Collaborative work on evaluation of ovarian toxicity 12) Effects of 2- or 4-week repeated dose studies and fertility study of indomethacin in female rats

Abstract

2-week and 4-week general toxicity studies of indomethacin, a nonselective inhibitor of cyclooxygenase 1 and 2, were performed using rats. A female fertility study was also conducted to compare the results to those of ovarian histopathological findings. The main purposes of the present studies are to assess whether a precise histopathological examination, taking the morphological changes the female reproductive organs undergo during each estrus phases into account, can evaluate toxicity to the ovaries, and to determine the optimal administration period for detecting ovarian toxicity. Indomethacin was administered on a daily basis to female Sprague-Dawley rats at doses of 0, 0.4, 1.3, or 4 mg/kg in the both the general toxicity studies and the female fertility study. In the general toxicity studies, unruptured follicles or luteinized cysts were observed histopathologically in the 4 mg/kg group in both the 2-week and 4-week studies. In addition, follicular cysts were found in the 4 mg/kg group in the 4-week study. Estrous cyclicity was not disturbed in both studies. There were no histopathological changes in the ovaries of the 1.3 mg/kg group in general toxicity studies. In the female fertility study, no toxic effects on female fertility parameters were detected in the 0.4 and 1.3 mg/kg group treated with indomethacin, but 8 of 10 rats in the 4 mg/kg group died or were sacrificed before completion of the dosing period. These results demonstrated that 2 weeks of indomethacin treatment is sufficient to detect unruptured follicles or luteinized cyst in the ovary. In addition, 4 weeks of dosing maybe required for induction of follicular cysts, although we could not clearly show that these histopathological changes would affect female fertility functions. These present studies suggest that a precise histopathological examination may be able to predict the effect of test articles on female reproductive functions.