title: Collaborative work on evaluation of ovarian toxicity. 3) Effects of 2- or 4- week repeated-dose toxicity and fertility studies with tamoxifen in female rats.
abstract: To assess whether ovarian histopathological examination in repeated-dose rodent toxicity study could reliably anticipate toxic effects on female reproductive function and to assess whether ovarian change could be detected in a 2-week repeated-dose toxicity study, tamoxifen was administrated orally to female rats at 0.005, 0.03, or 0.2 mg/kg/day for 2 and 4 weeks in the repeated-dose toxicity studies, and for 2 weeks prior to cohabitation, during cohabitation, and through Gestation Day 7 in a female fertility study. The relationship between ovarian histopathological findings and fertility results was investigated. Findings at 0.03 and 0.2 mg/kg/day included decreases in body weight gains associated with decreases in food consumption, in 2- and 4-week repeated-dose toxicity studies and fertility study. The ovarian histopathological findings included increases in large atretic follicles, increases in interstitium cells and absence of newly-formed corpus lutea at 0.2 mg/kg/day in the 2-week study and at 0.03 and 0.2 mg/kg/day in the 4-week study. The treatment induced estrogenic and antiestrogenic reactions in the uterus, while mucinous degeneration was detected in the vagina. Effects on female fertility consisted primarily of disturbance of estrus cycle and decreases in numbers of pregnant rats which were considered to be related to ovarian histopathological changes. Based on these findings, ovarian histopathological evaluation in the repeated-dose toxicity study could anticipate the effects of tamoxifen on female fertility via ovarian dysfunction at slightly toxic doses, and 2-week treatment of tamoxifen at appropriate dose could be sufficient to detect ovarian toxicity by microscopic examination.
authors.affiliation: Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. shigeharu_tsujioka@merck.com
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Tsujioka
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ban
authors.forename: L David
authors.initials: LD
authors.lastname: Wise
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sato
authors.forename: Kenta
authors.initials: K
authors.lastname: Matsue
authors.forename: Takanori
authors.initials: T
authors.lastname: Ikeda
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D005298:Fertility / Q000187:drug effects* / Q000502:physiology; D007564:Japan; D008136:Longevity / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000633:toxicity*; D012958:Societies, Scientific; D013629:Tamoxifen / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000473:pathology
chemical_list: D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen