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

Abstract

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 17α-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. 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 17α-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. Polycystic ovary syndrome (PCOS) 1The abbreviations used are: PCOS, polycystic ovary syndrome;P450scc, P450 side chain cleavage; StAR, steroidogenic acute regulatory protein; LH, luteinizing hormone; CYP17, 17α-hydroxylase/17,20-lyase; RT, reverse transcriptase; atRA, all-trans-retinoic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RoDH2 and -4, retinol dehydrogenase 2 and 4, respectively; ALDH6, aldehyde dehydrogenase 6; TGF, transforming growth factor; TIG1, tazarotene-induced gene 1; IGFBP3, insulin-like growth factor-binding protein 3; FSH, follicle stimulating hormone; DHEA, dehydroepiandosterone. is characterized by failure of ovulation, excessive ovarian androgen production, and, consequently, infertility (1Ehrmann D.A. Barnes R.B. Rosenfield R.L. Endocr. Rev. 1995; 16: 322-353Crossref PubMed Scopus (515) Google Scholar, 2Legro R.S. Spielman R. Urbanek M. Driscoll D. Strauss III, J.F. Google PCOS ovaries and a than in a 1995; PubMed Scopus Google theca of and the of the increased androgens in PCOS women R.S. Spielman R. Urbanek M. Driscoll D. Strauss III, J.F. Google studies have suggested that the ovarian hyperandrogenemia with PCOS in and to be inherited as an autosomal dominant R.S. Spielman R. Urbanek M. Driscoll D. Strauss III, J.F. Google However, the genetic etiology of PCOS not been and and long term of theca cells have demonstrated that androgen synthesis is increased in PCOS with normal theca cells, suggesting that this PCOS phenotype is an intrinsic of the theca cell (1Ehrmann D.A. Barnes R.B. Rosenfield R.L. Endocr. Rev. 1995; 16: 322-353Crossref PubMed Scopus (515) Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, R.S. Strauss III, J.F. PubMed Google theca cell been to increased of the and dehydrogenase (1Ehrmann D.A. Barnes R.B. Rosenfield R.L. Endocr. Rev. 1995; 16: 322-353Crossref PubMed Scopus (515) Google Scholar, PubMed Scopus Google Scholar, R.S. Strauss III, J.F. PubMed Google and increased expression of the P450 side chain and Furthermore, is increased in PCOS with normal theca cells R.S. Strauss III, J.F. PubMed Google Scholar, R.S. Strauss III, J.F. PubMed Scopus Google In the abundance of the for steroidogenic acute regulatory protein which the in Strauss III, J.F. PubMed Scopus Google and dehydrogenase which is the theca cell that is to be responsible for the of PubMed Scopus Google as as the of the not between normal and PCOS theca cells R.S. Strauss III, J.F. PubMed Google Scholar, R.S. Strauss III, J.F. PubMed Scopus Google Scholar, Rosenfield R.L. R.S. Strauss III, J.F. PubMed Scopus Google Thus, studies have defined a stable steroidogenic phenotype for the PCOS theca cell that altered expression of a of that for androgen in the ovarian theca cell is by luteinizing which to the increased of Endocr. Rev. 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