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J. Biol. Chem., Vol. 278, Issue 29, 26380-26390, July 18, 2003

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The Molecular Phenotype of Polycystic Ovary Syndrome (PCOS) Theca Cells and New Candidate PCOS Genes Defined by Microarray Analysis^*,

Jennifer R. Wood , Velen L. Nelson , Clement Ho , Erik Jansen ¶, Clare Y. Wang , Margrit Urbanek ||, Jan M. McAllister , Sietse Mosselman ** and Jerome F. Strauss, III  

From the Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, the ^||Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine of Northwestern University, Chicago, Illinois 60611, and the ^¶Target Discovery Unit and ^**Department of Pharmacology, NV Organon, 5340 BH Oss, The Netherlands

Polycystic ovary syndrome (PCOS) affects 5% of reproductive aged women and is the leading cause of anovulatory infertility. A hallmark of PCOS is excessive theca cell androgen secretion, which is directly linked to the symptoms of PCOS. Our previous studies demonstrated that theca cells from PCOS ovaries maintained in long term culture persistently secrete significantly greater amounts of androgens than normal theca cells, suggesting an intrinsic abnormality. Furthermore, previous studies suggested that ovarian hyperandrogenemia is inherited as an autosomal dominant trait. However, the genes responsible for ovarian hyperandrogenemia of PCOS have not been identified. In this present study, we carried out microarray analysis to define the gene networks involved in excess androgen synthesis by the PCOS theca cells in order to identify candidate PCOS genes. Our analysis revealed that PCOS theca cells have a gene expression profile that is distinct from normal theca cells. Included in the cohort of genes with increased mRNA abundance in PCOS theca cells were aldehyde dehydrogenase 6 and retinol dehydrogenase 2, which play a role in all-trans-retinoic acid biosynthesis and the transcription factor GATA6. We demonstrated that retinoic acid and GATA6 increased the expression of 17-hydroxylase, providing a functional link between altered gene expression and intrinsic abnormalities in PCOS theca cells. Thus, our analyses have 1) defined a stable molecular phenotype of PCOS theca cells, 2) suggested new mechanisms for excess androgen synthesis by PCOS theca cells, and 3) identified new candidate genes that may be involved in the genetic etiology of PCOS.

Received for publication, January 21, 2003 , and in revised form, April 9, 2003.

^* The experiments in this paper were supported by National Institutes of Health Grants T32-HD07305 and U54-HD34449 and the Mellon Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains six additional tables.

To whom correspondence should be addressed: Center for Research on Reproduction and Women's Health, 1349 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0147; Fax: 215-573-5408; E-mail: jfs3{at}mail.med.upenn.edu.

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