In-vivo angiogenesis and progestogens.
BACKGROUND
Progestogens are used clinically for contraception, to control excessive menstrual bleeding, and to prevent estrogen-induced endometrial hyperplasia. A significant problem with progestogen-only methods of contraception is the induction of breakthrough bleeding.


METHODS
The effects of different progestogens on angiogenesis were examined using two approaches. The mouse sponge angiogenesis assay employed direct delivery of the dose ranges achieved therapeutically. The angiogenic response to long-term intrauterine levonorgestrel exposure, compared with unexposed premenopausal endometrium, was also studied.


RESULTS
In the mouse sponge assay, norethisterone and medroxyprogesterone acetate stimulated angiogenesis at all doses, but was dose-dependent for levonorgestrel and nomegestrol. Levonorgestrel stimulated angiogenesis in the dose range 100 pmol/l to 10 nmol/l, but not at higher doses. In contrast, nomegestrol acetate stimulated angiogenesis at high, but not low, doses. Expression of acidic and basic fibroblast growth factors, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin were unaltered in levonorgestrel-exposed endometrium compared with premenopausal controls. Vascular density was increased but endothelial proliferation reduced in levonorgestrel-exposed endometrium.


CONCLUSIONS
This is the first report of the direct effects of a wide range of doses of different progestogens on angiogenesis; results suggest that vascular targeting may be an effective strategy to deal with progestogen-induced abnormal bleeding.
Hague
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Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
MacKenzie
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Bicknell
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Rees
Margaret C P
MC
D000282:Administration, Intravaginal; D053607:Adrenomedullin; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003278:Contraceptives, Oral, Hormonal / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000378:metabolism; D017697:Premenopause / Q000502:physiology; D011372:Progestins / Q000008:administration & dosage / Q000009:adverse effects*; D013939:Thymidine Phosphorylase / Q000378:metabolism
D003278:Contraceptives, Oral, Hormonal; D006133:Growth Substances; D010455:Peptides; D011372:Progestins; D053607:Adrenomedullin; D013939:Thymidine Phosphorylase