title: Valproate inhibits the conversion of testosterone to estradiol and acts as an apoptotic agent in growing porcine ovarian follicular cells.
abstract: OBJECTIVE
  Long-term valproate (VPA) treatment has been associated with hyperandrogenism and polycystic ovaries in women with epilepsy. The exact mechanisms of action of the drug on sex steroid hormone function are still unsettled. The aim of the present study was to investigate the action of VPA on basal and gonadotropin-stimulated steroid secretion in porcine ovarian follicular cells and to measure the conversion of testosterone to estradiol. Second, the action of VPA on proliferation and apoptosis of follicular cells was investigated.
  
  
  METHODS
  Small and medium follicles were obtained from pig ovaries on days 8-10 and 14-16 of the estrus cycle. Both follicular compartments, theca and granulosa cells, were cultured as a coculture resembling follicles in vivo. VPA in concentrations of 100 and 250 micrg/ml was added to the control or gonadotropin-stimulated cultures.
  
  
  RESULTS
  VPA caused a significant increase in basal and luteinizing hormone (LH)-stimulated testosterone secretion from small follicles, whereas in medium follicles, an increased basal but decreased LH-stimulated testosterone secretion was found. VPA caused decreased basal and follicle-stimulating hormone (FSH)-stimulated estradiol secretion by small follicles, whereas only the higher concentration decreased estradiol secretion in medium follicles. The conversion of testosterone to estradiol by small follicles was decreased under the influence of VPA in testosterone-alone and in testosterone-plus-FSH-stimulated cultures, whereas this was seen at only the higher VPA concentration in medium follicles. VPA had no effect on cell proliferation and viability, whereas in a dose-dependent manner, VPA increased caspase-3 activity.
  
  
  CONCLUSIONS
  VPA affected steroidogenesis in both unstimulated and gonadotropin-stimulated porcine ovarian follicular cells and inhibited the conversion of testosterone to estradiol. In addition, VPA may act as an apoptotic agent in both small and medium-sized follicles.
authors.affiliation: Department of Neurology, Rikshospitalet, University of Oslo, Norway. erik.tauboll@klinmed.uio.no
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
authors.forename: Ewa L
authors.initials: EL
authors.lastname: Gregoraszczuk
authors.forename: Anna
authors.initials: A
authors.lastname: Kołodziej
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Kajta
authors.forename: Erik
authors.initials: E
authors.lastname: Ropstad
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D047072:Aromatase Inhibitors; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000494:pharmacology; D010053:Ovary / Q000166:cytology / Q000187:drug effects*; D012636:Secretory Rate / Q000187:drug effects; D013552:Swine; D013739:Testosterone / Q000378:metabolism*; D013799:Theca Cells / Q000187:drug effects*; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D047072:Aromatase Inhibitors; D013739:Testosterone; D004958:Estradiol; D014635:Valproic Acid; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone