Polycystic Ovaries and Hyperandrogenism in Women Taking Valproate for Epilepsy

Isojärvi, Jouko; Laatikainen, Timo; Pakarinen, Arto; Juntunen, Kaisa; Myllylä, Vilho V.

doi:10.1056/nejm199311043291904

Cited by 619 publications

(96 citation statements)

References 17 publications

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“…A number of reports describe adverse effects in women receiving VPA, including reproductive (Isojarvi et al, 1993;Duncan, 2001;O'Donovan et al, 2002) and endocrine (Rattya et al, 2001) disorders, obesity (Luef et al, 2002) and a decrease in bone mass (Sato et al, 2001). We demonstrate that VPA and TSA, known deacetylase inhibitors, clear ERa from, and preclude oestrogen signalling in all ERa positive cell lines evaluated.…”

Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 56%

“…We demonstrate that VPA and TSA, known deacetylase inhibitors, clear ERa from, and preclude oestrogen signalling in all ERa positive cell lines evaluated. The mean serum concentration of VPA in patients is around 4707135 mM, (n ¼ 69; data combined from Isojarvi et al, 1993;Sato et al, 2001; O'Donovan et al, 2002. We report that VPA mediated inhibition of oestrogen signalling and loss of ERa have respective in vitro IC 50 values around three-fold higher than this.…”

Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 99%

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Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

et al. 2005

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Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-a (ERa), resulting in subsequent clearance of ERa protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERa positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERa mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERa expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERa from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERa, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

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Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 56%

Section: Vpa Induced Adverse Effects In Womenmentioning

confidence: 99%

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

et al. 2005

View full text Add to dashboard Cite

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“…Although not all studies have analyzed the role of VPA dosage, the literature [5,6,7, 17, 24], as well as our experience [4], demonstrate that there is no correlation between the degree of weight gain and the daily VPA dosage and/or serum VPA concentration.…”

Section: Valproate and Weight Gainmentioning

confidence: 97%

“…The increase in body weight appears to occur most frequently in post-pubertal girls taking VPA [3, 4, 6, 8, 9, 12, 15, 17, 19, 20,25,26,27], although VPA-induced weight gain has also been reported also in pre-pubertal patients [4,5,6,7, 10, 24, 26, 28]. Finally, a recent population-based study reported that increase in body weight is more common in patients treated with VPA during puberty if epilepsy and medication continue into adulthood [16].…”

Section: Valproate and Weight Gainmentioning

confidence: 99%

Valproate-Induced Insulin Resistance and Obesity in Children

et al. 2009

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Background: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial. Methods: In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically. Results: Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic β-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects. Conclusions: The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.

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“…It has been associated with an increased frequency of reproductive endocrine disorders in females [2] and abnormal growth and pubertal development in children [3,4,5]. The pathogenic mechanisms underlying the endocrine disorders may be related to impaired hypothalamic regulation of the pituitary by epileptic discharges in the medial temporal lobe [6,7,8] and/or antiepileptic drugs [9,10]. In males, carbamazepine (CBZ), a liverenzyme-inducing antiepileptic drug, can progressively in- crease circulating levels of sex-hormone-binding globulin (SHBG), with resultant diminished bioactivity of free testosterone and estradiol and, ultimately, sexual dysfunction [11].…”

Section: Introductionmentioning

confidence: 99%

Endocrine Effects of Valproate versus Carbamazepine in Males with Epilepsy: A Prospective Study

Goldberg‐Stern

Itzhaki²,

Landau³

et al. 2015

Horm Res Paediatr

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Background/Aims: To prospectively evaluate the long-term impact of valproate (VPA) versus carbamazepine (CBZ) on anthropometric, hormonal, and metabolic parameters in young male patients treated for epilepsy. Methods: Of 61 boys with newly diagnosed epilepsy followed up, 24 were excluded from analysis (17 were lost to follow-up and 7 changed therapy within <1 year). Findings were compared by time, treatment (VPA or CBZ), and epilepsy type (generalized or partial) as well as against a matched control group with adequately treated hypothyroidism. Results: Twenty-four boys were treated with VPA and 13 with CBZ. The weight-standard deviation score (SDS) significantly increased during the first 6 months of treatment (p < 0.001), irrespective of the drug type, but decreased between the first and the last visit (p = 0.01). In patients with generalized epilepsy, there was a slight decrease in height- and weight-SDS between the first and the last visit (p = 0.04 and p = 0.01, respectively). The height-SDS at the last visit was comparable to the parental height-SDS. The mean age at puberty onset was 11.2 and 11.4 years in the study and the control group, respectively (p = 0.08). There were no significant differences in the other parameters by treatment or epilepsy type. Conclusions: Long-term therapy with VPA or CBZ has no significant endocrinological or metabolic adverse effect on male children and adolescents with epilepsy.

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Polycystic Ovaries and Hyperandrogenism in Women Taking Valproate for Epilepsy

Abstract: Menstrual disturbances, polycystic ovaries, and hyperandrogenism are often encountered in women taking valproate for epilepsy.

Cited by 619 publications

References 17 publications

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Valproate-Induced Insulin Resistance and Obesity in Children

Endocrine Effects of Valproate versus Carbamazepine in Males with Epilepsy: A Prospective Study

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