Abstracts

Women with epilepsy have an increased risk for reproductive health disorders. This is, at least in part, due to the use of antiepileptic drugs. Valproate has been shown to induce hyperandrogenism and polycystic ovaries, while enzyme inducing drugs reduce free fractions of sex steroid hormones. Levetiracetam (LEV) is a new antiepileptic drug with rapidly increasing use. Endocrine effects of the drug have so far not been reported and LEV may therefore represent an alternative drug for women of fertile age. The aim of the study was to investigate the effect of long-term LEV treatment on ovary weight and ovarian morphology in rats. Sixty-two female Wistar rats were fed perorally through a gastric tube with LEV 50 mg/kg (n=15), 150 mg/kg (n=21) or control (n=26) solution twice daily for 90-95 days. They were killed in diesterous/early proestrous phase. The ovaries were weighed and stained by hematoxylin-eosin before light microscopical evaluation. A blinded visual evaluation was performed using a mid-ovarian section of one ovary from each animal, and the numbers of cysts, follicles and corpora lutea were counted. All animals accepted the gastric tube feeding without signs of discomfort or reduced motor activity. However, four animals died because of oesophageal rupture induced by the gastric tube. Mean LEV concentration 4 h after sacrification was 122 and 277 umol/l in low- and high dose treated animals, respectively . Mean ovary weight showed a dose-dependent and significant increase after LEV treatment (93.5 mg, 97.3 mg and 110.5 mg in controls, low- and high-dose treated animals. Controls vs high-dose: p=0.02). Mean body weight was the same in all three groups. Mean number of cysts were 0.40 cysts/section in all LEV treated animals (low dose: 0.0 cysts/section; high-dose 0.67 cysts/section) compared to 0.83 cysts/section in control animals (not statistically different). The number of corpora lutea was significantly higher in the treated animals (mean 11.8/section) compared to controls (mean =9.8/section)(p=0.045). The number of secondary follicles is also significantly higher in the treated animals (mean=8.6/section) compared to controls (mean= 6.8/section) (p=0.034). The study is the first to indicate a probable effect of LEV on reproductive function in females. Ovary weight is significantly higher in high dose LEV treated animals compared to untreated controls. The number of corpora lutea and secondary follicles are also significantly higher in the treated animals, together with a trend towards reduced number of ovarian cysts. This may indicate a higher number of ovulatory cycles. The clinical relevance of these findings is uncertain, but our observations should encourage further studies on the possible reproductive endocrine effects of LEV.