Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, Room 314 FMB, PO Box 208063, New Haven, CT 06520-8063, USA.
Menopause. 2011 Apr;18(4):408-11. doi: 10.1097/GME.0b013e31820bf288.
Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESC) during the progesterone-dominated luteal phase. Progesterone also augments a second HESC hemostatic factor, plasminogen activator inhibitor-1 (PAI-1). In contrast, progestins inhibit HESC matrix metalloproteinase (MMP)-1, 3 and 9 expression to stabilize endometrial stromal and vascular extracellular matrix. Through these mechanisms decidualized endometrium is rendered both hemostatic and resistant to excess trophoblast invasion in the mid-luteal phase and throughout gestation to prevent hemorrhage and accreta. In non-fertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-expression and increased MMP activity and inflammatory cytokine production promoting the controlled hemorrhage of menstruation and related tissue sloughing. In contrast to these well ordered biochemical processes, unpredictable endometrial bleeding associated with anovulation reflects absence of progestational effects on TF, PAI-1 and MMP activity as well as unrestrained angiogenesis rendering the endometrium non-hemostatic, proteolytic and highly vascular. Abnormal bleeding associated with long-term progestin-only contraceptives results not from impaired hemostasis but from unrestrained angiogenesis leading to large fragile endometrial vessels. This abnormal angiogenesis reflects progestational inhibition of endometrial blood flow promoting local hypoxia and generation of reactive oxygen species that increase production of angiogenic factors such as vascular endothelial growth factor (VEGF) in HESCs and Angiopoietin-2 (Ang-2) in endometrial endothelial cells while decreasing HESC expression of angiostatic, Ang-1. The resulting vessel fragility promotes bleeding. Aberrant angiogenesis also underlies abnormal bleeding associated with myomas and endometrial polyps however there are gaps in our understanding of this pathology.
组织因子（TF）的表达，是凝血的主要启动子，在孕激素主导的黄体期，在分化的人子宫内膜基质细胞（HESC）中增强。孕激素还增强了第二种 HESC 止血因子，纤溶酶原激活物抑制剂-1（PAI-1）。相比之下，孕激素抑制 HESC 基质金属蛋白酶（MMP）-1、3 和 9 的表达，以稳定子宫内膜基质和血管细胞外基质。通过这些机制，分化的子宫内膜既止血，又能抵抗中黄体期和整个妊娠期间过多的滋养层侵入，以防止出血和粘连。在非生育周期中，孕激素撤退导致 HESC TF 和 PAI-1 表达减少，MMP 活性和炎症细胞因子产生增加，促进月经和相关组织脱落的控制性出血。与这些有序的生化过程相反，与无排卵相关的不可预测的子宫内膜出血反映了孕激素对 TF、PAI-1 和 MMP 活性的作用缺失，以及不受限制的血管生成，使子宫内膜失去止血、蛋白水解和高度血管化的功能。与长期单独孕激素避孕药相关的异常出血不是由于止血功能受损，而是由于不受限制的血管生成导致脆弱的大子宫内膜血管。这种异常的血管生成反映了孕激素抑制子宫内膜血流，促进局部缺氧和活性氧的产生，增加了血管生成因子的产生，如 HESCs 中的血管内皮生长因子（VEGF）和子宫内膜内皮细胞中的血管生成素-2（Ang-2），同时减少了 HESC 对血管生成抑制因子、Ang-1 的表达。由此产生的血管脆弱性促进了出血。异常的血管生成也是与肌瘤和子宫内膜息肉相关的异常出血的基础，但我们对这种病理学的理解还存在差距。
