Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium

Ov Slayden, Nihar R. Nayak, Kevin A. Burton, Kristof Chwalisz, Sharon T. Cameron, Hilary O D Critchley, David T. Baird, Robert M. Brenner

    Research output: Contribution to journalArticle

    107 Citations (Scopus)

    Abstract

    Antiprogestins (APs) inhibit estradiol (E2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E2 alone, E2 + progesterone (P), E2 + mifepristone (RU 486), and E2 + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E2 significantly increased AR expression above vehicle controls; E2 + RU 486 increased binding further; E2 + P decreased AR binding; and E2 + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E2 alone, stromal AR staining was predominant, and P treatment suppressed that staining. E2 + RU 486 or E2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E2 treatment in macaques) and lowest during the late secretory phase in women (or after E2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E2 action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.

    Original languageEnglish (US)
    Pages (from-to)2668-2679
    Number of pages12
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume86
    Issue number6
    DOIs
    StatePublished - 2001

    Fingerprint

    Androgen Receptor Antagonists
    Androgen Receptors
    Endometrium
    Macaca mulatta
    Progesterone
    Mifepristone
    Macaca
    Staining and Labeling
    Primates
    Therapeutics
    In Situ Hybridization
    Up-Regulation
    Immunohistochemistry

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium. / Slayden, Ov; Nayak, Nihar R.; Burton, Kevin A.; Chwalisz, Kristof; Cameron, Sharon T.; Critchley, Hilary O D; Baird, David T.; Brenner, Robert M.

    In: Journal of Clinical Endocrinology and Metabolism, Vol. 86, No. 6, 2001, p. 2668-2679.

    Research output: Contribution to journalArticle

    Slayden, O, Nayak, NR, Burton, KA, Chwalisz, K, Cameron, ST, Critchley, HOD, Baird, DT & Brenner, RM 2001, 'Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium', Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 6, pp. 2668-2679. https://doi.org/10.1210/jc.86.6.2668
    Slayden, Ov ; Nayak, Nihar R. ; Burton, Kevin A. ; Chwalisz, Kristof ; Cameron, Sharon T. ; Critchley, Hilary O D ; Baird, David T. ; Brenner, Robert M. / Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium. In: Journal of Clinical Endocrinology and Metabolism. 2001 ; Vol. 86, No. 6. pp. 2668-2679.
    @article{f9bcbd186be741a28e817200d9003a90,
    title = "Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium",
    abstract = "Antiprogestins (APs) inhibit estradiol (E2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this {"}antiestrogenic{"} action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E2 alone, E2 + progesterone (P), E2 + mifepristone (RU 486), and E2 + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E2 significantly increased AR expression above vehicle controls; E2 + RU 486 increased binding further; E2 + P decreased AR binding; and E2 + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E2 alone, stromal AR staining was predominant, and P treatment suppressed that staining. E2 + RU 486 or E2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E2 treatment in macaques) and lowest during the late secretory phase in women (or after E2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E2 action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, {"}antiestrogenic{"} effects of APs in primates.",
    author = "Ov Slayden and Nayak, {Nihar R.} and Burton, {Kevin A.} and Kristof Chwalisz and Cameron, {Sharon T.} and Critchley, {Hilary O D} and Baird, {David T.} and Brenner, {Robert M.}",
    year = "2001",
    doi = "10.1210/jc.86.6.2668",
    language = "English (US)",
    volume = "86",
    pages = "2668--2679",
    journal = "Journal of Clinical Endocrinology and Metabolism",
    issn = "0021-972X",
    publisher = "The Endocrine Society",
    number = "6",

    }

    TY - JOUR

    T1 - Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium

    AU - Slayden, Ov

    AU - Nayak, Nihar R.

    AU - Burton, Kevin A.

    AU - Chwalisz, Kristof

    AU - Cameron, Sharon T.

    AU - Critchley, Hilary O D

    AU - Baird, David T.

    AU - Brenner, Robert M.

    PY - 2001

    Y1 - 2001

    N2 - Antiprogestins (APs) inhibit estradiol (E2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E2 alone, E2 + progesterone (P), E2 + mifepristone (RU 486), and E2 + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E2 significantly increased AR expression above vehicle controls; E2 + RU 486 increased binding further; E2 + P decreased AR binding; and E2 + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E2 alone, stromal AR staining was predominant, and P treatment suppressed that staining. E2 + RU 486 or E2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E2 treatment in macaques) and lowest during the late secretory phase in women (or after E2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E2 action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.

    AB - Antiprogestins (APs) inhibit estradiol (E2)-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E2 alone, E2 + progesterone (P), E2 + mifepristone (RU 486), and E2 + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E2 significantly increased AR expression above vehicle controls; E2 + RU 486 increased binding further; E2 + P decreased AR binding; and E2 + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E2 alone, stromal AR staining was predominant, and P treatment suppressed that staining. E2 + RU 486 or E2 + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E2 treatment in macaques) and lowest during the late secretory phase in women (or after E2 + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E2 action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.

    UR - http://www.scopus.com/inward/record.url?scp=0034967057&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=0034967057&partnerID=8YFLogxK

    U2 - 10.1210/jc.86.6.2668

    DO - 10.1210/jc.86.6.2668

    M3 - Article

    C2 - 11397870

    AN - SCOPUS:0034967057

    VL - 86

    SP - 2668

    EP - 2679

    JO - Journal of Clinical Endocrinology and Metabolism

    JF - Journal of Clinical Endocrinology and Metabolism

    SN - 0021-972X

    IS - 6

    ER -