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首页> 美国卫生研究院文献>other >Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding
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Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding

机译：孕激素上调人子宫内膜基质细胞中FKBP51的表达以诱导功能性孕酮和糖皮质激素的退出：避孕相关异常子宫出血的影响。

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Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription. The resultant PR and/or GR-mediated functional withdrawal may contribute to associated endometrial inflammation, aberrant angiogenesis, and bleeding.
机译：仅使用长效孕激素避孕药（LAPC）提供了一种离散且高效的计划生育方法。子宫异常出血（AUB）是LAPC停用的主要副作用，并引起中断。经LAPC治疗的妇女的子宫内膜显示异常增大，血管脆弱，子宫内膜血流量减少和氧化应激。为了了解潜在的AUB机制，我们建议在人子宫内膜基质细胞（HESCs）中识别LAPC调节的独特基因簇。通过定量实时（q）-PCR和免疫印迹分析从用雌二醇（E2）或E2 +甲羟孕酮乙酸酯（MPA）或E2 +乙孕酮（ETO）或E2 +孕酮（P4）处理7天的培养的HESC中分离的蛋白质和RNA。确定HSCORES进行MPA（DMPA）治疗的妇女和用安慰剂或E2或MPA或E2 + MPA治疗21天的去卵巢豚鼠（GPs）免疫前后配对的子宫内膜免疫染色。在HESC中，全基因组分析确定了由所有三个孕激素调节的67个基因组，而有235个基因组由E2 + ETO和E2 + MPA调节，但不受E2 + P4调节。独创性途径分析确定了糖皮质激素受体（GR）激活是235 MPA和ETO特异性基因的上游调节子之一。其中，微阵列结果显示MPA和ETO均可显着增强FKBP51（PR / GR转录活性的阻遏物）。 q-PCR和免疫印迹分析证实了微阵列结果。在DMPA后给药的妇女与DMPA给药前的妇女的子宫内膜中，FKBP51表达在子宫内膜间质和腺细胞中显着增加。在GP中，与安慰剂和E2给药组相比，E2 + MPA或MPA在子宫内膜基质细胞和腺细胞中显着提高了FKBP51免疫反应性。施用MPA或ETO可激活GR信号传导并增加子宫内膜FKBP51表达，这可能是通过抑制PR和GR介导的转录而引起AUB的机制之一。最终的PR和/或GR介导的功能性撤退可能导致相关的子宫内膜炎症，异常的血管生成和出血。

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