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Troglitazone, an Insulin-Sensitizing Thiazolidinedione, Represses Combined Stimulation by LH and Insulin of de Novo Androgen Biosynthesis by Thecal Cells in Vitro

Division of Endocrinology, Department of Internal Medicine, National Institutes of Health Specialized Cooperative Center in Reproductive Research, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, M.D., Endocrinology Division, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908. E-mail: . jdv{at}virginia.edu

Abstract

Polycystic ovarian syndrome (anovulatory hyperandrogenism) is marked by adolescent onset of systemic hyperinsulinism, oligoovulation, hirsutism, excessive LH and androgen secretion, and variable reduction in fertility. Insulin and LH are believed to act in concert to promote ovarian androgen hypersecretion in this disorder. Administration of troglitazone, an insulin-sensitizing agent and putative PPAR agonist, can decrease hyperinsulinism, suppress T production, and ameliorate oligoovulation in some women with this endocrinopathy. The present study tests the hypothesis that troglitazone directly inhibits de novo androgen biosynthesis stimulated jointly by LH and insulin in primary cultures of (porcine) thecal cells. We show that troglitazone dose-dependently antagonizes LH/insulin’s combined stimulation of androstenedione and T production by thecal cells in vitro. Consistent steroidogenic inhibition of 80–95% was achieved at drug concentrations of 3–6.8 µM (P < 0.001). Exposure of thecal cells to the thiazolidinedione derivative also blocked bihormonally stimulated accumulation of CYP17 (cytochrome P450 17 -hydroxylase/C_17–20 lyase) gene expression, as reflected by decreased accumulation of cognate heterogeneous nuclear RNA and mRNA (by 30–65%; P < 0.05). Moreover, troglitazone suppressed LH/insulin-induced phosphorylation of the 52-kDa immunoprecipitated CYP17 enzyme by 88% (P < 0.001). A putative natural agonist of PPAR nuclear transcription, 15-deoxy--12,14-prostaglandin J₂, also inhibited LH/insulin-driven androstenedione biosynthesis and CYP17 gene expression in thecal cells. In conclusion, a synthetic thiazolidinedione (troglitazone) and a natural ligand of PPAR (15-deoxy--12,14-prostaglandin J₂) effectively impede the concerted stimulation by LH and insulin of in vitro thecal cell androgen production, CYP17 gene expression, and CYP17 protein phosphorylation. This ensemble of inhibitory actions on LH/insulin-stimulated steroidogenesis offers a plausible mechanistic basis for at least part of the observed clinical efficacy of troglitazone in mitigating androgen excess in women with polycystic ovarian syndrome.

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