REVIEW The Search for Biomarkers in Endometriosis: a Long and Windy Road Milena Králíčková 1,2,3 & Vaclav Vetvicka 4 & Luděk Fiala 5 & Antonio Simone Laganà 6 & Simone Garzon 6,7 Received: 11 January 2021 /Accepted: 11 June 2021 # Society for Reproductive Investigation 2021 Abstract Endometriosis is a complex and chronic estrogen-dependent disease, affecting a significant proportion of women of reproductive age. Despite the long interest and extensive research, the pathogenesis of the disease is still debated. Although available non- invasive diagnostic methods have adequate accuracy, an invasive approach by laparoscopy is often necessary to obtain histo- logical confirmation. In this scenario, the search for an accurate, reliable, cost-effective, clinically applicable non-invasive biomarker plays a crucial role in a potentially early diagnosis and, in this way, shape the future management of the disease. Considering these elements, the current review aims to summarize the most significant and novel results about biomarkers for the diagnosis and follow-up of women affected by endometriosis. Keywords Endometriosis . Biomarker . Immunology . MicroRNA . Human epididymis protein 4 . CA-125 . Stem cells Introduction Endometriosis is a common, chronic, hormone-dependent, in- flammatory disease affecting 2–18% of women of reproduc- tive age and over 40% of infertile patients [1]. The presence of endometrial-like tissue outside the uterine cavity characterizes the disease. Retrograde menstruation with transplantation of shaded en- dometrium is considered the primary etiopathogenetic mech- anism [2]. However, after more than a century of intensive research, we are still far from understanding endometriosis etiopathogenesis with multiple proposed molecular, genetic, and epigenetic mechanisms [3]. Indeed, the endometrium is a dynamic tissue with numerous molecular pathways activated and cyclically involved in cell proliferation, invasion, attach- ment, and possible migration [4]. All these mechanisms may participate in endometriosis development and represent tar- gets for therapy and markers for diagnosis [4–6]. Understanding the endometriosis pathogenesis is para- mount to develop further treatment options, given that avail- able treatments have side effects, and not all patients benefit from them, particularly for non-surgical strategies [7–9]. However, developing new methods for an early diagnosis is of paramount importance as well. A median delay of 8 years has been reported from the onset of symptoms to a diagnosis of endometriosis [10]. Therefore, although clinician education and public awareness are essential to prevent delayed diagno- sis and decrease the long-term morbidity resulting from un- treated endometriosis [10], identifying possible disease markers may help reduce this issue. Nevertheless, despite the significant efforts in establishing non-invasive methods to diagnose endometriosis, reliable tests are still missing. Most of the available studies are focused on finding a single marker in which expression would be significantly changed in patients with endometriosis. With this * Antonio Simone Laganà antoniosimone.lagana@uninsubria.it 1 Department of Histology and Embryology, Faculty of Medicine, Charles University, Pilsen, Czech Republic 2 Department of Obstetrics and Gynecology, University Hospital, Faculty of Medicine, Charles University, Pilsen, Czech Republic 3 Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Pilsen, Czech Republic 4 Department of Pathology, University of Louisville, Louisville, KY, USA 5 Institute of Sexology, First Faculty of Medicine, Charles University, Prague, Czech Republic 6 Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy 7 Department of Obstetrics and Gynecology, AOUI Verona, University of Verona, Verona, Italy Reproductive Sciences https://doi.org/10.1007/s43032-021-00668-2