title: Dilated thin-walled blood and lymphatic vessels in human endometrium: a potential role for VEGF-D in progestin-induced break-through bleeding.
abstract: Progestins provide safe, effective and cheap options for contraception as well as the treatment of a variety of gynaecological disorders. Episodes of irregular endometrial bleeding or breakthrough bleeding (BTB) are a major unwanted side effect of progestin treatment, such that BTB is the leading cause for discontinued use of an otherwise effective and popular medication. The cellular mechanisms leading to BTB are poorly understood. In this study, we make the novel finding that the large, dilated, thin walled vessels characteristic of human progestin-treated endometrium include both blood and lymphatic vessels. Increased blood and lymphatic vessel diameter are features of VEGF-D action in other tissues and we show by immunolocalisation and Western blotting that stromal cell decidualisation results in a significant increase in VEGF-D protein production, particularly of the proteolytically processed 21 kD form. Using a NOD/scid mouse model with xenografted human endometrium we were able to show that progestin treatment causes decidualisation, VEGF-D production and endometrial vessel dilation. Our results lead to a novel hypothesis to explain BTB, with stromal cell decidualisation rather than progestin treatment per se being the proposed causative event, and VEGF-D being the proposed effector agent.
authors.affiliation: Centre for Women's Health Research, Department of Obstetrics and Gynaecology and Monash Institute for Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Donoghue
authors.forename: C Jay
authors.initials: CJ
authors.lastname: McGavigan
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Lederman
authors.forename: Leonie M
authors.initials: LM
authors.lastname: Cann
authors.forename: Lulu
authors.initials: L
authors.lastname: Fu
authors.forename: Eva
authors.initials: E
authors.lastname: Dimitriadis
authors.forename: Jane E
authors.initials: JE
authors.lastname: Girling
authors.forename: Peter A W
authors.initials: PA
authors.lastname: Rogers
mesh_terms: D000328:Adult; D000818:Animals; D003656:Decidua / Q000187:drug effects / Q000473:pathology; D004717:Endometrium / Q000098:blood supply* / Q000473:pathology*; D005260:Female; D006470:Hemorrhage / Q000378:metabolism*; D006801:Humans; D016912:Levonorgestrel / Q000009:adverse effects / Q000627:therapeutic use; D042601:Lymphatic Vessels / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D011372:Progestins / Q000009:adverse effects / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: D011372:Progestins; D042643:Vascular Endothelial Growth Factor D; D016912:Levonorgestrel