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Mode Of Action Of The Anti-Convulsant Valproate

Researchers from Australia have recently shown, using a yeast-based in vitro bioassay for steroid hormones that valproate, a commonly used anti-convulsant for the treatment of epilepsy and bipolar disorder, 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.

The researchers examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-a-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER).

Bioassays were performed to detect agonist activity by exposing yeast to CBZ or valproate or to detect antagonist activity by exposing yeast stimulated with testosterone, progesterone or estradiol together with either valproate or CBZ for 4 (PR) or 16 (AR, ER) hours. Valproate showed dose-dependent 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.

Valproate also showed a dose-dependent blockade of DHT's suppression of AR-mediated NF-êB 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 it did antagonize PR activity.

The authors writing in the journal Steroids (available online 13 September 2005) conclude that valproate is a non-steroidal antagonist for human AR and PR but not ER. Valproate’s androgen and progesterone antagonism at concentrations within therapeutic blood levels seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with valproate.

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