氯米酚治疗后子宫内膜增殖不良与雌激素作用改变有关。
Poor Endometrial Proliferation After Clomiphene is Associated With Altered Estrogen Action.
机构信息
Department of Obstetrics & Gynecology, Division of Reproductive Endocrinology & Infertility, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
出版信息
J Clin Endocrinol Metab. 2021 Aug 18;106(9):2547-2565. doi: 10.1210/clinem/dgab381.
CONTEXT
Suboptimal endometrial thickening is associated with lower pregnancy rates and occurs in some infertile women treated with clomiphene.
OBJECTIVE
To examine cellular and molecular differences in the endometrium of women with suboptimal vs optimal endometrial thickening following clomiphene.
METHODS
Translational prospective cohort study from 2018 to 2020 at a university-affiliated clinic. Reproductive age women with unexplained infertility treated with 100 mg of clomiphene on cycle days 3 to 7 who developed optimal (≥8mm; n = 6, controls) or suboptimal (<6mm; n = 7, subjects) endometrial thickness underwent preovulatory blood and endometrial sampling. The main outcome measures were endometrial tissue architecture, abundance and location of specific proteins, RNA expression, and estrogen receptor (ER) α binding.
RESULTS
The endometrium of suboptimal subjects compared with optimal controls was characterized by a reduced volume of glandular epithelium (16% vs 24%, P = .01), decreased immunostaining of markers of proliferation (PCNA, ki67) and angiogenesis (PECAM-1), increased immunostaining of pan-leukocyte marker CD45 and ERβ, but decreased ERα immunostaining (all P < .05). RNA-seq identified 398 differentially expressed genes between groups. Pathway analysis of differentially expressed genes indicated reduced proliferation (Z-score = -2.2, P < .01), decreased angiogenesis (Z-score = -2.87, P < .001), increased inflammation (Z-score = +2.2, P < .01), and ERβ activation (Z-score = +1.6, P < .001) in suboptimal subjects. ChIP-seq identified 6 genes bound by ERα that were differentially expressed between groups (P < .01), some of which may play a role in implantation.
CONCLUSION
Women with suboptimal endometrial thickness after clomiphene exhibit aberrant ER expression patterns, architectural changes, and altered gene and protein expression suggesting reduced proliferation and angiogenesis in the setting of increased inflammation.
背景
子宫内膜厚度不理想与妊娠率降低有关，并且在一些接受克罗米酚治疗的不孕女性中会出现这种情况。
目的
研究克罗米酚治疗后子宫内膜厚度不理想和理想的女性的子宫内膜中细胞和分子的差异。
方法
这是一项 2018 年至 2020 年在大学附属医院进行的转化前瞻性队列研究。对接受 100mg 克罗米酚治疗的不明原因不孕的育龄妇女进行研究，克罗米酚在周期第 3 天至第 7 天服用，这些妇女的子宫内膜厚度达到最佳（≥8mm；n=6，对照组）或不理想（<6mm；n=7，观察组）。进行排卵前血液和子宫内膜取样。主要观察指标为子宫内膜组织形态、特定蛋白的丰度和位置、RNA 表达和雌激素受体（ER）α 结合。
结果
与对照组相比，观察组的子宫内膜表现为腺体上皮体积减少（16%比 24%，P=0.01），增殖标志物（PCNA、ki67）和血管生成标志物（PECAM-1）的免疫染色减少，白细胞标志物 CD45 和 ERβ 的免疫染色增加，但 ERα 免疫染色减少（均 P<0.05）。RNA-seq 鉴定出两组间差异表达基因 398 个。差异表达基因的通路分析表明，观察组增殖减少（Z 评分=-2.2，P<0.01）、血管生成减少（Z 评分=-2.87，P<0.001）、炎症增加（Z 评分=+2.2，P<0.01）和 ERβ 激活（Z 评分=+1.6，P<0.001）。ChIP-seq 鉴定出 6 个被 ERα 结合的差异表达基因（P<0.01），其中一些可能在着床中发挥作用。
结论
克罗米酚治疗后子宫内膜厚度不理想的女性表现出异常的 ER 表达模式、结构变化以及基因和蛋白表达改变，提示在炎症增加的情况下增殖和血管生成减少。
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