Hormone Profiles in Young Adults with Epilepsy Treated with Sodium Valproate or Lamotrigine Monotherapy

Abstract

Summary:Purpose: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation.Methods: Hormone profiles in men and women taking VPA (n ‫ס‬ 40) or LTG (n ‫ס‬ 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high-and low-density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone-binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), folliclestimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured.Results: There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA-treated women were hyperinsulinaemic (p ‫ס‬ 0.05); three with abnormal menstrual cycles; one with raised testosterone. Testosterone (p ‫ס‬ 0.02), FAI (p ‫ס‬ 0.03), and TG (p ‫ס‬ 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p ‫ס‬ 0.01) and VPA-treated men (p ‫ס‬ 0.03) had higher insulin concentrations.Conclusions: VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA-treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA. Key Words: Sodium valproate-Lamotrigine-Insulin-Testosterone-Lipids.Sodium valproate (VPA) is a broad-spectrum antiepileptic drug (AED) that has been in use as a first-line agent for >30 years (1). VPA is a branched-chain fatty acid that undergoes similar metabolism to endogenous fatty acids (2,3). Weight gain is a recognised side effect and may be a consequence of mitochondrial inhibition by oxidative metabolites (4-8). Treatment with VPA has been associated with polycystic ovarian syndrome (PCOS) (9-12). This is a heterogeneous condition for which the diagnostic criteria remain a subject of contention (13). It tends to be characterised by ovarian cysts, chronic anovulation, hyperandrogenism, hyperinsulinaemia, and dyslipidaemia (6,(10)(11)(12)(13)(14). Affected women can also have an elevated serum luteinising hormone (LH)/ follicle-stimulating hormone (FSH) ratio, but this is a less sensitive marker (12,15). Although these abnormalities are often linked with obesity, this is not always so.Recent results from studies in Finnish women suggested that ∼60% of patients taking VPA had biochemical and clinical changes associated with PCOS (9,10). As this was not our anecdotal experience...

Valproate-Induced Insulin Resistance and Obesity in Children

“…Apart from one study that showed that patients with generalized versus partial seizures tend to be at greater risk for weight increase [13], the literature does not differentiate the incidence of weight gain between generalized and partial epilepsy patients [8, 9, 11, 14, 17, 19, 28, 29]. Our experience confirms this lack of a difference [4].…”

“…Increased appetite and excessive weight gain were reported in 23 boys and 21 girls; 31 of 66 patients with generalized epilepsy and 13 of 34 with partial epilepsy were affected in this way. In the following years, many studies [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20] quantified the amount of weight gain. Also, in our experience we have found that the percentage of obesity in a group of 40 epileptic patients without mental retardation is significantly higher in VPA-treated patients (37.5%) than in a group of 40 epileptics treated with other anticonvulsant drugs (10%).…”

“…Weight gain due to VPA treatment is usually observed during the first 3 months of therapy [8, 12], reaching a maximum after 6 months [3,21,22,23]. In contrast, data from many studies [3, 12, 16, 17, 20] make it clear that patients with weight gain received the medication for a significantly longer time than those who did not gain weight.…”

“…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].…”

Polycystic Ovarian Syndrome: Diagnosis and Management

“…Some evidence suggests that some women on this therapy have higher levels of insulin, testosterone, and triglycerides than those on another agent (lamotrigine), although few actually had a clear biochemical suggestion of PCOS. 117 Further study into this complex issue is needed, but in the meantime women with seizure disorders, perhaps especially those on valproic acid, deserve careful monitoring of their menstrual function clinically and potentially biochemically (i.e., assessment for hyperandrogenism).…”