THE EFFECTS OF ETANERCEPT AND CABERGOLINE ON ENDOMETRIOTIC IMPLANTS, UTERUS AND OVARIES IN RAT ENDOMETRIOSIS MODEL☆
Introduction
Endometriosis is a chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. Chronic pelvic pain, dysmenorrhea, dyspareunia, menstrual irregularities, infertility, and decreased quality of life are the major consequences of the disease. The true incidence of endometriosis is unclear. Endometriosis affects 2-10 % of reproductive-aged women and up to 50% of infertile women (Eskenazi and Warner, 1997; Meuleman et al., 2009).
The pathophysiology and treatment of endometriosis are still controversial. Searches focus on immunologic factors, angiogenesis, stem cells, and inflammatory factors in the pathogenesis. The intraperitoneal immune system is a complex network that interacts through the autocrine/paracrine system(Wu and Ho, 2003). There is much evidence of activation of peritoneal macrophages with increased cytokine production in women with endometriosis (Leibovic et al., 2001). Vascular endothelial growth factor (VEGF) is an essential promoter of angiogenesis. TNF-α is a secretory factor of active macrophages known to have potent inflammatory cytotoxic and angiogenic characteristics leading to pelvic adhesions, fibrosis, and ectopic lesions (Richter et al., 2005). Several studies have demonstrated women with endometriosis have a high concentration of TNF-α and VEGF levels in the peritoneal fluid These levels correlate with disease severity. (Ahn et al., 2015; Gazvani and Templeton, 2002). Therefore, suppression of VEGF or TNF-α suggests promising therapy of endometriosis.
Prior studies assessed the effects of cabergoline or etanercept on endometriotic implant size. To the best of our knowledge, this is the first study exploring the effects of cabergoline and etanercept treatment on the ovary, eutopic and ectopic endometrial tissue via searching TNF-α, VEGF, CD 146/PDGF-Rβ staining (endometrial stem cell marker), AMH, antral follicle count and some immunologic cells’ surface markers.
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Animals
This study was conducted in Kocaeli University Experimental Medicine Research Laboratory (DETAB) with the approval of the local animal ethics committee of Kocaeli University (No: 3/9-2014). The research followed the institutional and national guidelines for the care and use of laboratory animals. Fifty adult female Wistar Albino rats were weighing between 205 and 275 grams and were caged in a controlled environment at 21 ± 2 °C and 60 ± 5 % humidity with 12 -h light/dark cycles and were fed ad
Results
The vascularized endometriotic implants developed in all rats in the study groups. Sh (n = 9), Cb (n = 9), E (n = 10) and E + Cb (n = 10). The implant volumes were similar in all groups at the second operation (p > 0.05). All treatment groups decreased implant size at the third operation comparing to the implant size of 2nd operation (p < 0.05). Fig. 1 shows the endometriotic implants before and after treatment. The decrease of endometriotic implant volume comparing to sham was highest in the E
Discussion
This study evaluated the effects of etanercept and cabergoline treatments on endometriotic implants, eutopic endometrium, and ovary in the endometriosis rat model. Briefly, all treatment modalities (E, Cb, E + Cb) significantly decreased TNF-α, VEGF, and CD 146/PDGF-Rβ staining and volume of ectopic endometrial tissue. Furthermore, E and E + Cb groups decreased TNF-α in the ovary, and the E + Cb group increased CD25+ cells in peripheral blood.
Prior studies showed that etanercept treatment
Financial support
This work was funded by grants from The Scientific Research Project (BAP) Coordination Unit of Kocaeli University (grant ref. 2014/066). The funding source were not involved in the design or conduction of the study or the decision to publish it.
Declaration of Competing Interest
The authors report no declarations of interest.
References (51)
- et al.
Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons
Fertil. Steril.
(2004) - et al.
Regulatory T cells and other leukocytes in the pathogenesis of endometriosis
J Reprod Immunol.
(2011) - et al.
Comparison of aromatase inhibitor (letrozole) and immunomodulators (infliximab and etanercept) on the regression of endometriotic implants in a rat model
European Journal of Obstetrics & Gynecology and Reproductive Biology
(2011) - et al.
Human CD4+ CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop
Blood
(2007) - et al.
Epidemiology of endometriosis
Obstet. Gynecol. Clin. North Am.
(1997) - et al.
IVF outcome in women with endometriosis about tumor necrosis factor and anti-Müllerian hormone
Reproductive BioMedicine Online
(2009) - et al.
Regression of endometrial autografts in a rat model of endometriosis treated with etanercept
Eur J Obstet Gynecol Reprod Biol.
(2011) - et al.
Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole
Fertil Steril.
(1999) Bromocriptine in Rheumatic and Autoimmune Diseases
Seminars in Arthritis and Rheumatism
(2001)- et al.
High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners
Fertil Steril.
(2009)
Interleukin-6, intracellular adhesion molecule-1, and glycodelin A levels in serum and peritoneal fluid as biomarkers for endometriosis
Int J Gynaecol Obstet.
Treating endometriosis as an autoimmune disease
Fertil Steril.
Effect of antiangiogenic treatment on peritoneal endometriosis-associated nerve fibers
Fertil Steril
The immunoregulatory role of dopamine: an update
Brain Behav Immun.
Studies on the surgical induction of endometriosis in the rat
Fertil Steril.
Effect of tumor necrosis factor alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: an in vitro system
Fertil Steril
CD molecules 2006-human cell differentiation molecules
J İmmunol Methods
Pathophysiology and Immune Dysfunction in Endometriosis
Biomed Res Int.
Anti-TNF-α therapy modulates mTORC1 signalling in hidradenitis suppurativa
J Eur Acad Dermatol Venereol.
Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis
Hum Reprod.
Induction of endometriosis alters the peripheral and endometrial regulatory T cell population in the non-human primate
Hum Reprod.
Differential expression of mTOR components in endometriosis and ovarian cancer: Effects of rapalogues and dual kinase inhibitors on mTORC1 and mTORC2 stoichiometry
Int J Mol Med.
Endometriosis
Endocr Rev
Decreased progesterone receptor B/A ratio in endometrial cells by tumor necrosis factor-alpha and peritoneal fluid from patients with endometriosis
Yonsei Med. J.
A rapid immunostaining method for frozen sections
Biotech. Histochem.
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This study won the best 3rd oral presentation award and the best endometriosis presentation award at the 11th International Congress of Turkish German Gynecology Association (May 15, 2016, Antalya-Türkiye).