Plasma proteins and persistent post-surgical pelvic pain among adolescents and young adults with endometriosis

Background Non-invasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biological pathways underlying endometriosis-associated pain and symptom progression. Thus, we evaluated plasma proteins in relation to persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. Methods We conducted a prospective analysis including 142 participants with laparoscopically- confirmed endometriosis from the Women’s Health Study: From Adolescence to Adulthood (A2A) observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (EPHect) tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1,305 plasma protein levels including markers for immunity, angiogenesis and inflammation using SomaScan. Worsening or persistent post-surgical pelvic pain was defined as having newly developed, persistent (i.e., stable), or worsening severity, frequency, or persistent life-interference of dysmenorrhea or acyclic pelvic pain at one-year post-surgery compared to pre-surgery. We calculated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression adjusted for age, body mass index, and fasting status and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. Results Median age at blood draw was 17 years (interquartile range 15-19), and most participants were white race (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year post-surgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, while pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain one-year post-surgery (nominal p<0.05). Compared to those with improved pelvic pain one year post-surgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (OR=2.98, 95% CI:1.44-6.19) and CD47 (OR=2.68, 95%CI=1.28-5.61), but lower levels of Sonic Hedgehog protein (SHH; OR=0.55, 95%CI=0.36-0.84) in pre-surgical blood. Pathways related to cell migration were upregulated and pathways related to angiogenesis were downregulated in those with worsening/persistent post-surgical pelvic pain compared to those with improved pain. When we examined change in proteins levels from pre- to post-surgery and its subsequent risk of worsening/persistent post-surgical pain at one-year follow-up, we observed increasing levels of SHH from pre- to post-surgery was associated with four-fold increase in risk of post-surgical pain (OR quartile 4 vs. 1=3.86, 1.04-14.33). Conclusion Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain post-surgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.