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Histopathologic Characterization of Mifepristone-induced Ovarian Toxicity in Cynomolgus Monkeys

Yoshikazu Taketa1, Kanta Horie2, Tetsuya Goto3

  • 11 Tsukuba Drug Safety, Global Drug Safety, Biopharmaceutical Assessments Core Function Unit, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.

Toxicologic Pathology
|March 22, 2018
PubMed

Insights

Mifepristone causes ovarian toxicity in cynomolgus monkeys by disrupting the menstrual cycle and sex steroid hormones. Histopathology reveals retained follicular development despite arrested cycles.

Area of Science:

  • Reproductive Toxicology
  • Endocrinology
  • Primate Research

Background:

  • Mifepristone is an orally active antiprogestogen with known ovarian toxicity.
  • Limited data exists on the histopathologic features of ovarian toxicity in nonhuman primates.

Purpose of the Study:

  • To investigate detailed histopathologic changes of mifepristone-induced ovarian toxicity in cynomolgus monkeys.
  • To correlate these changes with menstrual cycle and sex steroid hormone alterations.

Main Methods:

  • Oral administration of 20 mg/kg mifepristone daily for 2 months to 4 cynomolgus monkeys.
  • Monitoring of menstrual cycles and circulating estradiol-17β and progesterone levels.
  • Detailed histopathologic examination of ovaries and uteri.

Main Results:

  • Mifepristone inhibited cyclic increases in estradiol-17β and progesterone, leading to amenorrhea.
  • Ovaries showed a follicular phase without increased atretic antral follicles.
  • Uteri exhibited reduced endometrial thickness.

Conclusions:

  • Mifepristone-induced ovarian toxicity in nonhuman primates involves menstrual cycle arrest despite retained antral follicle development.
  • Detailed histopathologic examination combined with menstrual stage knowledge is crucial for detecting ovarian toxicity.
  • Monitoring menstrual signs and hormone levels aids in understanding the mechanism of ovarian toxicity.
Keywords:
cynomolgus monkeyestradiol-17βmifepristoneovarian toxicityprogesterone

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