HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 77/6/1017    most recent biolreprod.106.059204v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y.-C. Articles by Clark, B. J Search for Related Content PubMed PubMed Citation Articles by Chen, Y.-C. Articles by Clark, B. J Agricola Articles by Chen, Y.-C. Articles by Clark, B. J

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

Departments of Biochemistry and Molecular Biology³ and Anatomical Sciences and Neurobiology,⁴ Division of Endocrinology, Metabolism and Diabetes,⁵ Department of Medicine, and The Center for Genetics and Molecular Medicine,⁶ University of Louisville, Louisville, Kentucky 40202

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.

activin, CDB-4022, CYP17A1, gene regulation, Leydig cells, steroid hormones, steroidogenesis, STAR, testis

¹Supported by a KY Collaborative Research Development Grant to S.J.W. and a National Institutes of Health grant (DK 51656) to B.J.C.

Correspondence: ²FAX: 502 852 6222; e-mail: bjclar01{at}gwise.louisville.edu

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]