Effects of CDB-4022 on Leydig Cell Function in Adult Male Rats1

Abstract

CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the present study, we investigated the effects of CDB-4022 on Leydig cell function. A single oral dose of CDB-4022 (2.5 mg/kg) resulted in a 2-fold decrease in serum testosterone levels after 7 days that was paralleled by a decrease in Cyp17a1 mRNA and protein levels and 17alpha hydroxylase enzymatic activity compared with vehicle-treated rats. Consistent with the lower serum testosterone levels, pituitary Lhb and Fshb mRNA levels were increased 3.2- and 2.3-fold, respectively, by CDB-4022 treatment. Ultrastructural analysis of pituitary gonadotrophs showed distended endoplasmic reticulum (ER) and fewer secretory granules in CDB-4022-treated rats, characteristic of enhanced secretory activity. Conversely, CDB-4022 increased serum progesterone levels, testicular Star mRNA and protein expression, and the number of Leydig cells per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats, while serum activin A levels were similar to controls, indicating that the CDB-4022-treated rats have an elevated activin A:inhibin B ratio. In the presence of hCG stimulation, activin A directly suppressed testosterone secretion but enhanced progesterone secretion from rat Leydig cell primary cultures. Likewise, treatment of MA-10 cells with activin A was found to enhance cAMP-stimulated progesterone secretion and STAR expression. Together, our data indicate that CDB-4022 treatment inhibits CYP17A1 and stimulates STAR expression, thereby decreasing testosterone but increasing progesterone production. We propose that unopposed actions of activin A most likely contribute to the steroid profile in rats after CDB-4022 treatment. Our findings establish CDB-4022 as a new model to examine intratesticular control mechanisms that modulate Leydig cell gene expression and function.

New frontiers in nonhormonal male contraception

“…CDB-4022 appears to target the Sertoli cell [59], as evidenced by the many parameters of Sertoli cell function that were shown to be affected within hours of CDB-4022 administration. For example, there was a significant decrease in serum inhibin B and FSH in rats treated with l -CDB-4022, suggestive of a disruption in spermatogenesis, but activin A, testosterone (however, in another study, serum testosterone was shown to decline in CDB-4022-treated adult rats [64]) and LH remained unchanged [60,61]. Equally important, the micro-tubule network, which gives the Sertoli cell its columnar shape, was disrupted and the steady-state levels of several adhesion proteins (e.g., cadherin, catenin, nectin, afadin and integrin β1) were shown to change in the rat testis following l -CDB-4022 treatment [65].…”