激素暴露对子宫内膜金属基质蛋白酶及其组织抑制物表达的影响

Influence of Hormone Therapy Exposure on Endometrial Expression of Matrix Metalloproteinase and Their Tissue Inhibitor

目的:了解联合激素替代治疗(HRT)对子宫内膜金属基质蛋白酶(MMP)9及其组织抑制物(TIMP)1表达的影响,探讨其表达与HRT妇女不规则子宫出血之间的关系。方法:宫腔镜活组织检查提取57例HRT合并不规则子宫出血妇女出血期间和出血停止后3月子宫内膜(A1,A2组),以同期HRT但不合并出血的绝经期妇女20例(B组)和未接受HRT绝经期妇女20例(C组)作对照。免疫组织化学标记观察MMP-9、TIMP-1蛋白质阳性表达及其分布。结果:不规则出血妇女中MMP-9低水平表达,与其他各组之间没有显著性差异,但其阳性细胞更多地分布于蜕膜化的基质细胞浆中。暴露于激素治疗妇女不规则子宫出血发生率显著增高,子宫内膜中TIMP-1表达显著高于未接受HRT的绝经期妇女。HRT伴出血妇女子宫内膜中TIMP-1表达均显著性增加,同一个体在出血期间的TIMP-1表达也显著高于出血停止后3月(χ2=5.643,P=0.003)。接受HRT但从未出现不规则出血妇女子宫内膜TIMP-1表达也明显高于未接受HRT妇女(χ2=4.411,P=0.036)。结论:HRT伴不规则出血妇女子宫内膜TIMP-1表达显著增加,与MMP-9之间平衡破坏,与正常月经出血表达方式完全不同。

Objective： To determine how hormone replacement therapy （HRT）exposure alters endometrial production of matrix metalloproteinase（MMP） - 9 and their tissue inhibitor of metalloproteinase（TIMP） - 1 and to assesse the relationship between MMP - 9, TIMP - 1 production and irregular uterine bleeding patterns in HRT users. Methods：Endometrial biopsies had been harvested from 57 postmenopausal women taking combined HRT during（group At）and outside（group A2）irregular bleeding by hysteroscope. A comparative observation was conducted with cohort of 20 postmenopausal women not taking HRT（group B）and 20 postmenopausal women taking HRT but not companied with IUB （group C）. Expression and immunolocalization of MMP- 9, TIMP - 1 had been detected by immunohistochemistry labelling respectively. Results ：Tenellous increase of MMP- 9 localization had been seen in association with irregular bleeding, but these did not reach statistical significance. However, the most prominent localization of MMP - 9 was seen in decidualized stromal cells. Incidence of irregular uterine bleeding was statistically augmented in HRT users. There was a statistically significant relationship between endometrial production of TIMP - 1 and irregular bleeding in HRT users and was significantly increased in those with irregular bleeding compared with those with amenorrhea. The most prominent TIMP - 1 production were seen in biopsies obtained during a bleeding episode rather than outside bleeding episode（χ^2 = 5.643, P = 0.003）.There was also a significant trend toward elevated endometrial TIMP - 1 production had been noticed in biopsies taken from subjects without a history of irregular bleeding compared with those menopause wemen with no HRT（χ^2 = 4.411,P = 0. 036）.Conclusion： Our observation suggests that the endometrial balance between MMP- 9 and TIMP- 1 contribute to vascular breakdown with HRT but by a different mechanism than that seen in normal menstruation breakthrough bleeding.