Histopathologic Characterization of Mifepristone-induced Ovarian Toxicity in Cynomolgus Monkeys

Abstract

Mifepristone, which is an orally active synthetic steroid with antiprogesterone activity, is known as an ovarian toxicant. Because the available data regarding the histopathologic characteristics of ovarian toxicity in nonhuman primates are limited, the present study was undertaken in order to investigate detailed histopathologic changes accompanying mifepristone-induced ovarian toxicity and its relationship to changes in menstrual cycle and circulating sex steroid hormone. Twenty mg/kg of mifepristone was orally administered daily to 4 cynomolgus monkeys for 2 months. Mifepristone inhibited the cyclic increases in circulating estradiol-17β and progesterone levels with associated absence of menstruation. Histopathologically, the ovary in the treated animals showed follicular phase without changes in the percentage of atretic antral follicles, and reduced endometrial thickness was noted in the uterus. These changes indicated that a certain degree of antral follicle development had been retained in spite of the menstrual cycle having been arrested in mifepristone-treated animals. Our investigation suggested that it is important to perform detailed histopathologic examination of reproductive organs with precise knowledge of the characteristics of each menstrual stage to detect ovarian toxicity in nonhuman primates. Monitoring menstrual signs and circulating sex steroid hormone levels provides additional evidence for the investigation of the mechanism of ovarian toxicity.

Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms

“…We found no statistically significant differences in FSH, LH, and E2 levels between groups for the 12-week treatment. Recently, the effects of selective progesterone receptor modulators on endometrial thickness and endometrial changes associated with progesterone receptor modulators have attracted much attention but remain controversial . Our study showed that endometrial thickness detected by ultrasonography after mifepristone treatment was thinner.…”

“…Recently, the effects of selective progesterone receptor modulators on endometrial thickness and endometrial changes associated with progesterone receptor modulators have attracted much attention but remain controversial. [34][35][36] Our study showed that endometrial thickness detected by ultrasonography after mifepristone treatment was thinner. a Safety population was defined as the participants with at least 1 dose of the intervention or placebo drug.…”

Toxicologic Pathology Forum*: Opinion on Sexual Maturity and Fertility Assessment in Long-tailed Macaques (Macaca fascicularis) in Nonclinical Safety Studies

“…The presence and characteristics of corpora lutea are also important. Detailed descriptions of the histomorphology of the ovary throughout the ovarian cycle have been published with a luteinized regressive corpus luteum in the early follicular phase, a dominant large antral follicle in the late follicular phase and various stages of small, growing, antral, and atretic follicles and an old corpus luteum in the menstrual phase (Buse, Zöller, and van Esch 2008; Taketa et al 2018). Since corpora lutea may be missed on a histological section through the ovary, it is recommended to generate gross photographs of the ovaries before they are embedded in paraffin wax.…”