Morphological changes in the testis after long-term valproate treatment in male Wistar rats

Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg(-1)(n= 15) or 400 mg kg(-1)(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4-6 hours after the last dose were 105 and 404 micromol l(-1)in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans.