{"paper_id":"6219d373-c891-4afb-9ac8-325875113722","body_text":"Editorial\nWhat the Transcriptome of the Eutopic Endometrium from\nWomen with Endometriosis tells us about the Disease\nPathophysiology: A Brief Re flection\nOmero Benedicto Poli-Neto 1 Juliana Meola 1 Julio Cesar Rosa-e-Silva 1\n1 Department of Gynecology and Obstetrics, Division of\nGynecological Surgery, Faculty of Medicine, Universidade de\nS ã oP a u l o ,R i b e i r ã oP r e t o ,S P ,B r a z i l\nRev Bras Ginecol Obstet 2020;42(10):593 –596.\nEndometriosis is characterized by the presence of endometrial-\nlike tissue outside the uterine cavity, usually represented by\ndeep peritoneal, ovarian and/or infiltrative lesions1,2 and, more\nrarely, in extrapelvic sites.3 The estimated prevalence is of 5 to\n10% of reproductive-age women,4–6 despite the suggestion of\nan actual lower prevalence, of up to 1.8%, in a recently\npublished study based on a population of two million individ-\nuals.\n7 The incidence, in turn, is more dif ficult to be estimated,\nbut seems to be between 1.3 to 1.6 cases per 1,000 women in\nthis same age group.\n8 Even considering this wide variation, if\nextrapolating to the Brazilian female population aged between\n15 and 50 years estimated in the last census of 2010, there may\nbe between 1 million and more than 5 million women with\nendometriosis, which is a very expressive number. Women\nwith endometriosis may be asymptomatic or have varied\nsymptoms, with the most frequent being pain (dysmenorrhea,\ndyskinesia, acyclic pain, dyspareunia) and infertility, followed\nby abnormal uterine bleeding and ovarian mass.\n9,10 Despite\nthese associations, there are no clinical symptoms or signs that\nare good predictors of the disease,11,12 which culminates in the\ndifficulty of an accurate clinical diagnosis. 13 Other important\naspects are the absence of a correlation between the severity of\nsymptoms and extent of the disease, 14 the presence of endo-\nmetriosis in a reasonable number of asymptomatic women,15\nand the lack of knowledge about the events determining the\nnatural evolution of the disease, be it spontaneous progression\nor regression.\n16 Nonetheless, the disease is associated with a\nsignificant psychological and social impact, negative repercus-\nsions on the woman’s quality of life17 and productivity,18 and\nrelevant socioeconomic burden.19,20\nSeveral theories have been proposed to explain the origin of\nthe disease, among which are theories of retrograde menstru-\nation (the most widespread and accepted), celomic metaplasia,\nlymphovascular metastasis, and, more recently, the theory of\nneonatal uterine bleeding.\n21,22 Although reasonable, by them-\nselves these theories do not explain the origin and evolution of\nthe disease in all its nuances, and other factors need to be\nconsidered, such as: genetic, endocrine, immunological,\ninflammatory, and neuroangiogenic. Regardless of controver-\nsies, the eutopic endometrium in women with the disease\ndefinitely has peculiarities and a relevant role in the patho-\nphysiological process of the disease.\n23–25 If we added genetic\nsusceptibility26 and immune system dysfunction to this con-\ntext, including autoimmunity and de ficient immune surveil-\nlance,27–29 we would already have a plausible explanation for\nthe question of why only some women develop the disease.\nStill, there would be another question: what would be or what\nwould lead to this initial alteration of the eutopic endometri-\num? A potential explanation would be the presence of somatic\nmutations in the epithelial and/or stromal endometrial com-\nponents. Despite their relevance to ovarian lesions (endome-\ntriomas), they do not appear to be crucial or signi ficant in\ncomponents of the eutopic endometrium.\n30 Another interest-\ning element is the importance of endometrial progenitor cells,\nor endometrial stem cells in their broadest concept. However,\nalthough admittedly associated with the development of the\nlesion at ectopic sites, 31 primary constitutive changes in\nthese cells, when isolated from the eutopic endometrium,\nare still controversial. In this scenario of uncertainties about\nthe triggering event of the first changes in the eutopic endo-\nmetrium of women with endometriosis, it is worth discussing\nan equally interesting, although less explored, hypothesis of\nmicrobiological contamination. Some authors defend intra-\nuterine microbial colonization as the trigger for pathophysio-\nlogical events that culminate in endometriosis.\n32 Furthermore,\ninfections can trigger cumulative genetic and epigenetic\nchanges with the potential to trigger or maintain endometri-\nosis.\n33 Although recently published, the concept of an initial\neutopic endometrial infection followed by sterile in flamma-\ntion has been proposed before. 34 These propositions are\nAddress for correspondence\nOmero Benedicto Poli-Neto, MD,\nPhD, Faculdade de Medicina,\nUniversidade de São Paulo, Av.\nBandeirantes, 3900, Vila Monte\nAlegre, Ribeirão Preto, SP, 14049-\n900, Brazil\n(e-mail: polineto@usp.br).\nDOI https://doi.org/\n10.1055/s-0040-1713807.\nISSN 0100-7203.\nCopyright © 2020 by Thieme Revinter\nPublicações Ltda, Rio de Janeiro, Brazil\nTHIEME\nEditorial 593\nArticle published online: 2020-10-31\n\nsupported by the association between endometriosis\nand endometritis, 13,35–39 by the microbial contamination\nobserved in the uterine cavity and ectopic lesions, 40–42 and\nby dysbiosis in the microbiome of the intestine and genital\ntract of women with endometriosis. 43\nConcomitant to these findings, the modernization of\nmolecular biology techniques in recent decades has allowed\ngreat advances in understanding the processes involved in\nthe evolution of several diseases. Currently, these methodol-\nogies are more affordable, easy to execute, and have good\nreproducibility.\n44,45 Transcriptome analysis, for example, is a\ndirect re flection of gene expression in tissues. In this sense,\nthe transcriptome analysis of the eutopic endometrium of\nwomen with endometriosis has an invaluable potential in\ncontributing to understand local events associated with the\ncondition. In fact, there are already relevant studies evaluat-\ning the transcriptome of the eutopic endometrium of women\nwith and without endometriosis.\n46–50 However, some limi-\ntations are inherent to these studies, such as: reduced\ncasuistry size; heterogeneous sample regarding phenotypic\ncharacterization, mainly of the menstrual cycle phase, the\nextent of the lesions, and associated symptoms; inadequate\nselection of healthy controls; non-optimized evaluation by\nthe bioinformatics tools available; and redundancy in the\ninterpretation of biological pathways, among others.\nTo try to remedy these limitations, our group conducted a\nmeta-analysis including raw eutopic endometrial transcrip-\ntome data available in international databases from healthy\nwomen and from women with endometriosis. We restricted\nthe control group to women with no known disease and\nstratified women with endometriosis into those with stages I\nand II disease and those with stages III and IV disease. For\nboth groups, we considered the phase of the menstrual cycle,\nsince it can interfere with the expression of the tissue tran-\nscriptome.\n51 By using some bioinformatics tools, we were\nable to predict the tissue microenvironment computational-\nly, that is, we could infer the types of cells present in each\nsample. The method used can identify 64 cell types, including\nimmune cells, stem cells, and stromal cells, among others.\nThus, we observed that the eutopic endometrium of women\nwith endometriosis in stages I and II has more proin flam-\nmatory characteristics than the endometrium of women\nin stages III and IV of the disease. Initial cases have a\npredominance of activated dendritic cells, effector memory\nCD4þ T-cells, eosinophils, type M1 macrophages and natural\nkiller T-cells, which are typical of an in flammatory process\ninduced by acute infections. In more advanced cases (stages\nIII and IV), there is a predominance of M2 macrophages and\nnatural killer T-cells. This last cell pro file is characteristic of\nan antiin flammatory process, of tissue healing and repair\n52\npresent in late stages of infectious diseases 53 that may be\nassociated with the promotion of tumor growth. 54 As for\nbiological pathways, in women with endometriosis there is a\ndirect involvement of the processes related to immune\nsurveillance, stem cell self-renewal, and epithelium-mesen-\nchymal transition. These mechanisms are already reported in\nthe literature, but we note that pathways related to greater\npermissiveness of the immune system to cells in ectopic\nenvironments and imbalance between cell growth and sur-\nvival\n55 are more evident in advanced disease. Anyway, the\npredominance of different cell types added to the interaction\nbetween genes and the predominant biological pathways in\neach condition, regardless of the phase of the menstrual\ncycle, indicates that the eutopic endometrium of women\naffected by endometriosis has peculiar characteristics of a\ntissue that suffered or has been suffering some harm, ag-\ngression, or stress caused by an external, potentially micro-\nbiological agent.\nBased on what was brie fly mentioned above, thinking\nabout an initial endometrial aggression, possibly by a micro-\nbiological agent, sustained for a variable period of time, and\nfollowed by the induction of genetic and epigenetic changes\nin the tissue and consequent self-sustained in flammation\n(sterile or not), all occurring in a genetically susceptible\nwoman, whose immune system behaves anomalously and\nis permissive to the presence of endometrial cells (especially\nstem cells) in ectopic environments, would be an at least\nplausible hypothesis and justify further investigations. How-\never, studies must be conducted to resolve limitations that\nmay skew the results obtained, especially a good phenotypic\ncharacterization of patients and a good selection of healthy\ncontrols.\nConflict of Interests\nThe authors have no con flict of interests to declare.\nAcknowledgments\nWe thank the Coordination for the Improvement of Higher\nEducation Personnel (CAPES in the Portuguese acronym)\nfor the support to our postgraduate program.\nReferences\n1 Agarwal N, Subramanian A. Endometriosis - morphology, clinical\npresentations and molecular pathology. J Lab Physicians. 2010;2\n(01):1–9. Doi: 10.4103/0974-2727.66699\n2 Nisolle M, Donnez J. Reprint of: Peritoneal endometriosis, ovarian\nendometriosis, and adenomyotic nodules of the rectovaginal\nseptum are three different entities. Fertil Steril. 2019;112(04,\nSuppl 1):e125 –e136. Doi: 10.1016/j.fertnstert.2019.08.081\n3 Andres MP , Arcoverde FVL, Souza CCC, Fernandes LFC, Abrão MS, Kho\nRM. 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Doi:\n10.1039/c5mb00101c\nRev Bras Ginecol Obstet Vol. 42 No. 10/2020\nWhat the Transcriptome of the Eutopic Endo metrium from Women with Endometriosis Poli-Neto et al.596","source_license":"CC0","license_restricted":false}