ergoline and Endometriosis

The aim of this study was to compare the efficiency of dopamine agonist, Cabergoline, in decreasing the size of endometrioma, with that of luteinizing hormone releasing hormone (LHRH) agonist, triptorelin acetate.. This was a prospective, randomized study.. The setting was in two private medical centers in the UAE, from January 2011 to February 2012.. One hundred and forty patients complaining of endometrioma, and fulfilling the eligibility criteria, were chosen and divided into two groups as follows: Group I comprised 71 patients; all of them received Cabergoline tablets, 0.5 mg tablets, twice per week for 12 weeks. Group II comprised 69 patients; all of them received LHRH agonist, decapeptyl, 3.75 mg subcutaneous, single injection, once a month for 3 months. All patients underwent vaginal ultrasound before and after the treatment period to compare the change in the size of endometrioma by the same sonography team in each hospital that was blind to the treatment groups.. The outcome was measured by the changes in the endometrioma size by vaginal ultrasound after completion of the 3 months' treatment period. The management line was considered to be significantly effective if the endometrioma size was reduced by more than 25 % of its original pretreatment size.. Group I: 46 out of the 71 patients (64.7 %) had significant decrease in endometrioma size. Group II: 15 out of 69 patients (21.7 %) had significant decrease in endometrioma size. Paired t test to compare the means of the two groups was highly significant (p < 0.05) CONCLUSION: Cabergoline (dostinex) yields better results in decreasing the size of endometrioma, compared to LHRH-agonist by exerting antiangiogenic effects through vascular endothelial growth factor receptor-2 (VEGFR-2) inactivation. It has no major side effects, easier to administer, and cheaper than LHRH agonists.

Topics: Administration, Oral; Adult; Cabergoline; Dopamine Agonists; Endometriosis; Ergolines; Female; Genital Diseases, Female; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Luteolytic Agents; Magnetic Resonance Imaging; Prospective Studies; Triptorelin Pamoate; Ultrasonography

Can endometrial mesenchymal stromal cells (E-MSCs) differentiate into endothelial cells in an in vitro co-culture system with human umbilical vein endothelial cells (HUVECs)?. E-MSCs can acquire endothelial markers and function in a direct co-culture system with HUVECs.. E-MSCs have been identified in the human endometrium as well as in endometriotic lesions. E-MSCs appear to be involved in formation of the endometrial stromal vascular tissue and the support of tissue growth and vascularization. The use of anti-angiogenic drugs appears as a possible therapeutic strategy against endometriosis.. This is an in vitro study comprising patients receiving surgical treatment of ovarian endometriosis (n = 9).. E-MSCs were isolated from eutopic and ectopic endometrial tissue and were characterized for the expression of mesenchymal and endothelial markers by FACS analysis and Real-Time PCR. CD31 acquisition was evaluated by FACS analysis and immunofluorescence after a 48 h-direct co-culture with green fluorescent protein +-HUVECs. A tube-forming assay was set up in order to analyze the functional potential of their interaction. Finally, co-cultures were treated with the anti-angiogenic agent Cabergoline.. A subpopulation of E-MSCs acquired CD31 expression and integrated into tube-like structures when directly in contact with HUVECs, as observed by both FACS analysis and immunofluorescence. The isolation of CD31+ E-MSCs revealed significant increases in CD31, vascular endothelial growth factor receptor 2, TEK receptor tyrosine kinase and vascular endothelial-Cadherin mRNA expression levels with respect to basal and to CD31neg cells (P < 0.05). On the other hand, the expression of mesenchymal genes such as c-Myc, Vimentin, neuronal-Cadherin and sushi domain containing 2 remained unchanged. Cabergoline treatment induced a significant reduction of the E-MSC angiogenic potential (P < 0.05 versus control).. Not applicable.. Further studies are necessary to investigate the cellular and molecular mechanisms underlying the endothelial cell differentiation.. E-MSCs may undergo endothelial differentiation, and be potentially involved in the development of endometriotic implants. Cell culture systems that more closely mimic the cellular complexity typical of endometriotic tissues in vivo are required to develop novel strategies for treatment.. This study was supported by the 'Research Fund ex-60%', University of Turin, Turin, Italy. All authors declare that their participation in the study did not involve actual or potential conflicts of interests.

Topics: Angiogenesis Inhibitors; Biomarkers; Cabergoline; Cadherins; Cell Communication; Cell Differentiation; Cell Proliferation; Coculture Techniques; Endometriosis; Endometrium; Ergolines; Female; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Mesenchymal Stem Cells; Models, Biological; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Primary Cell Culture; Proto-Oncogene Proteins c-myc; Receptor, TIE-2; Syndecan-2; Vascular Endothelial Growth Factor Receptor-2; Vimentin

To determine the effect of dopamine agonists in a surgically induced endometriosis model on rats.. In this prospective randomized experimental study, surgical induction of endometriosis was performed by autotransplantation technique on 52 adult female Wistar-Albino rats. Endometriosis formation was confirmed by a second-look laparotomy (n:48) 1 month later. Four study groups were randomly generated according to their treatment regimens: group 1 (leuprolide acetate, n = 12), group 2 (bromocriptine, n = 12), group 3 (cabergoline, n = 12) and group 4 (control, n = 12). Endometriotic implants were excised for histopathological examination after treatment at the setting of laparotomy. The mean surface areas and histopathological glandular tissue (GT) and stromal tissue (ST) scores of endometriotic implants were studied and compared among groups.. After 30 days of treatment, the mean surface area of the endometriotic implants of leuprolide acetate, bromocriptine and cabergoline groups was significantly decreased. The regression of endometriotic foci size in comparison to control was highest in group 1, followed by group 2, then group 3. In the histopathological evaluation both the ST and GT scores of group 1, 2 and 3 were significantly decreased in comparison to controls without a statistically significant difference between the groups.. Dopamine agonists are as effective as GnRH agonists in the regression of experimental endometriotic implants in rats. Further trials are needed to elucidate the pathways affected by dopamine agonists.

Topics: Adult; Animals; Antineoplastic Agents; Bromocriptine; Cabergoline; Disease Models, Animal; Dopamine Agonists; Endometriosis; Endometrium; Ergolines; Female; Gonadotropin-Releasing Hormone; Humans; Laparotomy; Leuprolide; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Triptorelin Pamoate

To investigate the effect of antiangiogenic treatment on experimental endometriotic lesion nerve fibers.. Heterologous mouse model of endometriosis.. University Institute IVI, University Hospital La Fe.. Ovariectomized nude mice (n = 16) receiving human endometrial fragments from oocyte donors (n = 4).. Endometrium fragments stuck in the peritoneum of 5-week-old female nude mice treated with vehicle (n = 8) and antiangiogenic agent cabergoline (n = 8; Cb(2,) 0.05 mg/kg/day) for 14 days.. Immunofluorescence analysis of von-Willebrand factor (vWF) and vascular smooth muscle cells (αSMA) for evaluating the number of immature blood vessels (IBV) and microvascular density (MVD); immunochemical analysis of protein-gene product 9.5 (PGP 9.5) to assess nerve fibers density (NFD), and blue toluidine staining to confirm presence of mast cells and macrophages in endometriotic lesions.. All the results were quantified by morphometric techniques. The IBV, NFD, and number of macrophages and mast cells were statistically significantly decreased in the Cb2-treated group when compared with controls.. Antiangiogenic treatment statistically significantly diminishes new blood vessel formation after macrophage, mast cell, and nerve fiber reduction, providing a rationale to test antiangiogenic agents as a novel therapeutic approach to severe pelvic pain associated with human peritoneal endometriosis.

Topics: Actins; Angiogenesis Inhibitors; Animals; Biomarkers; Cabergoline; Disease Models, Animal; Endometriosis; Endometrium; Ergolines; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Macrophages; Mast Cells; Mice; Mice, Nude; Microvessels; Neovascularization, Pathologic; Nerve Fibers; Ovariectomy; Peritoneal Diseases; Time Factors; von Willebrand Factor

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.

Topics: Animals; Blood Vessels; Cabergoline; Cell Count; Cell Proliferation; Claviceps; Disease Models, Animal; Dopamine Agonists; Endometriosis; Endometrium; Ergolines; Female; Humans; Mice; Neovascularization, Pathologic; Receptors, Dopamine D2; Uterine Diseases; Vascular Endothelial Growth Factor Receptor-2

Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist (DA) cabergoline (Cb2) reduces angiogenesis and endometriotic lesions, hypothetically binding to the dopamine receptor type-2 (DRD2). To date, this has not been described in human endometrium and/or endometriotic lesions. Thus, we aimed to investigate the presence of DRD2 in said tissues. Endometrium fragments were implanted in nude mice treated with different doses of Cb2. Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions (respectively) of DRD2, VEGF, and VEGF receptor-2 (KDR). In addition, lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile. In experimental endometriosis, DRD2 was expressed at gene and protein levels in all three groups. VEGF gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls. KDR protein expression was significantly lower in experimental lesions treated with Cb2 than in controls. In eutopic endometria, there was a significant decrease in DRD2 expression and an increase in VEGF in women with mild and severe endometriosis with respect to healthy patients. In endometriosis, KDR expression was significantly higher in red than in white and black lesions. VEGF expression was significantly lower in black than in red lesions. DRD2 is present in the human eutopic and ectopic endometrium and is regulated by DA, which provides the rationale for pilot studies to explore its use in the treatment of endometriosis.

Topics: Adolescent; Adult; Animals; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Endometriosis; Endometrium; Ergolines; Female; Gene Expression Regulation; Humans; Mice; Mice, Nude; Molecular Targeted Therapy; Oocyte Donation; Receptors, Dopamine D2; Severity of Illness Index; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Young Adult

Implantation of a retrogradely-shed endometrium during menstruation requires an adequate blood supply. The endometrium has angiogenic potential, and endometriotic lesions grow in areas with a rich vascularization, suggesting that angiogenesis is a prerequisite for endometriosis development. Targeting vascular endothelial growth factor (VEGF) leads to an inhibition of endometriosis. Dopamine and its agonists, such as cabergoline (Cb2), promote VEGF receptor-2 (VEGFR-2) endocytosis in endothelial cells, preventing VEGF-VEGFR-2 binding and reducing neoangiogenesis. The aim of this study was to evaluate the anti-angiogenic properties of Cb2 on growth of established endometriosis lesions and investigate the molecular mechanisms by which Cb2 exerts the anti-angiogenic effect.. Human endometrium fragments were implanted in female nude mice peritoneum, and mice were treated with vehicle, 0.05 or 0.1 mg/kg/day oral Cb2 for 14 days. After treatment, the implants were processed to assess proliferative activity, neoangiogenesis, VEGFR-2 phosphorylation and angiogenic gene expression.. A significant decrease in the percentage of active endometriotic lesions (P < 0.05) and cellular proliferation index (P < 0.001) was found with Cb2 treatment. Neoangiogenesis was reduced by Cb2 treatment, as observed at gross morphological level and by significant changes in gene expression. The degree of VEGFR-2 phosphorylation was significantly lower in Cb2-treated animals than controls.. Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation. These findings support the testing of dopamine agonists as a novel therapeutic approach to peritoneal endometriosis in humans.

Topics: Animals; Cabergoline; Cell Proliferation; Disease Models, Animal; Dopamine Agonists; Endometriosis; Ergolines; Female; Gene Expression Regulation; Humans; Mice; Neovascularization, Pathologic; Phosphorylation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2