Valproate is an anti-androgen and anti-progestin.
Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-beta-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 microM CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 x 10(-9) M, AR), progesterone (1.6 x 10(-9) M, PR) or estradiol (2.6 x 10(-11) M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 microM) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 microM) blockade of DHT's suppression of AR-mediated NF-kappaB activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 microM) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 microM) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA.
Death
Alison K
AK
Heart Research Institute, 145 Missenden Road, Camperdown, NSW 2050, Australia. deatha@hri.org.au
McGrath
Kristine C Y
KC
Handelsman
David J
DJ
D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D001681:Biological Assay; D002220:Carbamazepine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013739:Testosterone / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology*; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D012739:Gonadal Steroid Hormones; D016328:NF-kappa B; D011372:Progestins; D011980:Receptors, Progesterone; D002220:Carbamazepine; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D014635:Valproic Acid