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Hum. Reprod. Advance Access published online on August 26, 2006
Human Reproduction, doi:10.1093/humrep/del282
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received April 10, 2006
Revised May 17, 2006
Accepted May 26, 2006

Article

Chronic progesterone antagonist-estradiol therapy suppresses breakthrough bleeding and endometrial proliferation in a menopausal macaque model

O.D. Slayden 1 *, M.B. Zelinski 1, K. Chwalisz 2, H. Hess-Stumpp 3, and R.M. Brenner 1

1 Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
2 TAP Pharmaceutical Products Inc., Lake Forest, IL, USA
3 Schering AG, Berlin, Germany

* To whom correspondence should be addressed.
O.D. Slayden, E-mail: slaydeno{at}ohsu.edu


  Abstract

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. METHOD: Ovariectomized rhesus macaques were treated for 5 months with either estradiol (E2) alone, E2 + progesterone (two doses) or E2 + ZK (0.01, 0.05 or 0.25 mg/kg). RESULTS: In the E2 + progesterone groups, progesterone suppressed endometrial proliferation and induced a thick decidualized endometrium. In the E2 + 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 E2 + ZK groups (17 days of spotting, all groups) than in the E2 and E2 + progesterone groups (155 bleeding days, all groups). ZK suppressed E2 effects in the cervix, but not in the vagina, oviduct or mammary glands. All serum chemistry and lipid profiles were normal. CONCLUSION: 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.

Keywords: endometrium/estradiol/hormone therapy/progestin antagonist/rhesus macaque.
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