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

Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates post-natal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperpla-sia, but their circulating androgen concentrations are report-edly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroido-genic 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 chori-onic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both basal and human chorionic gonadotropin (hCG)-stimulated testosterone con-centrations were similar. Purified Leydig cells from pubertal MIS-KO mice had lower testosterone but higher androstan-ediol and androstenedione production rates. In contrast, tes-tosterone, androstanediol, and androstenedione production rates were all lower in adult MIS-KO Leydig cells. Steroido-genic acute regulatory protein expression was lower in pu-bertalMIS-KOmicecomparedwithWT,whereas17-hydroxy-steroid dehydrogenase and 5-reductase were greater, and P450c17 and P450scc were similar. The expression of steroi-dogenic acute regulatory protein and 17-hydroxysteroid de-hydrogenasewas lower in adultMIS-KOmice, 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 bemediated by a direct loss of MIS action in Leydig cells as well as by indirect effects via the hypotha-lamic-pituitary-gonadal axis. (Endocrinology 146: 589–595