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

Ov Slayden, Mary Zelinski, K. Chwalisz, H. Hess-Stumpp, R. M. Brenner

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)3081-3090
    Number of pages10
    JournalHuman Reproduction
    Volume21
    Issue number12
    DOIs
    StatePublished - Nov 12 2006

    Fingerprint

    Estrogen Antagonists
    Metrorrhagia
    Macaca
    Progesterone
    Progestins
    Estrogens
    Hormones
    Endometrium
    Atrophy
    Therapeutics
    Oviducts
    Vagina
    Human Mammary Glands
    Macaca mulatta
    Cervix Uteri
    Estradiol
    Epithelium
    Hemorrhage
    Lipids
    Serum

    Keywords

    • Endometrium
    • Estradiol
    • Hormone therapy
    • Progestin antagonist
    • Rhesus macaque

    ASJC Scopus subject areas

    • Physiology
    • Developmental Biology
    • Obstetrics and Gynecology
    • Reproductive Medicine

    Cite this

    Chronic progesterone antagonist-estradiol therapy suppresses breakthrough bleeding and endometrial proliferation in a menopausal macaque model. / Slayden, Ov; Zelinski, Mary; Chwalisz, K.; Hess-Stumpp, H.; Brenner, R. M.

    In: Human Reproduction, Vol. 21, No. 12, 12.11.2006, p. 3081-3090.

    Research output: Contribution to journalArticle

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    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.",
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    AU - Zelinski, Mary

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    AU - Brenner, R. M.

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