Estradiol receptor-mediated regulation of steroidogenesis in gonadotropin-desensitized Leydig cells.

The steroidogenic lesion produced in Leydig cells by gonadotropin stimulation has been attributed to an inhibitory effect of estrogen on 17a-hydroxylase and 17,20-desmolase activity, with impaired conversion of progesterone to androgens. In animals treated with doses of human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) that caused the decrease in desmolase activity, administration of the estrogen antagonist, Tamoxifen, prevented the development of the steroidogenic lesion. The changes in cytosol and nuclear estradiol receptors caused by treatment with hCG or GnRH were compared with testicular estradiol levels during hormone treatment. The 9 S cytosol estradiol receptor was of high affinity (K, = 2.8 x I O e M-’) and low capacity (286 fmol/testis) and underwent nuclear translocation to a 5 S form after estradiol or gonadotropin treatment. Administration of hCG (2 pg) or GnRH (100 pg) caused reduction of cytosol estradiol receptors to 40% at 6 h, followed by a return to 70% at 18 h. The nuclear concentration of estradiol receptors reached a maximum of +200% (120 fmol/ testis) at 6 h and fell to +35% at 18 h. Testicular estradiol content rose after 2 yg of hCG from 22 & 3 to 68 k 6 pg/testis at 6 h, and gradually returned to normal between 2 and 3 days. The steroidogenic lesion in desensitized Leydig cells, which was preceded by elevation of testicular estradiol and nuclear translocation of estradiol receptors, was prevented by Tamoxifen-induced depletion of cytosol estradiol receptors. These findings indicate that nuclear actions of testicular estradiol are responsible for the 17a-hydroxylase/l7,20desmolase lesion induced by hCG or GnRH. Such effects of endogenous estradiol formation on testosterone production may reflect a continuous modulating action of intratesticular estradiol upon androgen secretion by the Leydig cell.