Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects

Physiol Genomics. 2005 Feb 10;20(3):233-43. doi: 10.1152/physiolgenomics.00193.2004. Epub 2004 Dec 14.


Valproic acid (VPA) is an anti-epileptic drug that has been associated with polycystic ovary syndrome (PCOS)-like symptoms, including increased ovarian androgen production. The hyperandrogenemia likely reflects the stimulatory action of VPA on theca cell androgen synthesis and has been correlated to its activity as a histone deacteylase inhibitor in these cells. To determine whether VPA induces a PCOS-like genomic phenotype, we compared the gene expression profiles of untreated (UNT) normal, VPA-treated normal, and UNT PCOS theca cells. Hierarchal cluster analysis demonstrated similarities in the gene expression profiles of VPA-treated normal and PCOS theca cells. Statistical analysis identified 1,050 transcripts that have significantly altered mRNA abundance in both VPA-treated normal and UNT PCOS theca cells compared with normal UNT theca cells. Among these 1,050 transcripts were cAMP-GEFII and TRB3, which have increased and decreased mRNA abundance, respectively. The altered abundance of these two mRNAs was correlated to increased basal and insulin-induced phosphorylation of protein kinase B (Akt/PKB). Thus these studies indicate that VPA- and PCOS-induced changes in gene expression enhance Akt/PKB signal transduction in human theca cells. Furthermore, common changes in gene expression in PCOS and VPA-treated normal theca cells suggest a possible mechanism for the development of PCOS-like symptoms, including increased steroid synthesis and arrested follicle development in women receiving chronic VPA therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anticonvulsants / pharmacology
  • Apoptosis / drug effects
  • Base Sequence
  • Cell Cycle / drug effects
  • DNA Primers
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Polycystic Ovary Syndrome / genetics
  • Polycystic Ovary Syndrome / pathology
  • Polymerase Chain Reaction
  • Reference Values
  • Reverse Transcriptase Polymerase Chain Reaction
  • Theca Cells / cytology
  • Theca Cells / drug effects
  • Theca Cells / physiology*
  • Valproic Acid / pharmacology*


  • Anticonvulsants
  • DNA Primers
  • Valproic Acid