{"paper_id":"8c57d0b0-34bf-4fa9-811a-042cd3e3b47c","body_text":"Journal of Interdisciplinary Medicine 2023;8(1):34-36\nCORRESPONDENCE\nTraian Irimia  \nStr. Gheorghe Marinescu nr. 38\n540136 Targu Mures, Romania\nTel: +40 265 215 551\nEmail: drtraianirimia@gmail.com\nARTICLE HISTORY\nReceived: June 29, 2023\nAccepted: August 1, 2023\nParadigm Shift for Endometriosis and \nthe Potential Role of Genetic Testing \n– Going Beyond the 2022 ESHRE \nGuidelines for Endometriosis\nTraian Irimia, Andrada Crișan, Teodora Cotruș, Vlad Tudorache, Mariam Dalaty, Marian Melinte, \nIoana Melinte\n“George Emil Palade” University of Medicine, Pharmacy, Science and Technology, Târgu Mureș, Romania\nCLINICAL UPDATE GYNECOLOGY // INFECTOLOGY\n DOI: 10.2478/jim-2023-0006\nABSTRACT\nEndometriosis is a chronic inflammatory gynecological disease affecting 190 million women \nor 10% of women of reproductive age worldwide. The disease is marked by the presence of \nendometrial-like tissue outside the uterus, being associated in many cases with chronic pain \nand infertility. The current recommendations of international professional societies underline \nthe need for laparoscopy, eventually followed by histological verification, as the gold standard \nfor diagnosis. However, many societies recommend the initiation of specific treatment be-\nfore obtaining a definitive surgical diagnosis. Various national and international societies have \nreleased guidelines for endometriosis assessment based on biomarkers; however, none of \nthese recommendations proved to be clinically useful or able to replace diagnostic laparosco-\npy. In recent years it was demonstrated that oxidative stress, defined as an imbalance between \nreactive oxygen species and antioxidants that is directly linked with an increased inflammatory \nresponse in the peritoneal cavity, may be involved in the pathophysiology of endometriosis. \nThe identification of a genetic predisposition for endometriosis can identify the patients at risk \nand may help clinicians promptly initiate therapeutic management of their patients in order to \nameliorate their prognosis.\nKeywords: endometriosis, laparoscopy, biomarkers, oxidative stress\nAndrada Crișan • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: crisanandrada@yahoo.com\nTeodora Cotruș • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: cotrus.teodora12@gmail.com\nVlad Tudorache • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: vlad.tudorache1994@gmail.com\nMariam Dalaty • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: mariam_dalaty@yahoo.com\nMarian Melinte • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: marianmelinte01@gmail.com\nIoana Melinte • Str. Gheorghe Marinescu nr. 38, \n540136 Târgu Mureș, Romania. Tel: +40 265 215 551, \nEmail: ioanammelinte@gmail.com\nEndometriosis is a chronic inflammatory condition associated with severe pain \nand subfertility affecting approximately 190 million women and adolescent girls \nworldwide.1,2 It is a complex disease of controversial etiology, defined by the pres-\nence of endometrial-like tissue outside the uterus. The socioeconomic burden of \nendometriosis, which affects not only the women with the disease but also their \npartners, may be similar to Crohn’s disease, diabetes, and rheumatoid arthritis, \nmostly because of the associated infertility and the way it affects the patient’s \nquality of life including work, education, social and intimate life, and general \n\nJournal of Interdisciplinary Medicine 2023;8(1):34-36 35\nwellbeing.3–6  Furthermore, the average time from symptom \nonset to diagnosis is currently between 8 to 12 years, which \nmay be explained by the lack of clearly established or accu-\nrate noninvasive diagnostic tests or biomarkers. \nTreatment options for endometriosis include: 1) surgi-\ncal treatment, consisting in the surgical removal of endo -\nmetriotic lesions and adhesions; 2) hormonal treatment, \nwhich suppresses endogenous estrogen levels and has pro-\napoptotic and anti-inflammatory effects on endometriotic \ntissues; 3) the management of chronic pain.1–6\nThe European Society of Human Reproduction and \nEmbryology (ESHRE) has published a series of evidence-\nbased recommendations in their 2022 guideline on the \ncare of women with endometriosis. While the role of these \nrecommendations is clearly established, there is a signifi-\ncant unmet clinical need to improve many aspects related \nto the diagnosis and treatment of this condition. 6 The aim \nof this paper is to challenge the current paradigm of lapa-\nroscopic identification of endometriotic lesions with his -\ntological verification as the gold standard for the diagnosis \nof endometriosis. \nRoutinely used in many countries for the diagnosis of \nendometriosis, laparoscopy is an invasive surgical proce -\ndure that requires general anesthesia and is associated with \nmorbidity and even mortality. 7–10  However, given the im-\nprovements in the technological caliber and accessibility of \nimaging modalities for some types of endometriosis on the \none hand, and the risks and costs associated with surgery, \nas well as the difficulty of accessing highly skilled surgeons \non the other, there is an urgent need for a revision of this \nparadigm. Furthermore, it is crucial to develop new non-\ninvasive techniques and improve those that already exist in \norder to accurately diagnose or rule out endometriosis. 6–8\nSeveral biomarkers have been proposed for the early, \nnoninvasive diagnosis of endometriosis, but their efficien-\ncy has to be demonstrated in clinical studies with adequate \noutcome measurement and standardized biological sam-\nple collection and storage protocols.6,11,12 So far, the results \nof the studies assessing the use of these biomarkers in the \ndiagnosis of endometriosis have been disappointing. 6,12,13\nSome of the biomarkers proposed for the diagnosis \nof endometriosis, such as neuronal marker protein gene \nproduct 9.5 (PGP 9.5), vasoactive intestinal polypeptide \n(VIP), substance P (SP), neuropeptide Y (NPY), or cal-\ncitonin gene-related peptide (CGRP), are used to differ-\nentiate ovarian endometrioma from other ovarian tumors. \nHowever, the available evidence does not support their \nuse for the diagnosis of endometriosis. 6,12–14\nAnother proposed biomarker is cancer antigen 125  \n(CA-125), an inexpensive and widely available tumor \nmarker. A systematic review of 19 prospective and 3 ret-\nrospective observational studies involving 3,626 partici-\npants with histologically confirmed endometriosis found \na specificity of 93% but a sensitivity of only 52% for endo -\nmetriosis.6,15 Evidence suggests that CA-125 can be used \nas a screening marker in symptomatic patients, but its low \nsensitivity means that a negative result does not rule out \nendometriosis,6 and a positive result may cause anxiety \nfor the patient and increase the risk of overtreatment. As \na result, studies suggest that CA-125 should not be used \nroutinely for the diagnosis of endometriosis. 6 \nOther studies, investigating the clinical usefulness of \nmiRNAs (known to control genes involved in the etiology \nof endometriosis) as biomarkers of endometriosis, have \nalso yielded mixed results.6,16,17\nOverall, evidence suggests that currently there are no \nbiological markers that can reliably aid the diagnosis of \nendometriosis. Therefore, the authors of the 2022 ES -\nHRE guideline concluded that “clinicians should not use \nmeasurement of biomarkers in endometrial tissue, blood, \nmenstrual or uterine fluids to diagnose endometriosis.” 6 \nThis makes genetic testing linked to the pathogenic pro -\ncess of endometriosis an intriguing area of study.18,19 \nRecent studies have focused on other factors that may \ncontribute to the development of endometriotic lesions \nsuch as familiar propensity and genetic predisposition. \nThe pathophysiology of endometriosis may involve oxida-\ntive stress, an imbalance between reactive oxygen species \nand antioxidants that results in a general inflammatory re -\nsponse in the peritoneal cavity. 19 Reactive oxygen species \nare intermediaries produced by the normal oxygen metab-\nolism and are inflammatory mediators known to modulate \ncell proliferation and to have deleterious effects.19\nOne of our previous studies sought to determine wheth-\ner there was a relationship between endometriosis-related \ninfertility and four genetic variants of antioxidant enzymes \ninvolved in oxidative stress.18 In this case-control study, the \nfirst of this kind in Eastern European women, we investi-\ngated the genetic polymorphism of four genes and selected \nthose that encode antioxidant enzymes involved in oxida-\ntive stress: glutathione peroxidase 1, GPX1 198Pro > Leu, \ncatalase CAT-262C > T, glutathione S-transferase M1, and \nT1 null genotype. We investigated the association between \nthese polymorphisms and endometriosis-related infertili-\nty in 103 patients with endometriosis-associated infertility \nand a control group of 102 post-partum women. The vari-\nant genotypes were significantly more frequent in the en-\ndometriosis group for the CAT-262C > T polymorphism, \nand the CT and TT genotypes were also significantly more \nfrequent compared in the endometriosis group in respect \n\nJournal of Interdisciplinary Medicine 2023;8(1):34-3636\nto the GPX1 198Pro > Leu. The null genotype of GSTM1 \nwas also detected with a significantly higher frequency \nin the endometriosis group. However, there were no sig-\nnificant differences between the two groups in respect \nto the frequency of GSTT1. These results suggested that \nGPX1 198Pro  > Leu, CAT-262C > T, and GSTM1 poly-\nmorphisms may predispose patients to develop endome -\ntriosis, the association between the GSTM1-GSTT1 null \ngenotype may play a significant role in endometriosis-\nassociated infertility, and the GSTT1 null genotype does \nnot influence the disease.18 These results are in accordance \nwith two meta-analyses that also concluded that the as -\nsociation of both null genotypes for GSTT1-GSTM1 may \nbe related to endometriosis. 20,21 Given that ethnicity and \nenvironmental factors play a significant role in the devel-\nopment endometriosis, some of our findings that are in \ncontrast with data from the literature may be explained by \ndemographic variances.18\nTherefore, the question arises: is it time to stop using \nmicroscopic confirmation of endometriotic lesions as the \ngold standard for diagnosing endometriosis? Looking at \nthe published results on biomarkers it is hard to declare \nthat this approach is obsolete. For the early diagnosis of \nthis condition, a panel of genetic or laboratory markers \nis required, especially in the case of young patients who \nintend to become pregnant in the future. Besides the \nconventional treatment methods, the management of \nendometriosis should include strategies that involve the \ncommunity and ensure a higher quality of life for these pa-\ntients. These strategies should focus on the establishment \nof readily available integrated services that increase the \nstandard of care for women with endometriosis, beginning \nfrom adolescence. \nOver the years, laparoscopy has become the gold stan-\ndard method for the diagnosis of endometriosis. The pre -\nferred method to replace laparoscopy would have to be \nnoninvasive, dependable, and affordable, with good sen-\nsitivity and specificity. Large-scale international, multi-\ncenter investigations with independent validation using \ncutting-edge technological platforms, thorough standard-\nized phenotyping, and sufficient financing are urgently \nneeded to move away from the reliance on invasive diag-\nnostic methods like laparoscopy under general anesthesia.\nCONFLICT OF INTEREST \nNothing to declare.\nREFERENCES\n1. Giudice LC. Endometriosis. N Engl J Med. 2010;362:2389–2398.\n2. Hickey M, Ballard K, Farquhar C. Endometriosis. BMJ. 2014;348:1–9.\n3. Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: \ncosts and quality of life of women with endometriosis and treated in \nreferral centres. Hum Reprod. 2012;27:1292–1299.\n4. Horne AW, Saunders PTK, Abokhrais IM, Hogg L. Top ten endometriosis \nresearch priorities in the UK and Ireland. Lancet. 2017;389:2190–2191.\n5. Culley L, Law C, Hudson N, et al. The social and psychological impact of \nendometriosis on women’s lives: a critical narrative review. Hum Reprod \nUpdate. 2013;19:625–639.\n6. Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis. \nHum Reprod Open. 2022;1–26. \n7. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the \ndiagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698–\n2704. \n8. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: \nmanagement of women with endometriosis. Hum Reprod. 2014;29:400–\n412.\n9. Bafort C, Beebeejaun Y, Tomassetti C, Bosteels J, Duffy JMN. \nLaparoscopic surgery for endometriosis. Cochrane Database Syst Rev. \n2020;10:CD011031.\n10. Chapron C, Querleu D, Bruhat MA, et al. Surgical complications of \ndiagnostic and operative gynaecological laparoscopy: a series of 29,966 \ncases. Hum Reprod. 1998;13:867–872.\n11. Duffy J, Hirsch M, Vercoe M, et al. A core outcome set for future \nendometriosis research: an international consensus development study. \nBJOG. 2020;127:967–974. \n12. Gupta D, Hull ML, Fraser I, et al. Endometrial biomarkers for the non-\ninvasive diagnosis of endometriosis. Cochrane Database Syst Rev. \n2016;4:Cd012165. \n13. Nisenblat V, Bossuyt PM, Shaikh R, et al. Blood biomarkers for the non-\ninvasive diagnosis of endometriosis. Cochrane Database Syst Rev. \n2016:Cd012179. \n14. Liu E, Nisenblat V, Farquhar C, et al. Urinary biomarkers for the non-\ninvasive diagnosis of endometriosis. Cochrane Database Syst Rev. \n2015:Cd012019. \n15. Hirsch M, Duffy J, Davis CJ, Nieves Plana M, Khan KS. Diagnostic accuracy \nof cancer antigen 125 for endometriosis: a systematic review and meta-\nanalysis. BJOG. 2016;123:1761–1768.\n16. Moustafa S, Burn M, Mamillapalli R, Nematian S, Flores V, Taylor HS. \nAccurate diagnosis of endometriosis using serum microRNAs. Am J \nObstet Gynecol. 2020;223:557e551–557e511. \n17. Bendifallah S, Dabi Y, Suisse S, et al. Validation of a Salivary miRNA \nSignature of Endometriosis — Interim Data. N Engl J Med. 2023;2. \n18. Irimia T, Puscasiu L, Mitranovici M, et al. Oxidative-Stress Related \nGene Polymorphism in Endometriosis-Associated Infertility. Medicina. \n2022;58:1105. \n19. Scutiero G, Iannone P, Bernardo G, Bonaccorsi G, Spadaro S, Nappi G. \nOxidative Stress and Endometriosis: A Systematic Review of the Literature. \nOxid Med Cell Longev. 2017;2017:7265238. \n20. Zhu H, Bao J, Liu S, Chen Q, Shen H. Null genotypes of GSTM1 and GSTT1 \nand endometriosis risk: A meta-analysis of 25 case-control studies. PLoS \nONE. 2014;9:e106761. \n21. Xin X, Jin Z, Gu H, et al. Association between glutathione S-transferase M1/\nT1 gene polymorphisms and susceptibility to endometriosis: A systematic \nreview and meta-analysis. Exp Med. 2016;11:1633–1646.","source_license":"CC0","license_restricted":false}