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*TESTOSTERONE
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 12 5925-5933
Copyright © 2001 by The Endocrine Society

Other Original Articles

The Biochemical Basis for Increased Testosterone Production in Theca Cells Propagated from Patients with Polycystic Ovary Syndrome

Velen L. Nelson, Ke-nan Qin, Robert L. Rosenfield, Jennifer R. Wood, Trevor M. Penning, Richard S. Legro, Jerome F. Strauss, III and Jan M. McAllister

Departments of Cellular and Molecular Physiology (V.L.N., J.M.M.) and Obstetrics and Gynecology (R.S.L.). Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; Center for Research on Reproduction and Women’s Health, University of Pennsylvania (J.R.W., J.F.S.), Philadelphia, Pennsylvania 19104; Department of Pharmacology, Biochemistry, and Biophysics, University of Pennsylvania (T.M.P.), Philadelphia, Pennsylvania 19104; and Departments of Pediatrics and Medicine, University of Chicago (K.Q., R.L.R.), Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Jan M. McAllister, Ph.D., Department of Cellular and Molecular Physiology, Pennsylvania State Hershey Medical Center, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: jmcallister{at}psu.edu

Abstract

Ovarian theca cells propagated from patients with polycystic ovary syndrome (PCOS) convert steroid precursors into T more efficiently than normal theca cells. To identify the basis for increased T production by PCOS theca cells, we examined type I–V 17ß-hydroxysteroid dehydrogenase (17ßHSD) isoform expression in long-term cultures of theca and granulosa cells isolated from normal and PCOS ovaries. RT-PCR analysis demonstrated that theca cells express type V 17ßHSD a member of the aldo-keto reductase (AKR) superfamily (17ßHSDV, AKR1C3), whereas expression of type I, II, and IV 17ßHSD, which are members of the short-chain dehydrogenase/reductase superfamily, was limited to granulosa cells. Type III 17ßHSD, the testicular isoform, was not detected in either granulosa or theca cells. Northern and real-time PCR analyses demonstrated that 17ßHSDV transcripts were not significantly increased in PCOS theca cells compared with normal theca cells. RT-PCR analysis revealed that theca cells also express another AKR, 20{alpha}HSD (AKR1C1). Both basal and forskolin-stimulated 20{alpha}HSD mRNA levels were increased in PCOS theca cells compared with normal theca cells. However, 17ßHSD enzyme activity per theca cell was not significantly increased in PCOS, suggesting that neither AKR1C3 nor AKR1C1 contributes to the formation of T in this condition. In contrast, 17{alpha}-hydroxylase/C17,20 lyase and 3ßHSD enzyme activities were elevated in PCOS theca cells, driving increased production of T precursors. These findings indicate that 1) increased T production in PCOS theca cells does not result from dysregulation of "androgenic" 17ßHSD activity or altered expression of AKRs that may express 17ßHSD activity; and 2) increased synthesis of T precursors is the primary factor driving enhanced T secretion in PCOS.




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