{"paper_id":"eb989a58-10c5-4b36-9b73-52b50da5733c","body_text":"Copyright@ J Bouquet de Joliniere | Biomed J Sci & Tech Res| BJSTR. MS.ID.002804.\n11803\nMini Review\nISSN: 2574 -1241\nA New Hypothesis for Endometriosis: To Change the \nClassification and Consider A New Concept of its Origin\nJ Bouquet de Joliniere*1, A Major1, JM Ayoubi2, R Frydman2 and A Feki1\n1Department of Gynecology and Obstetrics, Cantonal Hospital of Fribourg, Switzerland\n2Department of Gynecology and Obstetrics, Foch Hospital, France\n3Department of Anatomopathology, Switzerland\n*Corresponding author: J Bouquet de Joliniere, Department of Gynecology and Obstetrics, HFR, Cantonal Hospital of Fribourg, \nSwitzerland\n DOI: 10.26717/BJSTR.2019.16.002804\nReceived: \n   March 11, 2019\nPublished: \n   March 19, 2019\nCitation: J Bouquet de Joliniere, A Ma -\njor, JM Ayoubi, R Frydman, A Feki.  A \nNew Hypothesis for Endometriosis: To \nChange the Classification and Consider \nA New Concept of its Origin . Biomed \nJ Sci & Tech Res 16(1)-2019. BJSTR. \nMS.ID.002804.\nARTICLE INFO abstract\nKeywords: Endometriosis; AFS Classification; Phenotype; Genotype; Breast Cancer\nAbbreviations: AFS: American Fertility Society; IVF: Vitro Fertilization Program; ESHRE: \nEuropean Society of Human Reproductive Medicine; PCD: Premature Centromere \nDisjunctions; LOH: Loss of Heterozygosity; FISH: Fluorescence in Situ Hybridization; \nROS: Reactive Oxygen Species; CGH: Comparative Genomic Hybridization\nIntroduction\nEndometriosis is a curious pathology that has been the \nsource of many international publications. Its etiology remains \nmysterious but seems to have multiple causes. It is a complex \ndisease whose lesions are very heterogeneous on the part of their \nlocation (deep endometriosis, superficial, ovarian cyst), extent, \nassociated symptoms, evolution or aggressiveness of the disease, \nand response to treatments [1]. This Disease Can Be Compared to \na Malignant Proliferation as a breast cancer for instance because \nthere are sexual receptors, differentiation grade, tumoral markers, \nmetastasis. Furthermore, it evolves in pushes, remains autonomous, \nand is responsible for superficial and deep lesions that explain its \ntwo challenges: pain and infertility. It has always been classified by \nthe size of its anatomical lesions-Acosta classification [2], revised by \nthe American fertility society (AFS) [3], and the American society of \nreproductive medicine (ASRM) classification with a description of \nthe disease at different stages: minimal (score of 1 to 5), mild [4-\n13], moderate [13-32], and severe (>40) [18]. If this classification \nprovides a complete repertoire of implants (anatomic) [11], the  \n \nattribution of points is arbitrary. In fact, the size of the lesions is \nnot synonymous with the difficulty to treat them surgically. Their \nlocation, if deep, is larger than the size of ovarian endometriomas. \nIn addition, small anatomical but evaluative lesions will have more \nimpact than big fibrous and stable lesions (Figure 1). \nFigure  1: Small inflammatory lesions of endometriosis.\n\n\nCopyright@ J Bouquet de Joliniere | Biomed J Sci & Tech Res| BJSTR. MS.ID.002804.\nVolume 16- Issue 1\nDOI: 10.26717/BJSTR.2019.16.002804\n11804\nThus, attempts to explain their inflammatory side effect have \nbeen proposed [11,33]. The French classification nodule, ovaries, \nadhesions, tube and inflammation (FOATI) [11] has had the merit \nof taking the phenomenon into account. In our opinion, we must \ngo much further and propose an amendment in this classification, \ntaking into account the evolution of the lesions and their deep \nmolecular biology because in reality, the lesions are not at the \nsame stage. We have begun to demonstrate [9] an embryological \norigin, chromosomal instability, as well as genomic and proteomic \nabnormalities [34-36]. These problems are related to pharmacologic \ntesting during a wild hormone therapy that does not take into \naccount the phenotype of lesions. Indeed, it is possible using a \ncommon model, breast cancer. An endometriosis profile is necessary \nto know its phenotype, such as hormone receptors, proliferation \nof rank, Mib-1or (Ki 67%), growth factors, and oncogenic factors \n[35–37]. The peritoneal fluid is one of the factors of endometriosis \ndiffusion in the ovaries [7,37], deep forms under and peritoneal. In \norder to address the need of improving endometriosis diagnosis \nand management, we have developed Endo Gram®, a prognostic \ntest based on a signature of 14 biomarkers and validated in a first \nprospective study. \nFor each patient, it allows to determine: \na) the risk of recurrence of the disease at two years in order \nto identify the patients with a high risk of recurrence from the \nfirst diagnostic surgery, and to adapt their follow-up to better \ndetect the recurrence of the disease; \nb) the presence or absence of the receptors targeted by the \nhormone treatments used at the present time-this information \non hormonal sensitivity will serve as a decision-making aid for \nthe surgeon to prescribe the most appropriate and effective \ntherapeutic strategy; and \nc) the best fertility strategy if desire for pregnancy. For the \nlast one, depending on the age of the patient and the profile of \nher lesion as defined by the Endo Gram® test, the surgeon will \nbe able to optimize the patient’s fertility strategy and reduce \nthe number of failed In Vitro Fecundation (Figure 2). \nFigure  2: Typical ectensiv small lesions in Douglas poach.\nThus, some minimal anatomical forms are very aggressive with \ninfertility, medication ineffectiveness, and persistence/recurrence \ndespite surgery [37], where large ovarian cysts accessible to lapa -\nroscopic surgery do not reoffend. This makes the surgical diagnosis \nof the disease and its management difficult, as well as still too de -\npendent on the experience and dexterity of the surgeon. To meet \nthis clearly identified need, the Endo Gram® program has the aim \nof identifying specific markers of this heterogeneity and giving a \nunique and personal photograph of the stage of endometriosis for \neach patient, through an innovative analysis of the biopsies taken \nduring diagnostic surgery. This information can then be used by \nthe surgeon to adjust the therapeutic approach in particular. This \narticle reveals all the characteristics of the disease for each patient. \nThis article allows defining a therapeutic attitude whose primary \ngoal is not to let the time of the in vitro fertilization program (IVF) \npass in young patients, and to respect the recommendations of the \nEuropean Society of human reproductive medicine (ESHRE) [38] \non a single, non-aggressive surgery that respects the ovaries and \ntheir follicular count. It should also be noted that this proliferative \nside explains that pregnancy and menopause do not cure the dis -\nease but can only improve it. New molecules can be used according \nto this profile.\nHypothesis, a Warburg Effect?\nThe origin of the disease remains obscure. However, a possible \nembryological origin has been demonstrated by a preliminary \nstudy [9]. The need to define proliferation markers is related to \nprevious studies of the causes of proliferation [5,7,36]. The lesions \nhave genetic abnormalities that are found statistically in almost all \nlesions: damage found by chromosomal instability of the nucleus \nDNA and on the p and q arms of chromosomes 1p, 7p, and 22q \n[7] (Figure 3). Furthermore, the chromosomal instability is an \nalteration of the chromosome constitution occurring in various \npathological conditions, such as the fundamental property of \nneoplastic cells, precancerous lesions, chronic inflammatory \nconditions, infectious diseases, and diseases induced by viruses \n(herpes, Human Papilloma Virus, Epstein Barr Virus).\nFigure  3: Genomic abnormalities in most of endometriosis \nimplants.\n\n\nCopyright@ J Bouquet de Joliniere | Biomed J Sci & Tech Res| BJSTR. MS.ID.002804.\nVolume 16- Issue 1\nDOI: 10.26717/BJSTR.2019.16.002804\n11805\nThe genomic instability appears in two different types: \ni) chromosomal alterations in non-neoplastic precursor \nlesions and mutation of the P53 gene, and \nii) errors in DNA replication detected by microsatellite \ninstability (deficiency in DNA mismatch repair mechanism). \nFor endometriosis, we have observed such instability with \nchromosome number changes [5], chromosomal deletions [7], \ntranslocations and point mutations in particular genes, nuclear \nDNA content, telomerase function, errors in DNA replication [36-\n37], presence of endo mitosis, premature centromere disjunctions \n(PCD), and micronuclei.\nIn a previous publication [7], the authors showed a loss of \nheterozygosity (LOH). These studies have been conducted using \nDNA from histologically homogeneous endometriotic tissues. \nForty lesions were studied, wherein the authors found that \ninactivation of tumor suppressor gene(s) may play a role in the \ndevelopment of endometriosis. Fluorescence in situ hybridization \n(Fish) analysis has revealed more clonal aberrations than \nconventional cytogenetic analysis in a number of altered tissues \n[27]. However, the comparative genomic hybridization (CGH) is \nthe best test as a molecular cytogenetic method able to discover \nand map genomic regions for chromosomal gains and/or losses \nin a single experiment [26]. Regions showing an increased copy \nnumber (gain or amplification) may harbor dominant oncogenes, \nwhereas regions with a decreased copy number (loss) may contain \ntumor suppressor genes [7]. Therefore, it is the loss of either \nessential genes or even entire chromosomes that explains the high \ninvasive potential of the endometriotic cells. Genomic alterations \n(rearrangements) initiated by telomere dysfunction, for instance, \ncan be a primary event that facilitates endometriosis initiation \nand spread [36]. In another publication [39], the authors showed \nthat an aerobic glycolysis marker expression is increased in \nendometriosis lesions compared to eutopic endometrium and in \nthe peritoneum of women with endometriosis compared to women \nwithout endometriosis.\nAnother Hypothesis\nIn the beginning, there are ectopic endometrial cells derived \nfrom cells having embryologic origin [9] that missed migration to \nthe urogenital sinus. These cells will therefore stay in an ectopic \nlocation. The other well-known cause is the retrograde flow of cells \nin the peritoneal cavity during menstruation. In 80–90% of women, \nretrograde menstruation is observed [32], but compared to these \nnumbers, only 10% of the female population present endometrioses. \nEndometrioses may be induced by mesenchymal cells, stem cells, \nor endometrial tissue [5,30]. All these cells will initiate a reaction of \nthe immune system. This reaction will be different depending on its \norigin and be influenced by the genetics of the cells. Once puberty \nstarts with the release of sexual hormones, ectopic endometrial \ncells are stimulated and even if they are in a vascular unfavourable \nplace, they start to propagate. This event initiates several processes \nin a cascade manner. First, production of reactive oxygen species \n(ROS) is stimulated by an increased metabolic turnover of cells \nand activation of factors for angiogenesis, attracting stem cells for \nneovascularization through cell signaling by ROS. \nSecond, oxidative stress is provoked by several factors including \nstimulation by sexual hormones in concert with propagation of \ncells (increased energy production in mitochondria), immune \nreaction of the peritoneum (an immunologic reactive organ), and \ndegradation of hemoglobin and toxic effect of iron by the Fenton \nreaction. ROS production itself serves as stimulus by cell signaling \nfor more propagation and immune reaction with a positive feedback \nmechanism potentiating it. Third, an important misbalance between \nROS and the anti-oxidative defence mechanism of the cell becomes \ntoxic and induces chromosome instability. If the shock is significant, \nDNA damage can occur followed by necrobiosis. Finally, all these \nprocesses can change the cell metabolism and induce aerobic \nglycolysis [30]. This switch, termed Warburg effect, is to satisfy \nthe needs for structural molecules like lipids, proteins, and nucleic \nacids, and at the same time, to diminish oxidative phosphorylation \nto protect the cell from the damaging effect of ROS by decreasing \nthe production of too much ROS. In certain circumstances, \ninflammation, acidosis, and continuous DNA damage by ROS \ncan even drive endometrioses to malignant transformation [29], \ndepending on four factors: origin of cells, reaction of the immune \nsystem, location of ectopic endometrial cells, and ingestion of \nhormones and toxic molecules. \nAll these factors interact with each other and are driving into \na new balance, which will be different depending on the staging of \nendometriosis and the endogram. Endometriosis causes important \ninflammation by the interaction with the environment, thereby \nincreasing ROS production [41-43]. In turn, ROS induces DNA \ndamage, while endometriosis produces cytokines. Unfortunately, \nthere is no efficient and causal treatment for endometriosis. This \nmakes the surgical diagnosis of the disease and its management \ndifficult, as well as still too dependent on the experience and \ndexterity of the surgeon. To meet this clearly identified need, \nEncoding has developed the EndoGram® program with the aim \nof identifying specific markers of this heterogeneity and giving a \nunique personal photograph of the stage of endometriosis for each \npatient, through an innovative analysis of the biopsies taken during \ndiagnostic surgery.\nReferences\n1. J Bouquet de Joliniere, A Major, JM Ayoubi, R Cabry, F Khomsi, et al. It \nIs Necessary to Purpose an Add-on to the American Classification \nof Endometriosis? This Disease Can Be Compared to a Malignant \nProliferation While Remaining Benign in Most Cases. EndoGram ® Is a \nNew Profile Witness of Its Evolutionary Potential. (under submission \nwith Frontiers on surgery).\n2. Acosta AA, Buttram VC, Besch PK, Malinak, L Rushell, et al. (1973) A \nproposed classification of pelvic endometriosis. Obstet Gynecol 42(1): \n19.\n\nCopyright@ J Bouquet de Joliniere | Biomed J Sci & Tech Res| BJSTR. MS.ID.002804.\nVolume 16- Issue 1\nDOI: 10.26717/BJSTR.2019.16.002804\n11806\n3. American Fertility Society (1985) Revised American Fertility Society \nclassification of endometriosis. Fertil Steril 43(3): 351-352.\n4. Bouquet de Joliniere J (2007) Effect of radiofrequency fields on \nendometriotic cell growth in vitro: a prospective study for laparoscopic \ntreatment. J Minim Invasive Gynecol 14(S6): 14-15.\n5. Bouquet de Joliniere J, Lesec G, Real C, Ayoubi JM (2011) Novel molecular \nstrategy tests, issued by laparoscopy, that can predict the progression \nand severity of endometriotic disease. J Minim Invasive Gynecol 18(S6): \n51.\n6. Fadhlaoui A, Bouquet de Joliniere J, Feki A (2014) Endometriosis and \ninfertility: how and when to treat? Front Surg 1: 24.\n7. Bouquet de Joliniere J, Ayoubi JM, Gianaroli L, Dubuisson JB, Gogusev J, et \nal. (2014) Endometriosis: a new cellular and molecular genetic approach \nfor understanding the pathogenesis and evolutivity. Front Surg 1: 16.\n8. Bouquet de Joliniere J, Ayoubi JM, Lesec G, Validire P , Goguin A, et al. \n(2012) Identification of displaced endometrial glands and embryonic \nduct remnants in female fetal reproductive tract: possible pathogenic \nrole in endometriotic and pelvic neoplastic processes. Front Physiol 3: \n444.\n9. Fadhlaoui A, Gillon T , Lebbi I, Bouquet de Joliniere J, Feki A (2015) \nEndometriosis and vesico-sphincteral disorders. Front Surg 2: 23.\n10. Carbonnel M, N’guyen HT , Abbou H, Bouquet de la Joliniere J, Ayoubi \nJM (2013) Robotic laparoscopy in benign gynecologic surgery: a \nretrospective study comparing vaginal, laparoscopic and robotic \nhysterectomy procedures. Reprod Syst Sex Disord 2: 1-5.\n11. Tran DK, Belaisch J (2012) Is it the time to change the ASRM classification \nfor endometriosic lesions? Proposal for a functional FOATIaRVS \nclassification. Gynecol Surg 9: 739.\n12. Bouquet de Jolini ère J, Feki A, JM Ayoubi (2014) The key points in \ngynecology: endometriosis, an atypical and topical disease. The \nEuropean of publishing. Régimédia 1: 17-24.\n13. Wicks MJ, Larson CP (1949) Histologic criteria for evaluating \nendometriosis. Northwest Med 48: 610-611.\n14. Huffmann JW (1951) External endometriosis. Am J Obstet Gynecol \n62(6): 1243-1252.\n15. Mitchell GW, Farber M (1974) “Medical versus surgical management \nof endometriosis” . In: Reed D, Christian D, Saunders W, editors. \nControversies in obstetrics and gynecology 2: 629.\n16. Kitsner RW, Siegler AM, Berhman SJ (1977) Suggested classification \nfor endometriosis: relationship to infertility. Fertil Steril (1977) 28(9): \n1008-1010.\n17. Buttram VC (1978) An expanded classification of endometriosis. Fertil \nSteril 30(2): 240-242.\n18. American Fertility Society (1979) Classification of endometriosis. Fertil \nSteril 32: 633.\n19. Tran DK, Belaish J (1991-1992) Classification of endometriosis. Vth \nWorld Congress on Endometriosis, Yokohama. In: Endometriosis today. \nParthenon Publishing Group, pp. 259-267.\n20.  Adamson GD, Pasta DJ (2010) Endometriosis fertility index: the new, \nvalidated endometriosis staging system. Fertil Steril 94(5): 1609-1615.\n21. Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, et al. \n(2012) The burden of endometriosis: costs and quality of life of women \nwith endometriosis and treated in referral centres. Hum Reprod 27(5): \n1292-1299. \n22. Palmisano GP , Adamson GD, Lamb EJ (1993) Can staging systems for \nendometriosis based on anatomic location and lesion type predict \npregnancy rates? Int J Fertil Menopausal Stud 38(4): 241-249.\n23. Vercellini P , Fedele L, Aimi G, Pietropaolo G, Consonni D, et al. (2007) \nAssociation between endometriosis stage, lesion type, patient \ncharacteristics and severity of pelvic pain symptoms: a multivariate \nanalysis of over 1000 patients. Hum Reprod 22(1): 266-271.\n24. Adamson GD (2011) Endometriosis classification: an update. Curr Opin \nObstet Gynecol 23(4): 213-220.\n25. De Conto E, Matte Ú, Bilibio JP , Genro VK, Souza CA, et al. (2017) \nEndometriosis-associated infertility: GDF-9, AMH, and AMHR2 genes \npolymorphisms. J Assist Reprod Genet 34(12): 1667-1672.\n26. Kallioniemi A, Kallionemi OP , Sudar D, Rutowitz D, Gray JW, et al. (1992) \nComparative genomic hybridization for molecular cytogenetic analysis \nof solid tumors. Science 258(5083): 818-821.\n27. Tapper J, Sarantaus L, Vahteristo P , Nevanlinna H, Hemmer S, et al. (1998) \nGenetic changes in inherited and sporadic ovatian carcinoma by CGH: \nextensive similarity except for a difference at chromosome 2q24-q32. \nCancer Res 58: 2715-2719.\n28. Latowska AM, Lillington MD, Shelling AN, Cooke I, Gibbons B, et al. \n(1994) FiSH analysis using cosmid probes to define chromosome 6q \nabnormalities in ovarian carcinoma cell lines. Cancer Genet Cytogenet \n77(2): 99-105. \n29. Jafarabadi M, Salehnia M, Sadafi R (2017) Evaluation of two \nendometriosis models by transplantation of human endometrial tissue \nfragments and human endometrial mesenchymal cells. Int J Reprod \nBiomed (Yazd) 15(1): 21-32.\n30. Iwabuchi T , Yoshimoto C, Shigetomi H, Kobayashi H (2015) Oxidative \nstress and antioxidant defense in endometriosis and its malignant \ntransformation. Oxid Med Cell Longev, pp. 848595. \n31. Young VJ, Brown JK, Maybin J, Saunders PT , Duncan WC, et al. (2014) \nTransforming growth factor-β induced Warburg-like metabolic \nreprogramming may underpin the development of peritoneal \nendometriosis. J Clin Endocrinol Metab 99(9): 3450-3459. \n32. Halme J, Becker S, Wing R (1984) Accentuated cyclic activation of \nperitoneal macrophages in patients with endometriosis. Am J Obstet \nGynecol 148(1): 85-90.\n33. Canis M, Bouquet de Joliniere J, Wattiez A, Pouly JL, Mage G, et al. (1993) \nClassification of endometriosis. Baillieres Clin Obstet Gynaecol 7(4): \n759-774.\n34. Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, et \nal. (2000) Genetic abnormalities detected by comparative genomic \nhybridization in a human endometriosis-derived cell line. Mol Hum \nReprod 6(9): 821-827.\n35. Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, et \nal. (2000) Cellular and genetic constitution of human endometriosis \ntissues. J Soc Gynecol Investig 7(2): 79-87.\n36. Gogusev J, Bouquet de Joliniere J, Telvi L, Doussau M, du Manoir S, \nStojkoski A, et al. (1999) Detection of DNA copy number changes in \nhuman endometriosis by comparative genomic hybridization. Hum \nGenet 105(5): 444-451.\n37. Bouquet de Joliniere J, Validire P , Canis M, Doussau M, Levardon M, et \nal. (1997) Human endometriosis-derived permanent cell line (FbEM-1): \nestablishment and characterization. Hum Reprod Update 3(2): 117-123.\n38. Bouquet de Jolini ère J, Feki A, JM Ayoubi (2014) The key points in \ngynecology: endometriosis, an atypical and topical disease. The \nEuropean of publishing. Régimédia 1: 17-24.\n39. Vinatier D, Dufour P , Oosterlynck D (1996) Immunological aspects of \nendometriosis. Hum Reprod Update 2(5): 371-384.\n40. Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, et al. (2002) Estrogen \nproduction and metabolism in endometriosis. Ann N Y Acad Sci 955: 75-\n85.\n41. Nephew KP , Ray S, Hlaing M, Ahluwalia A, Wu SD, et al. (2000) Expression \nof estrogen receptor coactivators in the rat uterus. Biol Reprod 63(2): \n361-367.\n\nCopyright@ J Bouquet de Joliniere | Biomed J Sci & Tech Res| BJSTR. MS.ID.002804.\nVolume 16- Issue 1\nDOI: 10.26717/BJSTR.2019.16.002804\n11807\n42. Da Broi MG, Navarro PA (2016) Oxidative stress and oocyte quality: \nethiopathogenic mechanisms of minimal/mild endometriosis-related \ninfertility. Cell Tissue Res 364(1): 1-7. \n43. Miller JE, Ahn SH, Monsanto SP , Khalaj K, Koti M, et al. (2017) \nImplications of immune dysfunction on endometriosis associated \ninfertility. Oncotarget 8(4): 7138-7147.\nSubmission Link: https://biomedres.us/submit-manuscript.php\nAssets of Publishing with us\n• Global archiving of articles\n• Immediate, unrestricted online access\n• Rigorous Peer Review Process\n• Authors Retain Copyrights\n• Unique DOI for all articles\nhttps://biomedres.us/\nThis work is licensed under Creative\nCommons Attribution 4.0 License\nISSN: 2574-1241\nDOI: 10.26717/BJSTR.2019.16.002804\nJ Bouquet de Joliniere. Biomed J Sci & Tech Res","source_license":"CC0","license_restricted":false}