Progestins provide safe, effective and cheap options for contraception as well as the treatment of a variety of\r\ngynaecological disorders. Episodes of irregular endometrial bleeding or breakthrough bleeding (BTB) are a major unwanted\r\nside effect of progestin treatment, such that BTB is the leading cause for discontinued use of an otherwise effective and\r\npopular medication. The cellular mechanisms leading to BTB are poorly understood. In this study, we make the novel\r\nfinding that the large, dilated, thin walled vessels characteristic of human progestin-treated endometrium include both\r\nblood and lymphatic vessels. Increased blood and lymphatic vessel diameter are features of VEGF-D action in other tissues\r\nand we show by immunolocalisation and Western blotting that stromal cell decidualisation results in a significant increase in\r\nVEGF-D protein production, particularly of the proteolytically processed 21 kD form. Using a NOD/scid mouse model with\r\nxenografted human endometrium we were able to show that progestin treatment causes decidualisation, VEGF-D\r\nproduction and endometrial vessel dilation. Our results lead to a novel hypothesis to explain BTB, with stromal cell\r\ndecidualisation rather than progestin treatment per se being the proposed causative event, and VEGF-D being the\r\nproposed effector agent
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