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Retinoids and Retinol Differentially Regulate Steroid Biosynthesis in Ovarian Theca Cells Isolated from Normal Cycling Women and Women with Polycystic Ovary Syndrome

Departments of Cellular and Molecular Physiology (J.K.W., V.L.N.-D., K.L.H., J.M.M.) and Obstetrics and Gynecology (R.S.L., J.M.M.), Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033; and the Center for Research on Reproduction and Women’s Health (J.F.S.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Jan M. McAllister, Ph.D., Pennsylvania State Hershey College of Medicine, Department of Cellular and Molecular Physiology, 500 University Drive, C4723, Hershey, Pennsylvania 17033. E-mail: jmcallister{at}psu.edu.

Context: Polycystic ovary syndrome (PCOS) is characterized by ovarian androgen excess and infertility. Recent experiments have suggested that several genes involved in retinoic acid synthesis may be differentially expressed in PCOS theca cells and may contribute to excessive theca-derived androgen production.

Objective: The study was performed to examine whether there are differential effects of retinol and retinoids on normal and PCOS theca cell function.

Design: We used in vitro assays.

Setting: The study was conducted at the university laboratory.

Patients: We studied theca interna cells isolated from normal-cycling women and women with PCOS.

Interventions: Theca cells were treated with all-trans-retinoic acid (atRA), 9-cis retinoic acid (9-cis RA), or the retinoic acid precursor retinol.

Main Outcome Measure(s): We measured dehydroepiandrosterone, testosterone, and progesterone biosynthesis as well as cytochrome P450 17-hydroxylase (CYP17), cytochrome P450 cholesterol side-chain cleavage, and steroidogenic acute regulatory protein mRNA abundance and promoter function.

Results: Dehydroepiandrosterone production was increased by atRA and 9-cis RA in normal cells and by atRA, 9-cis RA, and retinol in PCOS. Testosterone production was increased by atRA in normal and by atRA, 9-cis RA, and retinol in PCOS. Progesterone production was not altered by retinoid treatment. Retinoids stimulated mRNA abundance and promoter function for CYP17 and steroidogenic acute regulatory protein in both cell types and cytochrome P450 cholesterol side-chain cleavage in normal cells. Retinol stimulated CYP17 mRNA accumulation and promoter function in PCOS but not normal theca cells. P < 0.05 was considered statistically significant.

Conclusions: Differential responses to retinol and retinoids in normal and PCOS theca suggest that altered retinoic acid synthesis and action may be involved in augmented CYP17 gene expression and androgen production in PCOS.

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