Collaborative work on evaluation of ovarian toxicity. 1) Effects of 2- or 4-week repeated-dose administration and fertility studies with medroxyprogesterone acetate in female rats.
As a part of the collaborative study to evaluate the relationship between histopathological changes of the ovary and functional changes in female fertility, 2- and 4-week repeated-dose toxicity studies and a female fertility study were conducted using female Crl:CD(SD) rats using a synthetic progestagen of medroxyprogesterone acetate (MPA) as a test compound. MPA was administered to female rats by gavage at 0, 0.4, 2.0 and 10 mg/kg/day for 2 and 4 weeks to assess the histopathological changes of ovaries and to pregnant rats at the same doses from 2 weeks prior to mating until day 7 of gestation to examine female fertility. The number of non-pregnant female rats with irregular estrous cycle increased in number and there was a decrease in weight of ovaries was observed at doses > or = 2.0 mg/kg in the 2- and 4-week-treatment groups. The histopathological examination revealed an increased number of large atretic follicles and decreases in currently formed corpora lutea and previously-formed large or small ones were observed at the same doses in the 2- and 4-week treatment groups. In female fertility study, the number of animals with an irregular estrous cycle and elongation of mean estrous cycle increased at 0.4 mg/kg, with no changes in fertility. A decreased number of copulating animals and a decreased gestation rate with low preimplantation loss were observed in the 2.0 mg/kg-treatment group and no copulation was observed in the group treated with 10 mg/kg. Based on these results, changes in fertility induced by MPA correlated well with histopathological changes of ovaries after 2 and 4 weeks of treatment, which suggests that a 2 weeks administration period is sufficient to detect ovarian toxicity of MPA with repeated dosing
Ohtake
Sachiyo
S
Safety Research Department, Developmental Research Center, ASKA Pharmaceutical Co., Ltd., Kawasaki, Kanagawa, Japan.
Fukui
Motoko
M
Hisada
Shigeru
S
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004622:Embryo, Mammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D005298:Fertility / Q000187:drug effects* / Q000502:physiology; D007564:Japan; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific
D015415:Biomarkers; D003271:Contraceptive Agents, Female; D018809:Proliferating Cell Nuclear Antigen; D017258:Medroxyprogesterone Acetate