Inflammatory Markers in Women with Endometriosis Before and After the COVID-19 Pandemic: A Matched Cohort Study from the Tehran Lipid and Glucose Study

Abstract

Background: Endometriosis (EM) is a common chronic inflammatory disorder affecting women. The coronavirus disease 2019 (COVID-19) pandemic may have been associated with changes in systemic inflammatory regulation. Objectives: This study aimed to measure and compare serum interleukin-6 (IL-6) levels, mRNA levels of vascular endothelial growth factor (VEGF), C-X-C motif chemokine 5 (CXCL5), and substance P (SP), as well as markers of neutrophil extracellular trap formation (NETosis), in patients with EM before and after the onset of the COVID-19 pandemic. Methods: We used data from the Tehran Lipid and Glucose Study (TLGS). Among 2558 women in the TLGS, 465 had a diagnosis of endometriosis. Of these, 13 women had biobanked samples available from both the pre-pandemic (Phase 6, 2016 - 2018) and post-pandemic (Phase 7, 2021 - 2023) periods and were included as matched pairs within the same individuals. The primary exposure was the post-pandemic calendar period; individual COVID-19 infection data were not collected. Real-time PCR was used to quantify the expression of genes associated with SP (TAC1), neurokinin 1 receptor (TACR1), VEGF, and CXCL5 in peripheral blood mononuclear cells. Markers of NETosis, including neutrophil elastase (NE), myeloperoxidase (MPO), peptidyl arginine deiminase 4 (PAD4), and matrix metallopeptidase 9 (MMP9), were assessed. Serum IL-6 concentrations were measured by enzyme-linked immunosorbent assay. Results: Gene expression analysis showed no significant changes in TAC1, TACR1, VEGF, or CXCL5; all 95% confidence intervals (CIs) included unity, and the study was underpowered to detect small differences. Evaluation of NETosis-related genes in neutrophils stimulated with patient sera showed no significant differences in PAD4, MMP9, or MPO expression; however, NE expression was significantly elevated after the pandemic (fold change = 1.5; 95% CI, 1.01 to 2.25; P = 0.048). Other NETosis markers and IL-6 did not differ significantly (eg, IL-6 median paired difference, +0.58 pg/mL; 95% CI, -0.89 to +2.34 pg/mL; P = 0.750); thus, all non-significant results are inconclusive. Conclusions: A preliminary signal of increased neutrophil elastase expression was observed after the pandemic, whereas other inflammatory and NETosis markers remained inconclusive. In this small investigation, the relative contributions of COVID-19 infection, vaccination, psychosocial stress, and lifestyle changes could not be disentangled. These hypothesis-generating findings require confirmation in larger, well-characterized cohorts.