Hague S, MacKenzie I Z, Bicknell R, Rees Margaret C P
Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Hum Reprod. 2002 Mar;17(3):786-93. doi: 10.1093/humrep/17.3.786.
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.
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.
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.
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.
孕激素在临床上用于避孕、控制月经过多以及预防雌激素引起的子宫内膜增生。仅使用孕激素的避孕方法的一个重要问题是突破性出血的诱导。
使用两种方法研究了不同孕激素对血管生成的影响。小鼠海绵血管生成试验采用直接递送治疗剂量范围的药物。还研究了与未暴露的绝经前子宫内膜相比，长期宫内左炔诺孕酮暴露的血管生成反应。
在小鼠海绵试验中，炔诺酮和醋酸甲羟孕酮在所有剂量下均刺激血管生成，但左炔诺孕酮和诺美孕酮呈剂量依赖性。左炔诺孕酮在100 pmol/l至10 nmol/l的剂量范围内刺激血管生成，但在更高剂量下则不然。相比之下，醋酸诺美孕酮在高剂量而非低剂量下刺激血管生成。与绝经前对照组相比，左炔诺孕酮暴露的子宫内膜中酸性和碱性成纤维细胞生长因子、胸苷磷酸化酶、血管内皮生长因子和肾上腺髓质素的表达未改变。左炔诺孕酮暴露的子宫内膜中血管密度增加但内皮细胞增殖减少。
这是关于不同剂量的多种孕激素对血管生成直接影响的首次报告；结果表明血管靶向可能是处理孕激素引起的异常出血的有效策略。
