Fundacion IVI-Instituto Universitario IVI, INCLIVA, Universidad de Valencia, C/Guadassuar 1 Bajo, 46015 Valencia, Spain.
Reproduction. 2011 Nov;142(5):745-55. doi: 10.1530/REP-11-0223. Epub 2011 Aug 23.
Implantation of a retrogradely shed endometrium during menstruation requires an adequate blood supply, which allows the growth of endometriotic lesions. This suggests that the development of endometriosis can be impaired by inhibiting angiogenesis. The growth of endometriotic foci is impaired by commercial oncological antiangiogenic drugs used to block vascular endothelial growth factor (VEGF) signaling. The dopamine agonist cabergoline (Cb2) inhibits the growth of established endometriosis lesions by exerting antiangiogenic effects through VEGFR2 inactivation. However, the use of ergot-derived Cb2 is associated with an increased incidence of cardiac valve regurgitation. To evaluate the potential usage of non-ergot-derived dopamine agonists for the treatment of human endometriosis, we compared the efficacy of quinagolide with that of Cb2 in preventing angiogenesis and vascularization in a heterologous mouse model of endometriosis. Nude mice whose peritoneum had been implanted with eutopic human endometrial fragments were treated with vehicle, 50 μg/kg per day oral Cb2, or 50 or 200 μg/kg per day quinagolide during a 14-day period. At the end of the treatment period, the implants were excised in order to assess lesion size, cell proliferation, degree of vascularization, and angiogenic gene expression. Neoangiogenesis was inhibited and the size of active endometriotic lesions, cellular proliferation index, and angiogenic gene expression were significantly reduced by both dopamine agonists when compared with the placebo. Given that Cb2 and quinagolide were equally effective in inhibiting angiogenesis and reducing lesion size, these experiments provide the rationale for pilot studies to explore the use of non-ergot-derived dopamine agonists for the treatment of endometriosis in humans.
在月经期间，逆行脱落的子宫内膜的植入需要充足的血液供应，这允许子宫内膜异位症病变的生长。这表明，通过抑制血管生成，可以损害子宫内膜异位症的发展。商业肿瘤血管生成抑制剂，用于阻断血管内皮生长因子（VEGF）信号，可损害子宫内膜异位症病灶的生长。多巴胺激动剂卡麦角林（Cb2）通过 VEGFR2 失活发挥抗血管生成作用，从而抑制已建立的子宫内膜异位症病变的生长。然而，使用麦角衍生的 Cb2 与心脏瓣膜反流发生率增加有关。为了评估非麦角衍生的多巴胺激动剂治疗人类子宫内膜异位症的潜在用途，我们比较了喹高利德与 Cb2 在预防异种小鼠子宫内膜异位症模型中的血管生成和血管形成的功效。将含有在位人子宫内膜碎片的腹膜植入裸鼠体内，并用载体、每天 50μg/kg 口服 Cb2 或每天 50 或 200μg/kg 喹高利德治疗 14 天。在治疗期末，切除植入物以评估病变大小、细胞增殖、血管化程度和血管生成基因表达。与安慰剂相比，两种多巴胺激动剂均抑制新生血管形成，减少活性子宫内膜异位症病变的大小、细胞增殖指数和血管生成基因表达。鉴于 Cb2 和喹高利德在抑制血管生成和减少病变大小方面同样有效，这些实验为探索非麦角衍生的多巴胺激动剂治疗人类子宫内膜异位症的初步研究提供了依据。
