Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.
Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.
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DOI：
10.1210/jcem.86.6.7606
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发表时间：
2001-06
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影响因子：
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通讯作者：
O. Slayden;N. Nayak;K. A. Burton;K. Chwalisz;S. Cameron;H. Critchley;D. Baird;R. Brenner
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文献类型：
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作者：
O. Slayden;N. Nayak;K. A. Burton;K. Chwalisz;S. Cameron;H. Critchley;D. Baird;R. Brenner
抗孕激素（AP）抑制雌二醇（E（2））刺激的妇女和非人灵长类动物子宫内膜生长，但这种“抗雌激素”作用的机制尚不清楚。在这里，我们报告说，AP上调子宫内膜雄激素受体（AR）在妇女和猕猴，可能发挥作用的抗增殖作用的AP对灵长类动物子宫内膜的影响。此外，由于在文献中的调节和本地化的AR在灵长类动物子宫内膜的差异，我们使用原位杂交和免疫细胞化学来评估激素对子宫内膜AR在妇女和猕猴的影响。在卵巢切除的猕猴中，给予以下治疗，每次4周：单独的E（2），E（2）+孕酮（P），E（2）+米非司酮（RU 486）和E（2）+ P + RU 486。在女性中，在正常月经周期期间和以2 mg/天RU 486治疗30天后或在周期日LH + 2单次口服200 mg RU 486后获得样品。在猕猴中，E（2）显著增加AR表达，高于溶剂对照; E（2）+ RU 486进一步增加结合; E（2）+ P降低AR结合; E（2）+ P + RU 486处理导致AR结合中度升高。在单用E（2）处理的猕猴中，基质AR染色占主导地位，而P处理抑制了这种染色。E（2）+ RU 486或E（2）+ P + RU 486处理可显著上调腺上皮AR染色，增强间质AR信号。原位杂交分析证实了免疫细胞化学数据。类似的诱导腺AR染色和增强的基质AR染色，获得了与ZK 137 - 316和ZK 230 - 211处理的猕猴。在妇女的自然周期中，基质AR染色占主导地位，并且在增殖期比分泌晚期染色更强。RU 486治疗女性在以2 mg/天每天治疗30天或单次口服剂量200 mg后上调腺上皮AR染色。总之，在人类增殖期（或在猕猴中E（2）治疗期间），基质中子宫内膜AR最高，在女性分泌晚期（或在猕猴中E（2）+ P治疗后）最低。在这两个物种中，RU 486诱导腺体中的AR表达并增强基质细胞中的AR表达。由于雄激素可以拮抗E（2）的作用，AP诱导的子宫内膜AR表达增强可能在AP的抗增殖、“抗雌激素”作用中发挥作用。
Antiprogestins (APs) inhibit estradiol (E(2))-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: E(2) alone, E(2) + progesterone (P), E(2) + mifepristone (RU 486), and E(2) + 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, E(2) significantly increased AR expression above vehicle controls; E(2) + RU 486 increased binding further; E(2) + P decreased AR binding; and E(2) + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E(2) alone, stromal AR staining was predominant, and P treatment suppressed that staining. E(2) + RU 486 or E(2) + 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 E(2) treatment in macaques) and lowest during the late secretory phase in women (or after E(2) + 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 E(2) action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.