Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy

Abstract

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin‐like growth factor binding protein‐1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate‐treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy. Ann Neurol 1999;45:444–450

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

“…The mean serum level of ADION was high in VPA-treated men, and furthermore, more than half of the patients taking VPA had serum levels of testosterone, ADION, or DHEAS above the reference range, which is comparable with the prevalence of hyperandrogenism reported in adult women and young girls taking VPA for epilepsy. 5,6,20 The serum concentration of ADION tended also to be high in a previous study in men taking VPA. 3 In the current study, serum levels of FSH were low in VPA-treated men, which is consistent with a previous observation.…”

“…In our previous study, hyperandrogenemia was common among young girls (aged 8 to 18 years) taking VPA for epilepsy, but the girls with hyperandrogenemia were not hyperinsulinemic, though their BMI tended to be higher than that of the control girls. 20,23 Therefore, in men and young girls, VPA-related hyperandrogenism is not associated with hyperinsulinemia, nor is it induced by increased LH stimulation. Accordingly, VPA-related hyperandrogenism does not seem to be mediated through changes in the serum concentrations of other hormones.…”

The effects of oxcarbazepine treatment on vitamin B12 and folate levels, thyroid functions, sex hormones, and bone mineral density in epileptic patients

“…It is not known whether such effects are due to the epilepsy itself or the antiepileptic drugs [26]. CBZ treatment has been reported to cause hyposexuality, impotence and menstrual disorders in adults by influencing the levels of sex steroids and SHBG.…”

The Impact of Epilepsy on Reproductive Functions

“…The first report suggesting a high incidence of menstrual disorders linked to obesity, hyperandrogenism, and polycystic ovaries in women taking VPA for epilepsy was published in 1993 (Isojarvi). Changes in serum androgen levels have been detected before and during pubertal development in young girls taking VPA for epilepsy (Vainionpää, 1999). Studies by Murialdo et al (1997) have also reported a high prevalence of menstrual disorders and hyperandrogenic anovulation in VPA treated women with epilepsy.…”