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Estrogen receptor- mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of Cyp17a1 (cytochrome P450, steroid 17-hydroxylase/17,20 lyase) expression

Fuminori Taniguchi^*,1, John F. Couse^,1, Karina F. Rodriguez, Judith M. A. Emmen^,2, Donald Poirier and Kenneth S. Korach^,3

^* Department of Obstetrics and Gynecology, Tottori University Hospital, Yonago, Japan;

Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA; and

Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Quebec (CHUQ), Pavillon CHUL, Quebec, Canada

³Correspondence: Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, NIH, MD B3–02, P.O. Box 12233, Research Triangle Park, NC 27709, USA. E-mail: korach{at}niehs.nih.gov

Excess androgen synthesis by thecal cells is invariably detrimental to preovulatory follicles in the ovary and is considered a fundamental characteristic of polycystic ovary syndrome in women. Investigators have long postulated that granulosa cell-derived estrogens modulate thecal cell steroidogenesis via a short negative-feedback loop within the follicle. To test this hypothesis, we assessed the steroidogenic capacity of individual wild-type (WT) and estrogen receptor- (ER)-null follicles when cultured in vitro under comparable conditions. Late-stage ER-null follicles exhibited markedly increased expression of the thecal cell enzyme CYP17A1 and secreted much greater amounts of its end product, androstenedione. This phenotype was reproduced in WT follicles when exposed to an aromatase inhibitor or ER-antagonist, and prevented when the former treatment was supplemented with an ER-specific agonist. ER-null follicles also exhibited increased testosterone synthesis due to ectopic expression of hydroxysteroid (17ß) dehydrogenase type 3 (HSD17B3), a testis-specific androgenic enzyme. These data indicate that ER functions within thecal cells to negatively modulate the capacity for androgen synthesis by repressing Cyp17a1 expression, and the biological activity of androgens produced by inhibiting Hsd17b3 expression. Hence, these findings provide novel evidence of an intraovarian ER function that may be critical to the latter stages of folliculogenesis and overall ovarian function.—Taniguchi, F., Couse, J. F., Rodriguez, K. F., Emmen, J. M. A., Poirier. D., Korach, K. S. Estrogen receptor- mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of CYP17A1 (cytochrome P450, steroid 17-hydroxylase/17,20 lyase) expression

Key Words: hydroxysteroid (17ß) dehydrogenase • hyperandrogenemia • folliculogenesis • aromatase

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