduces the elevated cyclic AMP responses to hCG in vitro. In FSH‐treated hypophysectomized rats, direct inhibitory actions of estrogen upon LH receptors and testosterone responses are demonstrable, indicating that intratesticular regulation of androgen biosynthesis could be exerted by locally formed estrogen.While low concentrations of LH are necessary for maintenance of Leydig cell function, elevation of plasma LH by treatment with LHRH or exogenous gonadotropin has a marked negative effect on LH receptors and subsequent steroidogenic responses. Such hormone‐induced loss of LH receptors leads to decreased sensitivity of the Leydig cell to gonadotropin, an effect that is most evident after subcutaneous treatment with hCG. More acute increases in plasma gonadotropin are followed by a post‐receptor lesion in the steroidogenic pathway, with loss of the maximum testosterone response during stimulation by gonadotropin or cyclic AMP in vitro. The retention of pregnenolone responses and the accumulation of progesterone and 17‐hydroxylated steroids in partially desensitized Leydig cells indicates that a transitory block of the 17–20 desmolase step is rcsponsible for the second lesion in receptor‐depleted Leydig cells. Thus, the negative effects of LH and hCG on Leydig cell responses result from the combination of receptor loss and enzymatic defect(s), attributable to the local inhibitory effects of steroids, such as estrogens, that are formed during the acute tcsticular response to gonadotropin.