Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESCs) 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 midluteal phase and throughout gestation to prevent hemorrhage and accreta. In nonfertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-1 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 the absence of progestational effects on TF, PAI-1, and MMP activities as well as unrestrained angiogenesis rendering the endometrium nonhemostatic, 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 the progestational inhibition of endometrial blood flow promoting local hypoxia and the generation of reactive oxygen species that increase the production of angiogenic factors such as vascular endothelial growth factor in HESCs and angiopoietin 2 in endometrial endothelial cells while decreasing HESC expression of angiostatic, angiopoietin 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.
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Yale-New Haven Hospital, New Haven, CT.
Received September 14, 2010; revised and accepted December 16, 2010.
Funding/support: This work was supported by the National Institutes of Health (2 R01HD33937-15).
Presented at the Premeeting Symposium: "Abnormal Uterine Bleeding: Causality, Diagnosis & Management"; October 6, 2010.
Financial disclosure/conflicts of interest: None reported.
Address correspondence to: Charles J. Lockwood, MD, 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. E-mail: Charles.Lockwood@yale.edu