Human Reproduction, Vol. 17, No. 3, 786-793,
March 2002
© 2002 European Society of Human Reproduction and Embryology
In-vivo angiogenesis and progestogens
1 Nuffield Department of Obstetrics and Gynaecology and 2 Molecular Angiogenesis Laboratory, Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
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.
Key words: angiogenesis/endometrium/endothelial proliferation/progestogens/vascular density
3 To whom correspondence should be addressed at: Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: margaret.rees{at}obs-gyn.ox.ac.uk
Submitted on July 5, 2001; resubmitted on September 27, 2001
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