Accuracy and utility of blood and urine biomarkers for the noninvasive diagnosis of endometriosis: a systematic literature review and meta-analysis

Objective: Endometriosis is a chronic, incurable condition associated with debilitating pain and subfertility affecting over 190 million women worldwide, which has no reliable noninvasive diagnostic tool. We aimed to determine the state-of-the-art in noninvasive liquid biopsy biomarker detection and predict the most promising biomarkers for endometriosis detection. Evidence Review: A systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines was conducted using the PubMed, MEDLINE, Scopus, and Cochrane Library databases. Primary research studies examining blood or urine biomarkers in humans published in English up until August 2022 were included. Studies with more than 10 patients with clear methodology and surgical staging of endometriosis were included, whereas studies that included gynecological malignancies or who did not perform laparoscopy in the control group were excluded. The articles were assessed for the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. One investigator extracted the data, and 2 investigators checked the accuracy. Extracted data were analyzed descriptively, the box plots of pooled data were calculated using RStudio, and the likelihood ratios were determined. Results: A total of 8,244 and 3,619 manuscripts for blood and urine biomarkers were identified. After screening on the basis of the title, abstract, full text, and quality assurance, 18 of these studies assessing blood biomarkers and 15 examining urine biomarkers were eligible for data extraction. However, there were inconsistencies in the results indicating that standardized techniques would be essential for direct comparisons to be made in the future. In 4 of the eligible studies, the urine biomarkers were juxtaposed with blood markers; however, in most cases, the combination of blood and urine biomarkers resulted in an increase in the area under the curve value, sensitivity, and specificity. One study presented biomarkers with a likelihood ratio of >10. However, currently, none of the biomarkers have been shown to be clinically useful, and further research is necessary to determine their utility in clinical practice. Conclusion: Multiple biomarkers described here provide exciting avenues for further study particularly as part of diagnostic panels, including the endometrial antigens tropomyosin 3, stomatin-like protein 2, and tropomodulin 3, microribonucleic acids, and interleukins. There is a need for standardized protocols to be used to achieve consistent, reproducible results that will facilitate the development of a clinically applicable noninvasive test for endometriosis.