THE EFFECTS OF ETANERCEPT AND CABERGOLINE ON ENDOMETRIOTIC IMPLANTS, UTERUS AND OVARIES IN RAT ENDOMETRIOSIS MODEL

https://doi.org/10.1016/j.jri.2021.103340Get rights and content

Highlights

  • Etanercept and/or cabergoline decreased volume of ectopic endometrial implants.

  • Etanercept and/or cabergoline decreased TNF-α and VEGF staining of ectopic endometrial implants.

  • Etanercept and/or Cabergoline decreased endometrial MSC-like cells of ectopic implants.

  • Etanercept and Etanercept + Cabergoline decreased TNF-α staining of the ovaries.

  • Etanercept + Cabergoline treatment increased peripheral blood CD25+ & CD5+ Cells.

Abstract

The pathophysiology of endometriosis is still unknown and treatment options remain controversial. Searches focus on angiogenesis, stem cells, immunologic and inflammatory factors. This study investigated the effects of etanercept and cabergoline on ovaries, ectopic, and eutopic endometrium in an endometriosis rat model. This randomized, placebo-controlled, blinded study included 50 rats, Co(control), Sh(Sham), Cb(cabergoline), E(etanercept), and E + Cb(etanercept + cabergoline) groups. After surgical induction of endometriosis, 2nd operation was performed for endometriotic volume and AMH level. After 15 days of treatment: AMH level, flow cytometry, implant volume, histologic scores, immunohistochemical staining of ectopic, eutopic endometrium, and ovary were evaluated at 3rd operation. All groups had significantly reduced volume, TNF-α, VEGF, and CD 146/PDGF-Rβ staining of endometriotic implants comparing to the Sh group (p < 0.05).TNF-α staining of eutopic endometrium in all treatment groups was similar to Sh and Co groups (p > 0.05). E and E + Cb groups significantly decreased TNF-α staining in the ovary comparing to Sh, Co, and Cb groups (p < 0.05). All treatment groups had significantly higher AFC compared to the Sh group. CD25+ Cells’ median percentage was significantly increased in the E + Cb group compared to Co, Sh, Cb, and E group. E + Cb group had a significantly higher CD5+ Cells’ level than the Co group (p = 0.035). In conclusion; Etanercept and/or Cabergoline decreased volume, TNF-α, VEGF, and CD 146/PDGF-Rβ staining of the ectopic endometrial implant. E and E + Cb treatment decreased TNF-α levels in the ovary. E + Cb also increased peripheral blood CD25+ & CD5+ Cell’s.

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.

Section snippets

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.

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