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This version published online on October 23, 2003
Endocrinology, doi:10.1210/en.2003-0940
A more recent version of this article appeared on February 1, 2004
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Submitted on July 24, 2003
Accepted on October 16, 2003

Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells

Velen L Nelson-DeGrave1, Jessica K Wickenheisser1, Jennifer E Cockrell1, Jennifer R. Wood1, Richard S Legro1, Jerome F Strauss III1, and Jan M McAllister1*

1 Departments of Cellular and Molecular Physiologyand Obstetrics and Gynecology, Penn. State College of Medicine, Hershey, PA, and the Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA.

* To whom correspondence should be addressed. E-mail: jmcallister{at}psu.edu.

In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome (PCOS)-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 µM - 3000 µM), we observed an increase in basal and forskolin-stimulated DHEA, androstenedione ({Delta}4A), and 17{alpha}-hydroxyprogesterone (17OHP4) production compared with control values. In contrast, low doses of VPA treatment (i.e. 30 µM - 300 µM) had no effect on basal and forskolin stimulated progesterone (P4) production, whereas higher doses of VPA (1000 µM - 3000 µM) inhibited P4 production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300 µM to 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 (StAR) was unaffected. In transient transfection studies, VPA was found to increase P450 17{alpha}-hydroxylase (CYP17) and P450 cholesterol side chain cleavage (CYP11A) promoter activity, whereas StAR promoter activity was unaffected.

Consistent with the ability of VPA to act as a histone deactylase (HDAC) inhibitor in other cell systems, VPA (500 µM) treatment was observed to increase histone H3 acetylation and CYP17 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 PCOS-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.
Key words: Polycystic ovary syndrome (PCOS) • rogen excess • theca cell • histone deacetylase (HDAC) inhibitor • valproate (VPA)




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