Collaborative work on evaluation of ovarian toxicity : 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats

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In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20mg/kg from >2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20mg/kg during the pre-coital phase, while treatment with 4mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.
日本トキシコロジー学会の論文

Collaborative work on evaluation of ovarian toxicity : 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats

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