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Pubertal and Adult Leydig Cell Function in Mullerian Inhibiting Substance-Deficient Mice

Departments of Pediatrics and Cell Biology (X.W., M.M.L.) and Academic Computing (S.P.B.), University of Massachusetts Medical School, Worcester, Massachusetts 01655; and Pediatric Endocrine Division (R.A.), Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Mary M. Lee, M.D., Pediatric Endocrinology, Department of Pediatrics and Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655. E-mail: mary.lee{at}umassmed.edu.

Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both basal and human chorionic gonadotropin (hCG)-stimulated testosterone concentrations were similar. Purified Leydig cells from pubertal MIS-KO mice had lower testosterone but higher androstanediol and androstenedione production rates. In contrast, testosterone, androstanediol, and androstenedione production rates were all lower in adult MIS-KO Leydig cells. Steroidogenic acute regulatory protein expression was lower in pubertal MIS-KO mice compared with WT, whereas 17ß-hydroxy-steroid dehydrogenase and 5-reductase were greater, and P450c17 and P450scc were similar. The expression of steroidogenic acute regulatory protein and 17ß-hydroxysteroid dehydrogenase was lower in adult MIS-KO mice, whereas that of 5-reductase, P450c17, and P450scc was similar. Collectively, these results suggest that in the absence of MIS, Leydig cells remain less differentiated, causing an altered intratesticular androgen milieu that may contribute to the infertility of MIS-KO mice. In immature mice, this deficit in steroidogenic capacity appears to be mediated by a direct loss of MIS action in Leydig cells as well as by indirect effects via the hypothalamic-pituitary-gonadal axis.

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