title: Contraceptive potential of RU 486 by ovulation inhibition: I. Pituitary versus ovarian action with blockade of estrogen-induced endometrial proliferation.
abstract: In previous studies, RU 486 administration arrested spontaneous folliculogenesis. To investigate the central versus peripheral effects of RU 486 on the ovarian/menstrual cycle, including endometrial proliferation, RU 486 was administered daily (10 mg/kg/day, im) from menstrual cycle day 3 or 7 to day 25 in normal adult cynomolgus monkeys receiving hMG treatment (37.5 IU/day) from days 3-8 (n = 6). RU 486 administration with hMG/hCG therapy did not inhibit ovarian response, as evidenced by steroidogenesis and ovulation. Nine of 23 oocytes retrieved by lavage or follicular aspiration at laparotomy after ovulation induction were morphologically classified as mature preovulatory status. Whereas an endometrial biopsy performed on cycle day 25 in control monkeys revealed an in phase mature secretory endometrium, histologic sections from RU 486 plus hMG/hCG treated females uniformly demonstrated atrophic to weakly proliferative endometrium on cycle day 25, despite serum estradiol levels greater than 300 pg/ml. Three months after the initial 25-day study endometrial biopsies revealed persistent atrophic endometrium, even though repeated ovulation induction with hMG/hCG therapy elevated serum estrogen concentrations. The findings prevailed whether RU 486 treatment began on cycle day 3 or 7. The intermenstrual interval was significantly (P less than 0.01) lengthened by RU 486 treatments (28.5 +/- 2.0, control vs 131.3 +/- 11.5 days, RU 486). In summary, RU 486 consistently blocked ovulation unless hCG was provided and elicited a persistent retardation of early proliferative endometrium when administered daily beginning in early or mid-follicular phase. The normal mitogenic effects of elevated ovarian estrogen secretion on endometrial tissue were quelled, uniformly resulting in amenorrhea. The long-lasting action of RU 486, causing ovulation inhibition and atrophic endometrium, may be due to the depot effect of im injection. In addition, RU 486 did not prevent ovarian steroidogenesis, ovulation or oocyte maturation when an ovulation induction regimen of hMG/hCG was given. These findings show that RU 486 prevented ovulation by diminishing pituitary gonadotropin secretion, rather than by direct effects on ovarian folliculogenesis, and induced amenorrhea by inhibiting estrogen-induced endometrial proliferation.
authors.affiliation: Department of Pathology, Eastern Virginia Medical School, Norfolk 23507.
authors.forename: J F
authors.initials: JF
authors.lastname: van Uem
authors.forename: J G
authors.initials: JG
authors.lastname: Hsiu
authors.forename: C F
authors.initials: CF
authors.lastname: Chillik
authors.forename: D R
authors.initials: DR
authors.lastname: Danforth
authors.forename: A
authors.initials: A
authors.lastname: Ulmann
authors.forename: E E
authors.initials: EE
authors.lastname: Baulieu
authors.forename: G D
authors.initials: GD
authors.lastname: Hodgen
mesh_terms: D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003270:Contraceptive Agents / Q000494:pharmacology*; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D004958:Estradiol / Q000097:blood / Q000502:physiology; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D005498:Follicular Phase / Q000187:drug effects; D008252:Macaca fascicularis; D008596:Menotropins / Q000494:pharmacology; D015735:Mifepristone; D010060:Ovulation / Q000187:drug effects; D011374:Progesterone / Q000097:blood
chemical_list: D006063:Chorionic Gonadotropin; D003270:Contraceptive Agents; D004963:Estrenes; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D008596:Menotropins