title: Long-term levetiracetam treatment affects reproductive endocrine function in female Wistar rats.
abstract: OBJECTIVE
  Several antiepileptic drugs (AEDs) induce changes in endocrine function in women with epilepsy. Levetiracetam (LEV) is one of the newer AEDs, and to date no endocrine side-effects have been reported in humans. However, a recent study on ovarian follicular cells from prepubertal pigs showed that LEV affected basal steroid hormone secretion. The aim of the present study was to investigate possible effects of the drug on endocrine function and ovarian morphology in non-epileptic rats.
  
  
  METHODS
  Thirty female Wistar rats were fed per-orally with either 50mg/kg LEV (n=15) or 150 mg/kg LEV (n=15) twice daily for 90-95 days. Twenty rats received a control solution. The rats were killed in the dioestrus phase of the oestrous cycle. Serum concentrations of testosterone, 17beta-oestradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and LEV were measured, and the ovaries examined histologically.
  
  
  RESULTS
  Mean ovarian weight showed a significant, dose-dependent increase after LEV treatment. Mean numbers of ovarian follicular cysts were not changed, but the numbers of corpora lutea and secondary follicles were significantly higher in the treated animals. Serum testosterone was significantly increased in treated animals (0.50 nmol/l versus 0.16 nmol/l in controls, p<0.05), while oestradiol was reduced (67.4 compared to 257.5 pmol/l in controls, p<0.05). The low-dose group had significantly lower serum progesterone concentrations than the control group (56.8 nmol/l versus 34.7 nmol/l, respectively, p<0.05). FSH was reduced in the treated animals (3.3 ng/ml versus 5.5 ng/ml, p<0.05) while LH was unaffected.
  
  
  CONCLUSIONS
  Our findings indicate a possible effect of LEV on the hypothalamic-pituitary-gonadal (HPG) axis and ovarian morphology in non-epileptic rats. The effects differ from those previously described for other AEDs. Caution must be taken before these results can be applied to humans.
authors.affiliation: Department of Neurology, Division of Clinical Neuroscience, Rikshospitalet Medical Centre, Rikshospitalet, 0027 Oslo, Norway. sigrid.svalheim@rikshospitalet.no
authors.forename: Sigrid
authors.initials: S
authors.lastname: Svalheim
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
authors.forename: Kristina
authors.initials: K
authors.lastname: Surdova
authors.forename: Lasse
authors.initials: L
authors.lastname: Ormel
authors.forename: Ellen
authors.initials: E
authors.lastname: Dahl
authors.forename: Mona
authors.initials: M
authors.lastname: Aleksandersen
authors.forename: Alan
authors.initials: A
authors.lastname: McNeilly
authors.forename: Leif
authors.initials: L
authors.lastname: Gjerstad
authors.forename: Erik
authors.initials: E
authors.lastname: Ropstad
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003338:Corpus Luteum / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004703:Endocrine System / Q000187:drug effects*; D005260:Female; D006065:Gonadotropins, Pituitary / Q000378:metabolism; D000077287:Levetiracetam; D008597:Menstrual Cycle / Q000187:drug effects; D010053:Ovary / Q000187:drug effects; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D006065:Gonadotropins, Pituitary; D000077287:Levetiracetam; D010889:Piracetam