The Holy Grail of endometriosis biomarkers in the diagnostic process – How much would it be worth and what does it look like?

Previously, the gold standard for the diagnosis of endometriosis involved the performance of laparoscopic surgery, which allows the visualization and histological examination of the endometrial tissue. According to the latest guidelines published by the European Society of Human Reproduction and Embryology (ESHRE) in 2022, surgery is recommended only in patients with diagnostic difficulties associated with the use of non-invasive methods or in case of inappropriate or unsuccessful empirical treatment. At the same time, it is not recommended to use the measurement of biomarkers in the endometrial tissue, blood, menstrual or uterine fluids to diagnose endometriosis as the ESHRE guideline development group indicated the need of larger, multi-center prospective studies on this matter. The aim of this narrative review is to present advances in knowledge on non-invasive endometriosis diagnostic opportunities with emphasis on proteomics, the use of endometrial aspiration biopsy, iron metabolism, vitamin D-binding protein, extracellular matrix signaling pathways, epithelial−mesenchymal transformation, and other molecular pathways, together with a critical analysis of studies cited in the recent ESHRE guidelines.