Plasma metabolites associated with endometriosis in adolescents and young adults

What are the plasma metabolomics profiles associated with endometriosis in adolescents and young adults? Our findings show dysregulation of plasma metabolomic profiles in adolescents and young adults with endometriosis, revealing systemic elevation of fatty acyls and ceramides in endometriosis cases compared to controls. Endometriosis is a gynecologic disease often presenting with severe pelvic pain impacting around 200 million reproductive-aged women worldwide. However, little is known about the pathophysiology and molecular features of endometriosis diagnosed during adolescence and young adulthood. We conducted a cross-sectional analysis including 190 laparoscopically confirmed endometriosis cases and 120 controls who participated in The Women's Health Study: From Adolescence to Adulthood, which enrolled participants from 2012 to 2018. Control participants were females without a diagnosis of endometriosis enrolled from the same clinics as the cases or recruited from the general population. Among the cases, 81 had blood samples collected before and after surgery. Plasma metabolites were measured in blood collected at enrollment using liquid chromatography-tandem mass spectrometry, and a total of 430 known metabolites were evaluated in our analysis. We used linear regression adjusting for age at blood draw, BMI, hormone use, and fasting status at blood draw. Metabolite set enrichment analysis (MSEA) was used to identify metabolite classes. Number of effective tests (NEF) and false discovery rate (FDR) were used for multiple testing correction. The median age was 17 years for endometriosis cases and 22 years for controls. The majority of endometriosis cases had rASRM stage I or II (>95%). We identified 63 plasma metabolites associated with endometriosis (NEF < 0.05). Endometriosis cases had higher levels of plasma metabolites associated with proinflammatory response [e.g. eicosatrienoic acid (β = 0.61, 95% CI = 0.37, 0.86)], increased oxidative stress response [e.g. xanthine (β = 0.64, 95% CI = 0.39, 0.88)], and downregulation of metabolites related to apoptosis [glycocholic acid (β = -0.80, 95% CI = -1.04, -0.56)]. MSEA revealed increased fatty acyls (FDR = 2.3e-4) and ceramides (FDR = 6.0e-3) and decreased steroids and steroid derivatives (FDR = 1.3e-4) in endometriosis cases compared to controls. When we examined the changes in plasma metabolite profiles before and after surgery among endometriosis cases, 55 endometriosis-associated metabolites significantly changed from before to after surgery. MSEA revealed steroids and steroid derivatives (FDR = 8.1e-4) significantly increased after surgery, while fatty acyls (FDR = 1.2e-4) significantly decreased after surgery. Ceramides did not change from pre- to post-surgery and were elevated in post-surgical blood compared to controls (FDR = 3.9e-3). Our study population mainly consists of self-reported non-Hispanic, white individuals and endometriosis cases with superficial peritoneal lesions only, so the generalizability may be limited. Furthermore, despite our large study population of adolescents and young adults with endometriosis, sample size was limited to conduct detailed stratified analyses of plasma metabolomic profiles, especially by post-surgical pelvic pain outcomes. Our study includes the utilization of state-of-the-art metabolomics technology with high reproducibility to comprehensively investigate the metabolites that were associated with endometriosis diagnosed in adolescents and young adults. Our results suggest a positive impact of endometriosis-related surgery for some, but not all, on systemic metabolic dysregulation in young patients with endometriosis. These results warrant further investigation on whether and how persistent systemic changes despite treatment may lead to long-term chronic disease risk among those diagnosed with endometriosis. Financial support for establishment of and data collection within the A2A cohort was provided by the J. Willard and Alice S. Marriott Foundation, and support for assay costs was in part provided by the Peery family. This project was funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development R21HD107266. S.A.M., A.L.S., and K.L.T. were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD094842. S.A.M. received grant funding from AbbVie, National Institutes of Health, Department of Defense, and Marriott Family Foundation; received honoraria from WERF, Huilun Shanghai, and University of Kansas Medical Center; travel support from SRI, ESHRE, FWGBD, University of Michigan, MIT, ASRM, LIDEA Registry, Taiwan Endometriosis Society, SEUD, Japan Endometriosis Society, NASEM, Endometriosis Foundation of America, Gedeon Richter Symposium at ESHRE; Board member receiving financial remuneration from AbbVie, Roche, LIDEA Registry, Editor of Frontiers in Reproductive Health, Roundtable participation for Abbott; Board member without financial remuneration from NextGen Jane and Statistical Advisory Board member of Human Reproduction; leadership role in Society for Women's Health Research, World Endometriosis Society, World Endometriosis Research Foundation, ASRM, ESHRE. N.S. and K.L.T. receive grant funding from Aspira Women's Health unrelated to this project. The remaining authors have no disclosures relevant to this manuscript. N/A.