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Regulation of 3ß-Hydroxysteroid Dehydrogenase in Gonadotropin-Induced Steroidogenic Desensitization of Leydig Cells

Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. M. L. Dufau, National Institutes of Health, Building 49, Room 6A-36, 49 Convent Road, Bethesda, Maryland 20892-4510. E-mail: dufau{at}helix

3ß-hydroxysteroid dehydrogenase/⁵-⁴ isomerases (3ß-HSD) are enzymes that catalyze the conversion of ⁵ to ⁴ steroids in the gonads and adrenal for the biosynthesis of sex steroid and corticoids. In gonadotropin-desensitized Leydig cells, from rats treated with high doses of human CG (hCG), testosterone production is markedly reduced, a finding that was attributed in part to reduction of CYP17 expression. In this study, we present evidence for an additional steroidogenic lesion induced by gonadotropin. Using differential display analysis of messenger RNA (mRNA) from Leydig cells of rats treated with a single desensitizing dose of hCG (2.5 µg), we found that transcripts for type I and type II 3ß-HSD were substantially (5- to 8-fold) down-regulated. This major reduction, confirmed by RNase protection assay, was observed at the high hCG dose (2.5 µg), whereas minor or no change was found at lower doses (0.01 and 0.1 µg). In contrast, 3ß-HSD mRNA transcripts were not changed in luteinized ovaries of pseudopregnant rats treated with 2.5 µg hCG. The down-regulation of 3ß-HSD mRNA in the Leydig cell resulted from changes at the transcriptional level. Western blot analysis showed 3ß-HSD protein was significantly reduced by hCG treatment, with changes that were coincidental with the reduction of enzyme activity and temporally consistent with the reduction of 3ß-HSD mRNA but independent of LH receptor down-regulation. The reduction of 3ß-HSD mRNA resulting from transcriptional inhibition of gene expression, and the consequent reduction of 3ß-HSD activity could contribute to the inhibition of androgen production in gonadotropin-induced steroidogenic desensitization of Leydig cells. The gender-specific regulation of 3ß-HSD by hCG reflects differential transcriptional regulation of the enzymes to accommodate physiological hormonal requirements and reproductive function.

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