Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
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DOI：
10.1093/humrep/dew359
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Critchley HO
中科院分区：
文献类型：
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作者：
Whitaker LH;Murray AA;Matthews R;Shaw G;Williams AR;Saunders PT;Critchley HO
选择性孕激素受体调节剂（SPRM）醋酸乌利司他（UPA）对子宫肌瘤妇女子宫内膜的影响是什么？UPA的管理改变了性类固醇受体和孕酮调节基因的表达，并与低水平的腺和基质细胞增殖。所有SPRM类成员的管理导致PAEC（孕酮受体调节剂相关的子宫内膜变化）。目前缺乏SPRM UPA给药对子宫内膜性类固醇受体表达、孕酮（P）调节基因和细胞增殖影响的数据。通过组织学和分子分析进行观察性研究，以描述UPA治疗对子宫内膜的影响。子宫内膜样本（n = 9）在子宫切除术时收集自年龄39至49岁的子宫肌瘤妇女，用UPA（口服5 mg，每日一次）治疗9-12周。来自患有纤维瘤的38-52岁女性的对照增殖（n = 9）和分泌（n = 9）子宫内膜来自机构组织档案。研究环境是一所大学研究所。在获得机构伦理批准和书面知情同意书的情况下收集子宫内膜活检。用qRT-PCR定量蜕膜化子宫内膜中类固醇受体、P调节基因和因子编码的mRNA浓度。免疫组化法检测孕激素（PR）、孕激素受体（PRB）、雄激素受体（AR）、雌激素受体（ERα）及FOXO 1、HAND 2、HOXA 10、PTEN同源基因的表达。使用Ki 67客观定量子宫内膜腺细胞和基质细胞增殖。UPA诱导的子宫内膜组织形态学变化与PAEC一致。与增殖期或分泌期样品相比，检测到PR和AR表达模式的显著变化。与分泌期样本相比，IGFBP-1、FOXO 1、IL-15、HAND 2、IHH和HOXA 10编码的mRNA表达模式发生显著变化，与子宫内膜中的低激动剂活性一致。FOXM 1是一种参与细胞周期进程的转录因子，其编码的mRNA在UPA处理的样品中表达较低。细胞增殖（Ki 67阳性细胞核）与UPA治疗的妇女的样本相比，在增殖阶段较低。N/A.对少数特征良好的患者进行了深入研究。SPRM、UPA给药对症状控制的形态学、分子和细胞变化的影响仍有待确定。P在子宫内膜功能中起关键作用。P-作用是通过与PR的相互作用介导的。这些数据为SPRM类化合物的进一步发展提供了支持，作为月经大出血的有效长期药物治疗。H. O. D.C.从Bayer Pharma Ag获得实验室耗材和工作人员的临床研究支持，并为Bayer Pharma Ag、PregLem SA、Gedeon Richter、Vifor Pharma UK Ltd、AbbVie Inc.提供咨询意见（无个人报酬）; A.R.W.W.已收到拜耳、Gedeon Richter、Preglem SA、HRA Pharma、L.H.R.W.上午，R.M.，G.S.和PTK没有利益冲突。研究部分由以下机构资助：医学研究理事会（G1002033; G1100356/1; MR/N 022556/1）;国家健康研究所（12/206/520）和TENOVUS苏格兰。
What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9–12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38–52 with fibroids were derived from institutional tissue archives. Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. N/A. A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.