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Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells

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

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

In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30–3000 µM), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30–300 µM) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000–3000 µM) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 µM, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 µM) treatment was observed to increase histone H3 acetylation and P450 17-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 µM) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 µM), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.

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