Valproate and Neuroendocrine Changes in Relation to Women Treated for Epilepsy and Bipolar Disorder: A Review

Yale University School of Medicine, New Haven, CT 06510, USA.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2007; 14(26):2799-812. DOI: 10.2174/092986707782360088
Source: PubMed


Valproic acid (2-n-propylpentanoic acid, VPA) is well-established as a mood-stabilizer for bipolar disorder, in addition to its application as a treatment in neurological disorders such as epilepsy, migraine headaches, and chronic neuropathic pain. Its mechanisms of actions in any of the disorders have not yet been fully elucidated but currently include GABA-ergic inhibitory effects, the suppression of NMDA-mediated excitatory neurotransmission, and possibly effects on monoamines and cerebral glucose metabolism. Given the rising use of VPA by women of reproductive age for various conditions it is increasingly important to understand how VPA affects reproductive and metabolic function in women, yet a number of key issues regarding VPA use in women of reproductive age remain unclear. These include the question of whether VPA use is associated with the development of polycystic ovary syndrome (PCOS)-like features (such as elevated androgen concentrations and/or chronic anovulation). The metabolic effects of VPA use, particularly on insulin sensitivity and weight gain, are also important to understand. Lastly, questions of VPA use during pregnancy and lactation require continued attention. This article reviews the current understanding of VPA's mechanisms of action, effects on the reproductive and metabolic system, and teratogenic qualities, highlighting important future areas of study.

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    • "Sodium valproate has many mechanisms of action, including enhancement of c-aminobutyric acid (GABA) inhibitory neurotransmission , modulation of voltage-dependent sodium channels, and decreased cerebral glucose metabolism (Reynolds et al. 2007). Various hypotheses have been proposed to explain SB, including genetics, sleep structure, psychological factors, the autonomic nervous system, central neurotransmitters, and pharmacological factors, but no single theory can fully explain the etiology of SB (de la Hoz-Aizpurua et al. 2011). "

    Full-text · Article · Oct 2013 · Journal of child and adolescent psychopharmacology
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    • "Valproic acid (VPA) is a mood stabilizer that has been commonly prescribed for the treatment of epilepsy and bipolar disorder over the last several decades (1). Antiepileptic drugs including VPA frequently cause cutaneous eruptions, especially during initiation of new therapy. "
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    ABSTRACT: The potential role of topical valproate (VPA) in hair regrowth has been recently suggested. However, safety reports of VPA as a topical formulation are lacking. Therefore, in the present study, we investigated whether VPA causes skin irritation in humans. We first performed a cell viability test and showed that VPA did not exhibit toxicity toward HaCaT keratinocytes, fibroblasts, and RBL-3H mast cells. We then performed clinical patch test and skin irritation test through transdermal drug delivery with the help of microneedle rollers. No significant findings were obtained in the clinical patch test. In the skin irritation test, only 1 patient showed erythema at 1 hr, but the irritation reaction faded away within a few hours. Erythema and edema were not observed at 24 hr. We concluded that VPA has minimal potential to elicit skin irritation. Therefore, we consider that VPA can safely be applied to human skin.
    Full-text · Article · Jun 2013 · Toxicological Research
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    • "VPA is also used in the treatment of bipolar disorders, migraines and neuropathic pain. The anti-convulsant and mood stabilizing properties of VPA have been attributed to modulation of voltage-dependent sodium channels, enhancement of GABA inhibitory neurotransmission and/or decreased cerebral glucose metabolism [5].VPA is also known to affect various intracellular signal transduction pathways including MAPK, PKB and PKC-mediated pathways [6], [7] as well as being an inhibitor of type 1 histone deacetylase (HDAC) [8]. "
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    ABSTRACT: Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.
    Full-text · Article · Nov 2012 · PLoS ONE
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