Polycystic ovary syndrome in women using valproate: A review

Epilepsy Center, Department of Neurological Sciences, Federico II University, Naples, Italy.
Gynecological Endocrinology (Impact Factor: 1.33). 11/2008; 24(10):562-70. DOI: 10.1080/09513590802288259
Source: PubMed


Valproate (VPA) is a highly effective drug successfully employed in several neuropsychiatric diseases. In the last 15 years, an increased prevalence of polycystic ovary syndrome (PCOS) associated with VPA use has been reported in both women with epilepsy and women with bipolar disorders. However, data on this subject are contrasting and it is possible that different factors might play a role in the development of PCOS in these patients. The risk of developing PCOS during VPA treatment seems to be higher in women with epilepsy than in women with bipolar disorders, and this might be due to an underlying neuroendocrine dysfunction related to the seizure disorder. Gynecologists must be aware of the possibility that PCOS in these populations of patients might be related to VPA use, and a careful multi-specialist approach is required for evaluating the risks and benefits of this treatment in the presence of features of PCOS.

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    • "Over the past 15 years it has emerged that there is an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms in epileptic women taking VPA suggesting that the drug can perturb ovarian function and androgen synthesis, possibly as a result of multiple effects on the hypothalamic-pituitary-ovarian axis (reviews: [2], [3], [5], [9]). PCOS is a very common reproductive endocrine disorder affecting 6–8% of women of reproductive age [10], [11]; despite intensive research, its aetiology remains largely unknown. "
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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.
    PLoS ONE 11/2012; 7(11):e49553. DOI:10.1371/journal.pone.0049553 · 3.23 Impact Factor
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    • "VPA is effective for a broad spectrum of seizures , including absence seizures and GTC seizures. However, there are some concerns regarding consequent gynecological problems in female epilepsy patients [18] and regarding alopecia, GI complaints, hepatotoxicity, and hyperammonemia. There is increasing caution in prescribing VPA in terms of quality of life. "
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    ABSTRACT: We performed this study to evaluate the long-term efficacy and tolerability of ethosuximide (ESX), valproic acid (VPA), and lamotrigine (LTG) as initial monotherapies for patients with newly diagnosed childhood absence epilepsy. We retrospectively reviewed the medical records of 128 patients (45 boys and 83 girls) diagnosed with childhood absence epilepsy at the Seoul National University Hospital. The diagnosis was based on the criteria proposed by Panayiotopoulos in 2005. We measured the seizure-free rate and the retention rate observed during 2 years of treatment. Follow-up electroencephalography (EEG), any reported adverse events, and reasons for antiepileptic drug (AED) discontinuation were reviewed. The seizure-free rate of ESX (84%) was significantly higher than that of VPA (62%) and LTG (53%) at 3 months. The seizure-free rate of ESX (90%) was significantly higher than that of LTG (63%) at 6 months. After 9 months, there was no significant difference in seizure-free rate among the three groups. There were no significant differences among the three groups in terms of normalization of EEG at 12 months (ESX, 77%; VPA, 83%; and LTG, 64%), retention rate throughout the whole treatment period, and adverse-event rates (ESX, 25%; VPA, 29%; and LTG, 14%). This study suggests that ESX, VPA, and LTG are equally effective in the long-term treatment of newly diagnosed CAE patients. However, the onset of efficacy was faster for ESX compared with VPA or LTG. Efficacy, tolerability, and adverse event profiles should be carefully considered when selecting AEDs to treat individual patients with CAE.
    Brain & development 09/2011; 34(5):344-8. DOI:10.1016/j.braindev.2011.08.007 · 1.88 Impact Factor
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    • "Studies in male epilepsy patients receiving valproate have shown increased serum androgen levels in 60% of patients, as well as increased levels of testosterone in 50% of patients (Rättyä et al., 2001). Women undergoing valproate therapy for treatment of epilepsy are at increased risk of developing polycystic ovary–like syndrome (Bilo & Meo, 2008). Treatment with carbamazepine can cause elevations in low-density lipoproteins, serum cholesterol, and triglyceride levels, increasing the risk of atherosclerosis and other cardiovascular sequelae (Mahmoudian et al., 2005). "
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    ABSTRACT: Lennox-Gastaut syndrome (LGS) is an intractable childhood-onset epileptic encephalopathy. Seizure freedom is rare in LGS. One of the hallmarks of LGS is medical intractability, with generally poor response to antiepileptic drugs (AEDs). Nevertheless, several treatment options are available that can mitigate the severity of seizures and curtail their frequency. New AEDs have been validated in randomized, controlled trials for the treatment of seizures in LGS. In some cases, nonpharmacologic options may be effective, although more data are needed to confirm efficacy outcomes. Comprehensive patient assessments are critical to achieve an optimal AED treatment regimen and minimize the potential for adverse effects.
    Epilepsia 08/2011; 52 Suppl 5(supplement 5):10-20. DOI:10.1111/j.1528-1167.2011.03178.x · 4.57 Impact Factor
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