Chronic progesterone antagonist-estradiol therapy suppresses breakthrough bleeding and endometrial proliferation in a menopausal macaque model.
BACKGROUND
Clinicians routinely prescribe progestins along with estrogens during menopausal hormone therapy (HT) to block estrogen-dependent endometrial proliferation. Breakthrough bleeding (BTB) can negate the utility of this treatment. Because progestin antagonists also inhibit estrogen-dependent endometrial proliferation in women and macaques, we used a menopausal macaque model to determine whether a potent progestin antagonist (ZK 230 211, Schering AG; ZK) combined with estrogen would provide a novel mode of HT.


METHODS
Ovariectomized rhesus macaques were treated for 5 months with either estradiol (E(2)) alone, E(2) + progesterone (two doses) or E(2) + ZK (0.01, 0.05 or 0.25 mg/kg).


RESULTS
In the E(2) + progesterone groups, progesterone suppressed endometrial proliferation and induced a thick decidualized endometrium. In the E(2) + ZK 230 211 groups, all doses of ZK blocked endometrial proliferation and induced endometrial atrophy. In all ZK-treated groups, the atrophied endometrium contained some dilated glands lined by an inactive, flattened, non-mitotic epithelium. BTB was much lower in the E(2) + ZK groups (17 days of spotting, all groups) than in the E(2) and E(2) + progesterone groups (155 bleeding days, all groups). ZK suppressed E(2) effects in the cervix, but not in the vagina, oviduct or mammary glands. All serum chemistry and lipid profiles were normal.


CONCLUSIONS
The ability of ZK to block estrogen-dependent endometrial proliferation, induce endometrial atrophy and suppress BTB in a menopausal macaque model indicates that progestin antagonists may provide a novel mode of HT.
Slayden
O D
OD
Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA. slaydeno@ohsu.edu
Zelinski
M B
MB
Chwalisz
K
K
Hess-Stumpp
H
H
Brenner
R M
RM
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004717:Endometrium / Q000187:drug effects* / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood; D004963:Estrenes / Q000008:administration & dosage*; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects; D006727:Hormone Antagonists / Q000008:administration & dosage*; D008253:Macaca mulatta; D008321:Mammary Glands, Animal / Q000187:drug effects; D008593:Menopause / Q000187:drug effects*; D008796:Metrorrhagia / Q000517:prevention & control*; D011374:Progesterone / Q000037:antagonists & inhibitors*; D005466:Fluorocarbons
D004958:Estradiol; D004963:Estrenes; D006727:Hormone Antagonists; D011374:Progesterone; C419162:lonaprisan; D005466:Fluorocarbons