Molecular biomarkers of endometriosis

Albeit endometriosis is one of the most common gynecological diseases, its diagnosis and treatment remain controversial. The reasons behind this include: 1) multifactorial pathogenesis and insufficiently studied mechanisms of endometriosis; 2) relatively low diagnostic value of minimally invasive examination in relation to this disease; 3) inefficiency of current therapeutic approaches in many patient settings. In our opinion, uncovering the causes of endometriosis and factors promoting its progression is the cornerstone of its successful management. Here we review the lessons from genome-wide and candidate gene association studies, discuss the expression of regulatory miRNAs and describe the role of heat shock protein 90, annexin A2, and peroxiredoxin 2 in controlling DNA integrity in the eutopic endometrium. Further, we highlight the role of cytokeratin-19 in urine as a feasible diagnostic marker of endometriosis. Clinicians and basic researchers concur that the molecular basis of endometriosis is still in its infancy and current understanding of its pathophysiology remains poor. Recent progress in -omics approaches and bioinformatics paved the way for complex investigations of regulated cell death, proliferation, cell invasion and angiogenesis, opening the avenue for the novel approaches to treat endometriosis. Yet, the diversity of symptoms and an absence of sensitive and specific biomarkers frequently delay and complicate the diagnosis. In addition, surgery represents the only appropriate option to reliably confirm the diagnosis and to establish the disease extent, reducing patient adherence and postponing the start of the treatment. In this review, we discuss challenges in the diagnosis of endometriosis as well as relevant and potentially informative biomarkers. 

1. Marcellin L, Morin C, Santulli P, Marzouk P, Bourret A, Dousset B, Borghese B, Chapron C. History of Uterine Surgery Is Not Associated With an Increased Severity of Bladder Deep Endometriosis. J Minim Invasive Gynecol. 2016;23(7):1130-1137. https://doi.org/10.1016/j.jmig.2016.08.817

2. Jarmolinskaja MI, Ajlamazjan JeK. Genital'nyj jendometrioz. Razlichnye grani problemy. Saint Peterburg : Jeko-Vektor; 2017. (In Russ.).

3. Damirov MM, Oleynikova ON, Mayorova OV. Genital'nyy endometrioz: vzglyad praktikuyushchego vracha. Мoscow: BINOM, 2013. (In Russ.).

4. Zhang L, Li H, Yuan M, Li D, Sun C, Wang G. Serum Exosomal MicroRNAs as Potential Circulating Biomarkers for Endometriosis. Dis Markers. 2020;2020:2456340. https://doi.org/10.1155/2020/2456340

5. Marzhevskay VV, Prisyazhnaya TS, Zhamoydik VI, Berlev IV, Malek AV. Molecular-genetic background of endometriosis: diagnostic potential of heritable and express. Journal of obstetrics and womans diseases. 2018;67(3):64-73. (In Russ.). https://doi.org/10.17816/JOWD67364-73

6. Tikhomirov AL, Lubnin DM. Pathogenetic substantiation of gonadotrophin-releasing hormone agonists application in patients with associated gynecological pathology. Gynecology, obstetrics and perinatology. 2006;5(1):82-87 (In Russ.). https://dlib.eastview.com/browse/doc/9930112

7. Peresada OA. Endometrioz: diagnosticheskie, klinicheskie, onkologicheskie i lechebnye aspekty. Medicinskie novosti. 2009;14:15-26. (In Russ.).

8. Adamyan LV, Kulakov VI, Andreeva EN. Endometriozy : rukovodstvo dlya vrachey. Мoscow: Meditsina, 2006. (In Russ.).

9. D'Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update. 2002;8(1):84-8. https://doi.org/10.1093/humupd/8.1.84

10. Halban J. Metastatic hysteroadenosis. Wien Klin Wochenschr. 1924;37:1205-1206.

11. Hansen T, Wulgaris S, Siggelkow W, Kölbl H, Kirkpatrick CJ. Massive Adenomyose bei einer Patientin mit Uterus septus completus [Massive adenomyosis in a patient with uterus septus completus]. Zentralbl Gynakol. 2006;128(3):153-156. https://doi.org/10.1055/s-2005-836818

12. Vinatier D, Orazi G, Cosson M, Dufour P. Theories of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2001;96(1):21-34. https://doi.org/10.1016/s0301-2115(00)00405-x

13. Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends Mol Med. 2003;9(5):223-228. https://doi.org/10.1016/s1471-4914(03)00051-0

14. Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004;25(6):947-970. https://doi.org/10.1210/er.2003-0030

15. Ebert AD, Bartley J, David M. Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors in endometriosis: new questions--old answers? Eur J Obstet Gynecol Reprod Biol. 2005;122(2):144-150. https://doi.org/10.1016/j.ejogrb.2005.04.017

16. Saha R, Pettersson HJ, Svedberg P, Olovsson M, Bergqvist A, Marions L, Tornvall P, Kuja-Halkola R. Heritability of endometriosis. Fertil Steril. 2015;104(4):947-952. https://doi.org/10.1016/j.fertnstert.2015.06.035

17. May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010;16(6):651-674. https://doi.org/10.1093/humupd/dmq009

18. Socolov R, Butureanu S, Angioni S, Sindilar A, Boiculese L, Cozma L, Socolov D. The value of serological markers in the diagnosis and prognosis of endometriosis: a prospective case-control study. Eur J Obstet Gynecol Reprod Biol. 2011;154(2):215-7. https://doi.org/10.1016/j.ejogrb.2010.10.008

19. Daraï E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod. 2003;18(8):1681-1685. https://doi.org/10.1093/humrep/deg321

20. Xavier P, Belo L, Beires J, Rebelo I, Martinez-de-Oliveira J, Lunet N, Barros H. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet. 2006;273(4):227-231. https://doi.org/10.1007/s00404-005-0080-4

21. Othman Eel-D, Hornung D, Salem HT, Khalifa EA, El-Metwally TH, Al-Hendy A. Serum cytokines as biomarkers for nonsurgical prediction of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):240- 246. https://doi.org/10.1016/j.ejogrb.2007.05.001

22. Ohata Y, Harada T, Miyakoda H, Taniguchi F, Iwabe T, Terakawa N. Serum interleukin-8 levels are elevated in patients with ovarian endometrioma. Fertil Steril. 2008;90(4):994-999. https://doi.org/10.1016/j.fertnstert.2007.07.1355

23. Vodolazkaia A, El-Aalamat Y, Popovic D, Mihalyi A, Bossuyt X, Kyama CM, Fassbender A, Bokor A, Schols D, Huskens D, Meuleman C, Peeraer K, Tomassetti C, Gevaert O, Waelkens E, Kasran A, De Moor B, D'Hooghe TM. Evaluation of a panel of 28 biomarkers for the noninvasive diagnosis of endometriosis. Hum Reprod. 2012;27(9):2698- 2711. https://doi.org/10.1093/humrep/des234

24. Feng L, Lixue L, Zheng J. Expression of annexin A2 in adenomyosis and dysmenorrheal. Archives of Gynecology and Obstetrics. 2019;300(3):711-716. https://doi.org/10.1007/s00404-019-05205-w

25. Schloer S, Pajonczyk D, Rescher U. Annexins in Translational Research: Hidden Treasures to Be Found. Int J Mol Sci. 2018 Jun 15;19(6):1781. https://doi.org/10.3390/ijms19061781

26. Fowler PA, Tattum J, Bhattacharya S, Klonisch T, Hombach-Klonisch S, Gazvani R, Lea RG, Miller I, Simpson WG, Cash P. An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex disease. Proteomics. 2007;7(1):130-142. https://doi.org/10.1002/pmic.200600469

27. Ametzazurra A, Matorras R, García-Velasco JA, Prieto B, Simón L, Martínez A, Nagore D. Endometrial fluid is a specific and non-invasive biological sample for protein biomarker identification in endometriosis. Hum Reprod. 2009;24(4):954-965. https://doi.org/10.1093/humrep/den450

28. Ferrero S, Gillott DJ, Remorgida V, Anserini P, Ragni N, Grudzinskas JG. Proteomic analysis of peritoneal fluid in fertile and infertile women with endometriosis. J Reprod Med. 2009;54(1):32-40.

29. Tokushige N, Markham R, Crossett B, Ahn SB, Nelaturi VL, Khan A, Fraser IS. Discovery of a novel biomarker in the urine in women with endometriosis. Fertil Steril. 2011;95(1):46-49. https://doi.org/10.1016/j.fertnstert.2010.05.016

30. Bártek J, Bártková J, Taylor-Papadimitriou J, Rejthar A, Kovarík J, Lukás Z, Vojtĕsek B. Differential expression of keratin 19 in normal human epithelial tissues revealed by monospecific monoclonal antibodies. Histochem J. 1986;18(10):565-575. https://doi.org/10.1007/BF01675198

31. Van der Linden PJ, Dunselman GA, de Goeij AF, van der Linden EP, Evers JL, Ramaekers FC. Epithelial cells in peritoneal fluid--of endometrial origin? Am J Obstet Gynecol. 1995;173(2):566-570. https://doi.org/10.1016/0002-9378(95)90283-x

32. Zondervan KT, Rahmioglu N, Morris AP, Nyholt DR, Montgomery GW, Becker CM, Missmer SA. Beyond Endometriosis GenomeWide Association Study: From Genomics to Phenomics to the Patient. Semin Reprod Med. 2016;34(4):242-254. https://doi.org/10.1055/s-0036-1585408.

33. Li Y, Hao N, Wang YX, Kang S. Association of EndometriosisAssociated Genetic Polymorphisms From Genome-Wide Association Studies With Ovarian Endometriosis in a Chinese Population. Reprod Sci. 2017;24(1):109-113. https://doi.org/10.1177/1933719116650753

34. Matalliotakis M, Zervou MI, Matalliotaki C, Rahmioglu N, Koumantakis G, Kalogiannidis I, Prapas I, Zondervan K, Spandidos DA, Matalliotakis I, Goulielmos GN. The role of gene polymorphisms in endometriosis. Mol Med Rep. 2017;16(5):5881-5886. https://doi.org/10.3892/mmr.2017.7398

35. Matalliotakis M, Zervou MI, Matalliotaki C, Arici A, Spandidos DA, Matalliotakis I, Goulielmos GN. Genetic association study in a threegeneration family with seven members with endometriosis. Mol Med Rep. 2017;16(5):6077-6080. https://doi.org/10.3892/mmr.2017.7337

36. Nothnick WB. MicroRNAs and Endometriosis: Distinguishing Drivers from Passengers in Disease Pathogenesis. Semin Reprod Med. 2017;35(2):173-180. https://doi.org/10.1055/s-0037-1599089

37. Moustafa S, Burn M, Mamillapalli R, Nematian S, Flores V, Taylor HS. Accurate diagnosis of endometriosis using serum microRNAs. Am J Obstet Gynecol. 2020;223(4):557.e1-557.e11. https://doi.org/10.1016/j.ajog.2020.02.050

38. Shariati F, Favaedi R, Ramazanali F, Ghoraeian P, Afsharian P, Aflatoonian B, Aflatoonian R, Shahhoseini M. Increased expression of stemness genes REX-1, OCT-4, NANOG, and SOX-2 in women with ovarian endometriosis versus normal endometrium: A case-control study. Int J Reprod Biomed. 2019;16(12):ijrm.v16i12.3684. https://doi.org/10.18502/ijrm.v16i12.3684

39. Aints A, Mölder S, Salumets A. EXTL3-interacting endometriosis-specific serum factors induce colony formation of endometrial stromal cells. Sci Rep. 2019;9(1):12562. https://doi.org/10.1038/s41598-019-48840-8