The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis

Abstract

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 mg/kg per day oral Cb2, or 50 or 200 mg/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.

Angiogenesis as a Therapeutic Target in Endometriosis

“…69 Thus, it is likely that quinagolide also suppresses the endometriosisassociated angiogenesis in a paracrine fashion by decreasing the production of VEGF-A by immune cells within the lesions. 70 Since endometriosis-associated inflammation and angiogenesis are closely related processes, numerous studies have been focused on anti-inflammatory drugs and immunomodulators. The principal enzyme in the conversion of arachidonic acid to prostaglandins, cyclo-oxygenase 2 (COX-2), is over-expressed in endometriotic lesions and eutopic endometrium of affected women, seeming to play multiple roles in the pathogenesis of endometriosis.…”

Treatment of Endometriosis with Non-Hormonal Agents: Review

“…37,38 Kabergolinle yapılan deneysel çalışmada, kabergolinin anjiyogenezisi inhibe ederek endometriyozis lezyonlarının oluşmasını engellediği gösterilmiştir. 39,40 Quinagolid, endotel hücrelerinde VEGF 2 reseptörü fosforilasyonunu azaltarak, damarların proliferasyonunu engellemektedir. Drd2-A kullanılarak gerçekleştirilen başarılı bir rektal endometriyozis tedavisi, Drd2-A'nın antianjiyojenik etkisinden kaynaklandığı hipotezini desteklemektedir.…”

The significance of prolactin in the pathogenesis of genital endometriosis and the possibilities of dopamine agonist therapy

“…На модели животных было показано, что агонисты дофаминовых рецепторов (D 2 ) могут подавлять ангиоге-нез в опухолях, инактивируя сигналы рецептора VEGF [40,41]. Описано, что агонисты дофамина могут снижать активность VEGF и подавлять неоангиогенез, в том числе в очагах эндометриоза.…”

“…В 2011 г. описан эффект применения агонистов дофа-мина для лечения эндометриоза в эксперименте с живот-ной моделью (линия мышей). Лабораторным животным моделировали эндометриоз, подсаживая на брюшину эн-дометриоидные гетеротопии, полученные при операциях у женщин с НГЭ [38,40]. Мышам с хирургически индуци-рованным эндометриозом на брюшине проводили лече-ние с применением каберголина 50 мг/кг ежедневно или хинаголида по 50 и 200 мг/кг ежедневно в течение 14 дней.…”

“…После окончания лечения с применением агонистов дофамина в обеих группах отмечалось угнетение неоангио-генеза по сравнению с контрольной группой [40,41]. Сле-дует отметить, что по таким показателям, как уменьшение размеров очагов эндометриоза, снижение уровней VEGF мРНК и VEGFR 2 мРНК, неэрголиновые агонисты дофа-мина показали такую же эффективность, как и эрголино-вые, что свидетельствует о возможности применения обе-их групп препаратов для лечения больных НГЭ [40].…”