Relationship between endometriosis diagnosis, staging, and typology and inflammatory cytokines

To study whether incident endometriosis diagnosis, staging, and typology are associated with concurrent elevated serum inflammatory markers interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF- $\alpha$ ).

Cross-sectional analysis using data from the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) study.

A total of 395 premenopausal females in Utah, with no prior endometriosis diagnosis, participating in diagnostic or therapeutic gynecologic laparoscopy/laparotomy, 2007-2009.

Endometriosis diagnosis, staging (minimal, mild, moderate, severe), and typology (superficial endometriosis [SE], deep infiltrating endometriosis [DE], ovarian endometrioma [OE]), determined through postoperative reports and the revised American Society for Reproductive Medicine classification.

Elevated serum cytokine concentrations defined as IL-6 ≥2 pg/mL, IL-8 ≥3 pg/mL, and TNF-α ≥7.5 pg/mL. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalized linear models controlling for age, body mass index (BMI), race/ethnicity, serum cotinine, and reported use of oral hormonal contraception within the past 2 years.

Participants were on average 33 years at time of gynecologic laparoscopy/laparotomy, non-Hispanic white (79%), married (75%), with a BMI of 18.5-24.9 kg/m² (39%), nonsmokers (83% serum cotinine <5 ng/mL), and reported use of oral hormonal contraception within the past 2 years (23%). Forty-two percent (n = 166) were diagnosed with incident endometriosis. Ten percent had elevated IL-6, 7% had elevated IL-8, and 13% had elevated TNF- $\alpha$ , with 26% having an elevation of at least one marker. We found no differences between those with, vs. without, endometriosis and prevalence of elevated serum IL-6 (10% vs. 10%; aPR: 1.17; 95% CI: 0.59, 2.30), IL-8 (5% vs. 8%; aPR: 0.60; 95% CI: 0.20, 1.84), or TNF- $\alpha$ (16% vs. 12%; aPR: 1.30; 95% CI: 0.68, 2.51). There was also no indication that endometriosis was associated with continuous measures of IL-6, IL-8, or TNF- $\alpha$ or that staging or typology was associated with any of the inflammatory biomarkers.

This study found no associations between incident endometriosis diagnosis, staging, typology, and concurrent serum inflammatory markers IL-6, IL-8, and TNF- $\alpha$ . Our results are in line with several other studies finding null associations between systemic cytokines, measured via blood-derived specimens, and endometriosis. Whether other cardiovascular disease risk biomarkers, including lipoprotein abnormalities, are associated with endometriosis warrants further research.