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

Abstract

-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 100 mg/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 20 mg/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 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implan-

The influence of reproductive hormones on the torpor patterns of the marsupial Sminthopsis macroura: Bet-hedging in an unpredictable environment

“…The effects of tamoxifen and RU486 on females are dose-dependent, with higher doses inflicting more disruption to oestrous cycles and body condition [38,39,71,73,59,74]. Our lower doses of tamoxifen and RU486 produced the disruption of oestrous cycles without complete abolishment of cycling, moderation of fat stores as seen by tail width modifications, and some body mass changes, similar to the effects of these doses on other species [39,38,72,73,59,74].…”

Altered gene expression profile in ovarian follicle in rats treated with indomethacin and RU486

“…Dose volumes for both agents were 5 mL/kg, according to twoor four-week repeated dose studies of IM (Tsubota et al, 2009) and RU (Tamura et al, 2009).…”

“…The study design and number of animals used in the experiment 1 are shown in Table 1. Dose levels, 4 mg/kg for IM and 100 mg/kg for RU, at which UFs were induced by multiple-dose, were selected (Tsubota et al, 2009;Tamura et al, 2009). The ovaries, uteri, and vaginas were removed, fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4 μm, and stained with hematoxylin and eosin (HE).…”

“…Hmox1-deficient mice (Zenclussen et al, 2012) ↓UF ↓UF Plat Anti-tPA antibody-treated rats (Tsafriri et al, 1989) ND ↓UF Pparg Pparg-conditional knock-out mice (Kim et al, 2008) ND ↓UF Pr Pr-deficient mice (Lydon et al, 1995), PR antagonist-treated rats (Tamura et al, 2009) ND ND Vegf VEGF Trap treatment in marmoset monkeys (Wulff et al, 2002) ↓UF ↓UF Wnt4…”

“…The National Institute of Health Science and pharmaceutical companies of the Japanese Pharmaceutical Manufacturers Association conducted collaborative work on evaluation of ovarian toxicity (Sanbuissho et al, 2009). Among findings detected in the studies, unruptured follicle (UF) was a significant finding which suggests blocked ovulation and therefore considered relevant to fertility (Tsubota et al, 2011;Tamura et al, 2009).…”