The reproductive endocrine function in 41 girls, 8 to 18 years old, treated with valproate for epilepsy and in 54 healthy control girls was evaluated at the University of Oulu, Finland. Mean serum testosterone concentrations of pubertal and pre- and post-pubertal girls taking valproate were significantly higher than in controls. Hyperandrogenism (serum testosterone levels 2SD above mean control levels) occurred in one third of prepubertal and pubertal valproate treated girls, and more than one-half of postpubertal girls were affected. Postpubertal girls taking valproate were more obese than controls, but the frequency of menstrual irregularities was not increased. [1]

COMMENT. Monitoring of serum testosterone, height, weight, and Tanner staging of genitalia and pubic hair, during valproate therapy in adolescent girls with epilepsy may be indicated, particularly when antiepileptic medication is required for extended periods, as in juvenile absence and myoclonic epilepsies. In adolescent girls and especially in patients developing hyperandrogenism, a substitute therapy such as lamotrigine should be considered. Hyperandrogenism is a complication of valproate therapy during pubertal maturation of girls with epilepsy, and the frequency of this side effect increases in postpubertal patients.

The University of Oulu investigators have previously reported on the incidence of obesity, polycystic ovaries, and hyperandrogenism in women taking valproate. Fourteen (64%) of 22 women receiving valproate were affected compared to 9 (21%) of 43 on carbamazepine and 8 (19%) of 43 untreated controls. Polycystic ovarian syndrome, hyperandrogenic chronic anovulation, is characterized by hirsutism and menstrual disorders. (see Progress in Pediatric Neurology II and III. PNB Publ, 1994 & 1997 for further commentary on endocrine effects of valproate, including pubertal arrest).

Valproate-induced biochemical abnormalities in pregnancy, including increased excretion of a-ketoglutarate, lactate, pyruvate, and other metabolites, were corrected by treatment with multivitamin supplements given from 13 to 28 weeks’ gestation. Fetal head growth, normal up to 30 weeks, was later slowed, and bitemporal narrowing was noted at birth [2]. Metabolic abnormalities, possibly related to the teratogenic effects of valproate, can be corrected with high-dose vitamin supplementation.

Valproate-induced male infertility is reported in a previously fertile 32-year-old man with epilepsy treated with valproate monotherapy. A low and abnormal sperm count returned to normal when valproate was discontinued and felbamate was substituted. [3]