Testis

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

Abstract
CDB-4022, an indenopryridine, suppresses spermatogenesis and decreases inhibin secretion in adult male rats. In the current 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 17 hydroxylase enymatic activity compared to 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 gonadotropes revealed 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 cell per testis. Serum inhibin B levels were undetectable in CDB-4022-treated rats while serum activin A levels were similar to controls, indicating 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.

Key words: Testis • Activin • Gene regulation • Leydig cells • Steroid hormones

This article has been cited by other articles:

				S. Koduri, S. A. Hild, L. Pessaint, J. R. Reel, and B. J. Attardi Mechanism of Action of l-CDB-4022, a Potential Nonhormonal Male Contraceptive, in the Seminiferous Epithelium of the Rat Testis Endocrinology, April 1, 2008; 149(4): 1850 - 1860. [Abstract] [Full Text] [PDF]