Abstract Title:

Collaborative work on evaluation of ovarian toxicity. 8) Two- or four-week repeated-dose studies and fertility study of Anastrozole in female rats.

Abstract Source:

J Toxicol Sci. 2009;34 Suppl 1:SP91-9. PMID: 19265294

Abstract Author(s):

Makoto Shirai, Ken Sakurai, Wataru Saitoh, Takuya Matsuyama, Munehiro Teranishi, Tadashi Furukawa, Atsushi Sanbuissho, Sunao Manabe

Article Affiliation:

Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd., Fukuroi-shi, Shizuoka, Japan. [email protected]

Abstract:

The main focus of this study was to determine the optimal administration period in terms of toxic effects on ovarian morphological changes. To assess the morphological and functional changes induced by anastrozole in ovaries, the compound was administered to female rats at dose levels or 0, 0.01, 0.1 and 50 mg/kg for 2 or 4 weeks in the repeated dose toxicity study and at levels of 0, 0.01, 0.1 and 5 mg/kg from 2 weeks prior to mating to Day 7 or pregnancy in the female fertility study. In the repeated dose toxicity study, large abnormal atretic follicles, follicular cysts, a decrease in corpus luteum and depletion of developing corpus luteum were observed in the 1 and/or 50 mg/kg groups of both the 2-week and 4-week studies in a histopathological examination of the ovaries. In the female fertility study, the pregnancy rate was decreased in the 5 mg/kg group. Irregular estrous cycles, such as an extended cycle or no cycle, were observed in the 0.1 and 5 mg/kg groups. At necropsy, decreased numbers of implantations, corpora lutea and live fetuses were noted in the 1 and/or 5 mg/kg groups. Based on these findings, histopathological changes in the ovary are important endpoints for the evaluation of drugs inducing ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of anastrozole in a repeated dose toxicity study.

Study Type : Animal Study

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