Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
J Clin Endocrinol Metab. 2011 Feb;96(2):412-21. doi: 10.1210/jc.2010-1450. Epub 2010 Nov 17.
Uterine leiomyomas occur in 30-70% of reproductive-age women. Leiomyoma reduce implantation, increase miscarriage risk, and increase menstrual bleeding. We hypothesized that endometrial defects induced by leiomyoma result in menorrhagia and reproductive dysfunction.
We evaluated the effect of leiomyoma on endometrial gene expression essential for implantation and hemostasis both in vivo and in primary endometrial stromal cells (ESC).
We conducted a case control and in vitro study at a university medical center.
The study included 24 subjects with or without leiomyoma. INTERVENTION/MAIN OUTCOME MEASURED: Endometrium, myometrium, leiomyoma, and ESC were obtained. Immunohistochemistry was used to evaluate TGF-β3, bone morphogenetic protein (BMP) receptors (BMPRs), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin in vivo. BMP-2 secretion was assessed by ELISA. ESC were treated with recombinant human (rh) BMP-2 or rhTGF-β3. Expression of HOXA10, LIF, BMPRs, antithrombin III (ATIII), thrombomodulin, and PAI-1 was assessed by quantitative RT-PCR.
ESC from controls secreted more BMP-2 than those from women with leiomyoma. HOXA10 and LIF expression increased after rhBMP-2 treatment of normal but not leiomyoma-associated ESC. In vivo leiomyoma-associated endometrium expressed lower levels of BMPR 1A, 1B, and 2 than controls. Leiomyoma expressed high levels of TGF-β3; TGF-β3 treatment of ESC reduced expression of BMPRs. Similarly, leiomyoma-associated endometrium expressed less PAI-1 and thrombomodulin in vivo. In ESC, TGF-β3 reduced expression of PAI-1, ATIII, and thrombomodulin.
Leiomyoma-secreted TGF-β3 induces BMP-2 resistance in endometrium by down-regulation of BMPR-2, likely causing defective endometrial decidualization. TGF-β3 also reduces expression of PAI-1, ATIII, and thrombomodulin in endometrium, likely contributing to menorrhagia. A single molecular signal targeting endometrium may mediate both leiomyoma-induced infertility and bleeding.
子宫肌瘤发生于 30-70%的育龄期妇女。子宫肌瘤会降低着床率，增加流产风险，并增加月经过多。我们假设子宫肌瘤引起的子宫内膜缺陷导致月经过多和生殖功能障碍。
我们评估了子宫肌瘤对着床和止血所必需的子宫内膜基因表达的影响，分别在体内和原发性子宫内膜基质细胞（ESC）中进行了评估。
我们在一所大学医学中心进行了病例对照和体外研究。
研究纳入了 24 名有或无子宫肌瘤的患者。
干预/主要观察指标：获取子宫内膜、子宫肌层、子宫肌瘤和 ESC。免疫组化用于评估体内 TGF-β3、骨形态发生蛋白（BMP）受体（BMPR）、纤溶酶原激活物抑制剂 1（PAI-1）和血栓调节蛋白。通过 ELISA 评估 BMP-2 的分泌。用重组人（rh）BMP-2 或 rhTGF-β3 处理 ESC。通过定量 RT-PCR 评估 HOXA10、LIF、BMPR、抗凝血酶 III（ATIII）、血栓调节蛋白和 PAI-1 的表达。
与对照组相比，子宫肌瘤患者的 ESC 分泌的 BMP-2 较少。rhBMP-2 处理正常 ESC 后 HOXA10 和 LIF 的表达增加，但处理子宫肌瘤相关 ESC 后无此改变。体内子宫肌瘤相关子宫内膜表达的 BMPR1A、1B 和 2 低于对照组。子宫肌瘤表达高水平的 TGF-β3；TGF-β3 处理 ESC 可降低 BMPR 的表达。同样，体内子宫肌瘤相关子宫内膜表达的 PAI-1 和血栓调节蛋白较少。在 ESC 中，TGF-β3 降低了 PAI-1、ATIII 和血栓调节蛋白的表达。
子宫肌瘤分泌的 TGF-β3 通过下调 BMPR-2 诱导子宫内膜中 BMP-2 抵抗，可能导致子宫内膜蜕膜化缺陷。TGF-β3 还降低了子宫内膜中 PAI-1、ATIII 和血栓调节蛋白的表达，可能导致月经过多。单一的靶向子宫内膜的分子信号可能介导子宫肌瘤引起的不孕和出血。
