Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients

Abstract

Objective: To determine the impact of endometriotic lesion removal on local and systemic inflammation.

Design: Multiplex cytokine analysis on samples from endometriosis patients before surgery, 2 weeks after surgery, and 3 months after surgery.

Setting: Academic teaching hospital and university.

Patient(s): A total of 43 endometriosis patients before and after excision of lesions by means of laparoscopic surgery, and 25 normal women.

Intervention(s): None.

Main outcome measure(s): Plasma, eutopic and ectopic tissue, and peritoneal fluid cytokine levels.

Result(s): Compared with presurgery plasma samples, levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-8, and IL-10 decreased significantly by 2 weeks after surgery in endometriosis patients. Interestingly, levels began to rise at 3 months after surgery in most cases. In tissue, levels of GM-CSF and IL-15 were lower in eutopic tissue, while levels of basic fibroblast growth factor, interferon-inducible protein 10, IL-1 receptor antagonist, granulocyte colony-stimulating factor, macrophage inflammatory protein 1β, IL-7, and IL-5 were higher in eutopic than in ectopic tissue. In peritoneal fluid, levels of IL-5 and IL-12 were higher in early versus advanced stages of endometriosis. Compared with normal women, plasma from endometriosis patients had higher levels of inflammatory cytokines.

Conclusion(s): Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis. The transitory nature of the change may reflect the recurrence of the condition and the influence of systemic factors in its onset.

Keywords: Cytokines; endometriosis; inflammation; plasma.

FIGURE 1

(A) Plasma levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-8, and IL-10 decreased significantly after removal of lesions. However, post hoc analysis revealed that this difference was significant only in pre- vs. post-op samples, not in pre- vs. 3-month samples. No significant differences were observed for other cytokines. One-way Friedman analysis of variance (ANOVA) and Tukey post hoc test; n = 19. (B) When stratified by disease stage, plasma levels of GM-CSF were found to decrease significantly after surgery in advanced endometriosis patients (stages III–IV), but not in early endometriosis patients (stages I–II). However, post hoc analysis revealed that these differences were not significant. One-way ANOVA and Tukey post hoc test; n = 14 (early stage); n = 5 (advanced stage). (C) When stratified by disease stage and time point, early-stage patients had lower plasma levels of Regulated on activation, normal T expressed and secreted (RANTES) than advanced-stage patients. No differences were seen in early- vs. advanced-stage patients at later time points. No differences were observed for other cytokines. Bars represent the mean, and the whiskers represent the 95% confidence intervals. t test; n = 14 (early stage); n = 5 (advanced stage). *P<.05. Monsanto. Cytokines in the endometriosis. Fertil Steril 2015.

FIGURE 2

Differential expression of nine cytokines was detected in eutopic tissue compared with ectopic tissue. Levels of GM-CSF and IL-15 were lower in eutopic tissue. In contrast, levels of basic fibroblast growth factor (FGF-basic), interferon-inducible protein (IP) 10, IL-1 receptor antagonist (IL-1ra), granulocyte colony–stimulating factor (G-CSF), macrophage inflammatory protein (MIP) 1β, IL-7, and IL-5 were higher in eutopic than in ectopic tissue. Other abbreviations as in Figure 1. Bars represent the mean, and the whiskers represent the 95% confidence intervals. *P<.05; paired t test or Wilcoxon signed ranked test for nonparametric data (n = 18). Monsanto. Cytokines in the endometriosis. Fertil Steril 2015.

FIGURE 3

When samples were stratified by stage of disease, differential expression of IL-1ra, IL-5, IL-7, IL-9, IL-15, FGF-basic, G-CSF, GM-CSF, IP-10, MIP-1β, and tumor necrosis factor (TNF) α was observed between eutopic and ectopic tissues of early-stage patients, but not in advanced-stage patients. Only IL-2 was found to be differentially expressed in eutopic vs. eutopic tissue from advanced-stage patients. Abbreviations as in Figures 1 and 2. Bars represent the mean, and the whiskers represent the 95% confidence intervals. *P<.05; n = 13; paired t test or Wilcoxon signed ranked test. Monsanto. Cytokines in the endometriosis. Fertil Steril 2015.