Endothelial cell dysfunction following prolonged activation of progesterone receptor

Progestin-only contraceptives are associated with breakthrough bleeding in up to 50% of users. The causes of blood vessel rupture are not well understood. Here we report that both normal and Norplant®-exposed endothelium express progesterone receptor. Experiments performed in vitro on endothelial cells isolated from human endometrium revealed that long-term progesterone exposure leads to suppression of endothelial cell proliferation, inhibition of migration and alteration in the profile of extra-cellular matrix proteins secreted by human endometrial endothelial cells. In addition, we detected increased levels of matrix metalloproteinase-9 in endothelial cultures treated with progesterone. The effect of progesterone on the cell cycle, along with the increased amounts of matrix-degrading enzymes, could account for breakdown of basement membrane components, vascular fragility and consequent vessel rupture leading to breakthrough endometrial bleeding.