{"paper_id":"c11bafd7-07d8-4bc1-9307-2dfb3ddf1d5d","body_text":"8\nJournal of Clinical Medicine of Kazakhstan: 2023 Volume 20, Issue 3\nReview Article DOI: https://doi.org/10.23950/jcmk/13329\nJOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN (E-ISSN 2313-1519)\nAbstract\nPain in relation to the menstrual cycle is representative of \nEndometriosis. It has been reported that Endometriosis can be easily \nconfounded with neoplasia. In the clinical practice of Gynecologic \nOncology we find with relative frequency patients who are unknown \ncarriers of endometriosis who present and are operated on because \nthey resemble a picture of gynecological cancer, predominantly of the \novary. It has been reported that Endometriosis can be easily confounded \nwith neoplasia. Endometriomas form part of the differential diagnosis \nalongside various ovarian cystic formations. \nOn the other hand, ovarian tumors are very common in women of \nreproductive age. Most are benign, but malignant ovarian tumors are a \nleading cause of cancer death in women. \nIn women with endometriosis, the risk of developing ovarian \ncancer has been estimated to be up to 50% higher than in the general \npopulation. The aim of our concise review was to establish the current \nstate of knowledge regarding adnexal tumors associated with pelvic \npain.\nKey words: endometrioma, tumor-associated pain, differential \ndiagnosis\nReceived: 2023-04-14. \nAccepted: 2023-05-23\nAdnexal masses associated \nwith pelvic pain: A review and \ncommentary on the evidence\nJuan Carlos Tirado-Tapia1, Enrique Sanchez-Valdivieso1,2\n1Department of Oncology, High Specialty Hospital of Veracruz, Mexico\n2Department of Research, School of Medicine, Cristobal Colon University, Veracruz, Mexico\nIntroduction\nEndometriosis affects approximately one in ten \nwomen at some point in their lives [1], mainly during \nreproductive age since it is an estrogen-dependent \ndisease, and who will manifest pain in relation to their \nmenstrual cycles, either as dyspareunia, dyschesia, \ndysmenorrhea or chronic pelvic pain with or without \nthe presence of infertility. Different theories have been \nproposed regarding its pathogenesis. \nAmong the most accepted theories are the \npredisposition due to genetic factors, increased secretion \nof cytokines and other inflammatory mediators, in utero \nexposure to estrogens or potent environmental toxins, or \nthe widely accepted retrograde menstruation secondary \nto subtle anatomical alterations. However, its appearance \nhas been reported even among patients who underwent an \nadnexal-sparing hysterectomy or in Mayer-Rokitansky-\nKüster-Hauser syndrome [2] where there is congenital \nabsence of the uterus as part of the syndromatic procession.\nIn our clinical practice of Gynecology Oncology we \nfind with relative frequency patients who are unknown \ncarriers of endometriosis who present and are operated on \nbecause they resemble a picture of gynecological cancer, \npredominantly of the ovary. It has been reported that \nEndometriosis can be easily confounded with neoplasia.\nTherefore, the objective of our review presented here \nwas to establish the current knowledge and intertwine the \ncurrent state of the art with our experience in managing \nclinical situations regarding adnexal tumors associated \nwith pelvic pain.\nOvarian endometriosis as a cause of \npelvic pain\nWhat is happening in endometriosis is that the \nendometrial tissue, both the stroma and glands, is actually \nlocated outside of the uterus. This entity can be detected \nclinically in approximately one in ten of patients during \nreproductive age, up to 50 % of them present infertility \nassociated with chronic pelvic pain [3,4,5]. \nJ Clin Med Kaz 2023; 20(3):8-13\nCorresponding author: \nEnrique Sanchez-Valdivieso. \nE-mail: easanchezv@gmail.com; \nORCID: 0000-0002-3609-8228\n\n9\nJournal of Clinical Medicine of Kazakhstan: 2023 Volume 20, Issue 3\nThe incidence of endometriosis in infertile women is about \n50% and it is estimated that around 190 million young women \nand adolescents worldwide suffer from the disease, although it \ncan also occur in menopausal women [6]. As for adolescents \ndiagnosed with endometriosis, it is estimated that 70-93% \npresent some discomfort associated with menstruation, as well \nas being associated with a higher risk of depression and anxiety \n[7]; therefore, this condition affects the quality of life not only \nthe woman who suffers it, but also the partner or relatives [6]. \nThe appearance of endometriosis at earlier ages is \nassociated with a delay in diagnosis [7]. The diagnosis is usually \nmade 8-12 years on average from the onset of symptoms [6]. \nTherefore, it is of great importance for the clinician to keep in \nmind the prevalence of this disease as well as manage a high \nindex of suspicion.\nOvarian endometriomas\nEndometriosis can have different forms of clinical \npresentation [8]. The most common form of presentation \nin 20-25% of patients with endometriosis are ovarian cysts \n(endometriomas) [9]; ovarian endometriomas (OMAs) are \nassociated with pain that usually goes from moderate to severe. \nHowever, severe pain may be associated with concomitant “deep \ninfiltrating endometriosis” (DIE) [10].\nOther forms of endometriosis are \"superficial \nendometriosis\" commonly found in the peritoneum, \ncharacterized by the endometrial tissue being found on the \nsurface of the subserosal soft tissue of the peritoneum or visceral \norgans [3,8,11] or as \"DIE\" which measures more than 5mm \n[8,11] reaching the muscle layer and is commonly located in the \nrecto-vaginal septum, bladder wall, diaphragm or other organs \n[3,11]; it usually causes significant pain and also gastrointestinal \nand/or urological abnormalities that do not respond to medical \ntreatment, most cases ending in surgical management [3] (Figure \n1).\nFigure 1 - The most common forms of endometriosis: The ovarian \nendometrial cyst (red mark) followed by superficial peritoneal \nendometriosis (blue mark) and deeply infiltrating endometriosis \n(green mark). GnRH agonist/antagonist exert an effect over the \nCNS. Progestins, SPRMs and combined contraceptives exert an \neffect over the hypophysis and directly over the endometrial \nlesions.\nEndometriosis-associated risk factors\nThere are some risk factors that have been related to the \ndisease, including genetic factors (family history), exposure \nto endogenous estrogens for long time, as happens with early \nmenarche, late menopause and short menstrual cycles, heavy \nmenstrual bleeding, outflow tract obstruction (Müllerian \nalterations) and exposure to to diethylstilbestrol in utero [5,7]. \nIt is believed that among the genetic factors, chromosomal \nalterations in 7p15.2 and 10q26 may be involved, as well as the \nARID1A and PIK3CA genes in ovarian cancer in patients with \nendometrial ovarian cysts [8].\nCauses of endometriosis\nThere have been proposed some theories as cause of \nendometriosis, like Samson's theory, which consists of a retrograde \nmenstruation, that is, menstrual bleeding that can reach the \nperitoneal cavity after passing through the tubes; however, 90% \nof normal women may present retrograde menstruation without \nproblems [5]. More recent studies have shown that endocrine, \nimmunological, pro-inflammatory and pro-angiogenic processes \nmust be present concomitantly with retrograde menstruation [8] \nThe GE theory (genetic and epigenetic changes) suggests that \na series of GE changes can occur during cell division, causing \nthe endometrial tissue to develop characteristics of cancer cells \n[12]. Another theory includes the generation of a coelomic \nmetaplasia in which there is a transformation of the mesothelium \nto a glandular endometrium or lymphatic or hematogenous \nmetastasis [8].\nThe reflux of endometrial tissue by itself contributes to the \nprogress of pain and development of infertility; for the evolution \nof OMAs the presence of hormonal fluctuations and ovulation \nduring menstruation are essential [10]. The endometrial tissue \nforms an ovarian cyst in the ovary that gives rise to a hematoma \n[5]. The formation of endometrioma causes ovarian reserve \nlevels to decrease and favor the adhesions between the tubes \nand the broad ligament with the ovary [9]. Ectopic endometrial \ntissue results in inflammation which causes or promotes pain, \ndyspareunia, dysmenorrhea, and infertility [5].\nSymptoms of endometriosis\nThe most common reported symptom among patients with \nendometriosis is dysmenorrhea. This symptom is the result of \nthe prostaglandin production within the pelvic cavity, which \ncauses endometrial hypertonia and secondary ischemia [10]; \nin a third of cases, ovarian endometriosis is bilateral [5]. The \nectopic endometrium causes a chronic estrogen-dependent \ninflammatory reaction, triggering pain secondary to compression \nof the adjacent nerves and/or an increase in the prostaglandin \nproduction [7]. We can find in the peritoneal fluid of patients \nwith endometriosis the presence of IL-10, IL-6, IL-8, COX-2, \nVEGF and TNF-α [13].\nCharacteristically, endometrial lesions have an increased \nexpression of ER beta, which promotes the growth of lesions \nby inhibition of TNF-alpha by increasing interleukin Iß which \nimproves cell adhesion and proliferation [8]; high levels of \nestradiol in turn causes PR to decrease [14]. Type A and B PR \nchange during the menstrual cycle in response to the variation \nof ovarian steroids, their maximum expression occurs in the \nmiddle of the cycle [15]. Progesterone triggers the PR beta \nduring the luteal phase, which promotes the transcription of \nthe 17-ß-hydroxysteroid dehydrogenase (17ß-HSD) -2, which \ntransforms estradiol-E2 into E1, which is a less potent form of \nestradiol [14,16]. However, ectopic endometrial tissue has an \nER-alpha lower expression, and increased ER-beta, compared to \nthe endometrium [16]; instead, PR expression may be decreased \nor even absent [17], which gives rise to resistance to progesterone \n[16]. COX-2 and aromatase are also responsible for stimulating \nthe synthesis of E2 [18].\n\n10\nJournal of Clinical Medicine of Kazakhstan: 2023 Volume 20, Issue 3\nEndometriosis-related pain\nThe characteristics of the pain depend on the location [19]. \nWhen endometriosis is found in the peritoneum or in the pelvic \nwall, the pain is usually of somatic type. Pain is usually more \nlocalized, supposedly because to the high density of sensory \nnerve fibers in the parietal peritoneum. Later, macrophages \ncolonize the nerve fibers [8,20] increasing the intensity of pain \n[20]; these macrophages have an increased expression of IGF-1, \nwhich in endometrial cells prevents apoptosis, and in stromal \ncells increases the expression of the ER beta [21]. Patients with \nendometriosis present an increase in neurotransmission from \nthe anterior insula to the medial prefrontal cortex, promoting \nchemical changes which alter brain functions, increasing pain \nintensity, and increasing the risk of cross-organ sensitization \ndue to the convergence of neuronal pathways [8]; interestingly, \nthis central sensitization effect may explain coexisting chronic \nsyndromes, irritable bowel syndrome, bulbodynia, or painful \nbladder syndrome [10].\nOn the other hand, the pain is usually of visceral type \nwhen endometrial lesions are found in the uterus, bladder or \nintestine, making the pain less localized and more spasmodic \n[19]. \"DIE\" usually develops other symptoms depending on the \nsite where the condition is found. For example, when the lesions \nare rectovaginal, it usually causes dyschetia, stool irregularities, \nand constipation; lesions located in the bladder usually cause \ncyclic dysuria or even hematuria when the urethra is involved \nand/or the bladder is infiltrated. \nIn women suffering from endometriosis, nerve growth \nfactor (NGF) has been found elevated in the peritoneal fluid, \nwhich gives rise to acyclic neurological inflammation causing \npain resistance to NSAID's and hormonal therapy that in the \nlong term can generate depression and somatoform disorders \n[19].\nAdnexal causes of pelvic pain\nEndometriosis can occur during a woman's reproductive \nlife as frequently as 5 to 15% [20]. When this common \ngynecological condition becomes symptomatic, it can manifest \nwith chronic pelvic pain, dyspareunia, or dysmenorrhea [21]. \nTherefore, the appearance of any pelvic pain during reproductive \nlife represents a significant diagnostic challenge.\nThe local inflammatory reaction caused by endometriotic \nimplants triggers, in turn, formation of adhesions which will \nproduce fibrosis and a modified pelvic anatomy. This progressive \nsequence of changes can lead to pelvic organ dysfunction, with \nthe onset of infertility and chronic pelvic pain.\nThe most frequent location of endometriotic implants \nis the ovary. This diagnosis should be considered, along with \ncancer, cystadenomas, tuboovarian abscesses, hemorrhagic \ncysts, and cystic adenomyoma, within the differential diagnoses. \nUltrasound is particularly useful for identifying the \"typical\" \nendometrioma in premenopausal women, as it can easily identify \nunilocular cysts with echogenicity of ground-glass content, poor \nvascularity on color Doppler evaluation, and debris/polar clots.\nThe clinical diagnosis, however, is sometimes not easy, \nparticularly when there are multiple cysts, since they can \nmake it difficult to distinguish the adnexal endometrioma from \nsome different masses, as mucinous cystadenomas (Figure 2). \nWhen there is intracystic vascularization, its presence can lead \nthe clinician to suspect the presence of cancer (endometrioid \nadenocarcinoma or a borderline tumor of the ovary) [22] since \n1% of these masses presumably suspected as endometriomas \nwill result in a clear neoplasia.\n \n \nPain evolution in endometriosis\nThe onset of pain is caused by biochemical signaling caused \nby the production of some pro-inflammatory molecules, as TNF-\nalpha, PGE2 and interleukin [8,10], which increase sensitivity \nand become a neuronal sign (peripheral sensations). This type \nof pain is usually well controlled with NSAIDs and hormonal \ntherapy (by decreasing the release of inflammatory mediators) \n[19]. Estradiol has been identified as the main mediator of \nmacrophages, as well as some chemoattractants such as IL-8, \nwhich causes neutrophil infiltration in the peritoneal fluid. It has \nbeen observed that macrophages invade the ectopic endometrium \nin greater numbers than the normal endometrium, activating \nNF-kB that promotes the expression of pro-inflammatory toxins \nand COX-9, which with the expression of pro-inflammatory \ncytokines such as IL-6, IL-1beta and TNF-alpha [23], stimulates \ncell proliferation, angiogenesis, inflammation and production of \nadhesion molecules of the endometrial tissue [13].\nBleeding within the pelvic cavity from the ectopic \nendometrial tissue trigger the secretion of pro-inflammatory and \npro-oxidants factors, producing free iron and reactive oxygen \nFigure 2A - Case of surgically and pathologically confirmed \nendometrioma. CT images showing a large lesion in the pelvis \nin which the significant perilesional inflammatory reaction is \nevident.\nFigure 2B - Case of surgically and pathologically confirmed \nendometrioma. CT images showing a large lesion in the pelvis \nin which the significant perilesional inflammatory reaction is \nevident.\n\n11\nJournal of Clinical Medicine of Kazakhstan: 2023 Volume 20, Issue 3\nspecies (ROS) [11,16]. Iron overload activates the transcription \nof NF-kB in the endometrial stromal cells [11,24] causing \noverexpression of the divalent metal transporter I (DMTI), which \npromotes oxidative stress [24] giving rise to macromolecular \noxidative damage [11]. In addition to this, oxidative stress and \npro-inflammatory factors interrupt the function of PR, causing \nresistance to progesterone [16] and, concomitantly, there \nmay be an alteration in the ROS elimination pathway, which \nincreases chronic inflammation [11]. Adaptive immunological \nmechanisms are also involved in the development of pain. IL-\n10 has been identified in the peritoneal fluid, which has been \nrelated to an increase in the severity of the disease, and IL-17 is \nbelieved that contributes to the progression of endometriosis, as \nwell as the stimulation of cytokines which induce angiogenesis \nand inflammation [23].\nIn severe dysmenorrhea, pain is initially regulated at the \nspinal level; however, in cyclic dysmenorrhea it triggers a process \nin which the release of neurotransmitters is altered, causing \nspinal hyperalgia [19]. Studies in mice with endometriosis have \nshown a significant increase in COX-2 and TNF-alpha in the \nspinal cord and brain [25] The pain can be so severe that can \ntrigger vegetative reactions (nausea, vomiting), and patient \nadopts different positions in order to relieve pain. At the same \ntime this can cause contraction of pelvic muscles which, in the \nlong term, leads to dysfunction of the pelvic floor [19].\nOverview of ovarian tumors\nOvarian tumors can frequently develop in women of \nreproductive age. Most are benign tumors, but malignancies are \na leading cause of cancer death in women. Due to the complexity \nof the different tissues of origin, there is a variety of patterns \nand types of ovarian tumors, so most of the time a certain \npreoperative diagnosis will not be possible, except in very few \npatients. Screening among women with no family history, has \nnot demonstrated an impact in the reduction of ovarian cancer \nmortality.\nMost women with early-stage ovarian tumors are mainly \nasymptomatic; some other may experience mild gastrointestinal \nsymptoms. In case of a palpable abdominal mass, patients \nfrequently present other data such as ascites, pressure on pelvic \nor abdominal organs, and sometimes pain.\nUltrasound is useful for making a differential diagnosis of \novarian masses among themselves or with extraovarian masses, \nand between those that are benign and those that have a greater \nmalignant potential. However, US has low sensitivity used as \nscreening in the low-risk group of patients.\nOnce a pelvic mass is detected, it should first of all be \ncategorized by the clinician. In terms of malignancies, the age \nof women is of crucial importance as a predictive factor, since \nin patients over 35 years of age the possibility of carrying a \nmalignant epithelial tumor increases exponentially. In underage \nwomen, this possibility decreases enormously, being replaced \nby benign or borderline epithelial tumors, or by malignant \ntumors of germinal lineage, much rarer and that should receive \nconservative management.\nOther relevant predictive factors to consider are ultrasound \nfindings, serum CA 125 level, whether the ovarian mass is single \nor bilateral, its size, and whether or not there is pain. Simple cyst \nless than 8 cm in size is mostly benign, especially if accompanied \nby pain. Most ot these simple cysts will undergo regression \nand resolve spontaneously; they should be just monitored with \nno surgical intervention. If the mass is symptomatic, surgical \nexploration is warranted. Likewise, an invasive procedure \nshould be indicated if the mass did not change in size on repeated \nultrasound evaluation. A clear advantage of using transvaginal \nover abdominal ultrasound has not been demonstrated, but \npatient preference, especially the discomfort of bladder filling \nrequired for abdominal ultrasound, should always be an \nimportant consideration by the clinician.\nIf the mass is 10 cm in diameter or larger, a surgical \nprocedure is warranted, especially if accompanied by pain. If the \ncontent of the cyst on ultrasound is considered hemorrhagic, with \ndebris inside and is accompanied by significant abdominopelvic \npain, especially cyclical, monthly repetitive, the diagnosis of \nendometrioma should be considered as a strong possibility, \nregardless of the data of suspicion of papillae or calcifications \nin the patient with less than 35 years, as well as a determination \nof serum CA 125 that reports levels < 200 units. In the case \nof a benign neoplasm, unilateral oophorectomy or even tumor \nexcision is usually performed. If malignancy were suspected, the \nevaluation must be carried out by an oncologist. \nFor early stage ovarian cancer, you will have to decide \nthe surgical approach depending on the patients' age. For \npatients over 35 years of age, the standard therapy should be \nsurgical staging including hysterectomy and bilateral salpingo-\noophorectomy with omentectomy, selective lymphadenectomy \nin some cases, and appendectomy in the case of mucinous \ntumors; all of this considering an epithelial ovarian cancer as the \nfirst possibility. \nAggressive removal of all visible tumor, seeking to achieve \nan optimal residual for intra-abdominal disease, would improve \nthe survival in the case of more advanced disease. In these \nwomen, adjuvant or postoperative chemotherapy is indicated, \nespecially the combination of Carboplatin with Paclitaxel, \nrescuing up to two thirds of these patients.\nIn the case of patients less than 35 years with a rare \ngermline cancer, a conservative surgical management is imposed, \nrespecting pelvic organs and fertility, with the administration of \npostoperative chemotherapy, which will be curative in these \npatients and will rescue the vast majority of women.\nEndometriosis mimicking adnexal tumors\nIn our clinical practice of Gynecology Oncology not \ninfrequently we find patients who are unknown carriers of \nendometriosis who present and are operated on because they \nresemble a picture of gynecological cancer, predominantly \nof the ovary. Endometriosis is often easily misdiagnosed as a \nmalignancy [26].\nIn addition, the diagnosis of a pelvic neoformative process, \nparticularly if it is a non-cystic malignancy, is favored by the \nmacroscopic appearance of the lesion. These unusual cases \nrepresent greater difficulties in management even in experienced \ncentres. The frozen-section pathological examination is a very \nuseful intraoperative analysis that helps to make a surgical \ndecision, increasing sensitivity and specificity for the risk \nclassification [27].\nIn the differential diagnosis, neither the clinical presentation \nnor the age of presentation of endometriosis can be taken into \naccount, which are largely similar to the other diagnoses.\nThe presentation of endometriosis is often retroperitoneal, \nclose to the uterus (i.e., paracervical and parametrial) [28]. We \nhave to include in the differential diagnosis the presence of a \nlateral spread of cervical cancer [29]. We have found endometrioid \nadenocarcinomas arising from an endometriotic cyst located in \nthe broad lateral ligament, in proximity to the pelvic wall, in \napposition to the ureter. Broad ligament endometriosis can also \ninfiltrate medially into paracervical tissues, and in many cases \neven appear as a solid mass [30]. In contrast, frank retroperitoneal \ncystic endometriosis is not common [26].\n\n12\nJournal of Clinical Medicine of Kazakhstan: 2023 Volume 20, Issue 3\nEndometriosis-associated ovarian cancer\nA 1.4 to 1.9% risk of developing ovarian cancer throughout \nlife has been reported among patients with endometriosis, \ncompared to the general population [31,32]. \nEpithelial ovarian cancer\nEndometriosis is tightly related to some subtypes of \nepithelial ovarian cancer (EOC), particularly ovarian clear \ncell carcinoma (OCCC) and endometrioid ovarian carcinoma \n(EnOC) [33]. \nThis association between endometriosis and EOC subtypes \nhas been confirmed by detecting mutations in cancer-associated \ngenes using molecular pathology [35,36]. The first time they \nwere reported in the literature, in 1925, they were described as \nendometriosis-associated endometrioid ovarian carcinoma [34].\nIt is known that, despite this, patients with endometriosis \nwill spend years suffering from this benign disease but will \nnever develop cancer related to endometriosis; it is also known \nthat OCCC and EnOC that can occur in younger women, most \nof them in the range between 35 and 55 years of age, are directly \nrelated to endometriosis. EnOC's constitute 10% of EOC's and, \nsimilarly, prevalence of OCCC's is between 5-12% [33].\nOvarian germ cell neoplasm\nA less frequent group of malignant neoplasms, ovarian \ngerm cell malignancies (OGCM's) most usually present in \nwomen under the age of 30. The most frequent symptom in \nthis group of very low-incidence tumors is abdominal pain \naccompanied by a mass, abdominal or pelvic, in 85% [37]. The \ndisease manifests clinically with pain as the first symptom in \n64% of patients and abdominal distension as the first sign in \n26% of cases [38]. Transvaginal bleeding and ascites are also \nreported. In a much smaller percentage of patients it can present \nacutely with symptoms due to ovarian torsion. The median age \nof OGCM patients at diagnosis is 24 years [38].\nDefinitive diagnosis\nThe definitive diagnosis depends to a great extent on the \nfindings in the ultrasonogram (US). In this study, endometriomas \nare frequently observed as thick-walled unilocular masses \nwith regular margins that are often bilateral and multiple, with \nhomogeneous content and fine internal echoes that result in an \nechogenic \"ground glass\" appearance, caused by the blood cells \nflaking off the walls [39].\nOvarian endometriomas constitute an important differential \ndiagnosis of a large number of ovarian cystic lesions such as \nbenign cystic teratomas or dermoid cysts, and hemorrhagic \nluteal cysts. The US is important to detect the characteristics of \nthe lesion, variable in each case. The edges may be serrated; \nthey can be infiltrated by the surrounding tissues. Most disease \ndeposits demonstrate vascularization on color Doppler.\nIn the absence of a conclusive US or with suspicion of \novarian cancer, a CAT or MRI scan is recommended [40]. Tumor \nmarkers must be interpreted in a prudent and judicious manner, \nmaintaining an important consideration of the context, with the \ndecision being made according to the age of the patient.\nConclusion\nBenign or malignant tumors can resemble and be \ndiagnosed as Ovarian Endometrioma. These cases represent \ngreater difficulties in management even in experienced centres. \nThe clinical presentation is generally not very helpful in \nthe differential diagnosis. The intraoperative frozen-section \nanalysis is of great help in making a surgical decision. Tumor \nmarkers must be interpreted in a prudent and judicious manner, \nmaintaining an important consideration of the context, with the \ndecision being made according to the age of the patient. In the \ncase of a malignant neoplasm, it will always be recommended \nthat the person responsible for performing the surgical evaluation \nand making the surgical decision be a gynecologic oncologist.\nDisclosures: There is no conflict of interest for all authors.\nAcknowledgements: None.\nFunding: None.\nReferences \n1. Bulun SE. Endometriosis. N Engl J Med. 2009; 360:268-79. https://doi.org/10.1056/NEJMra0804690\n2. Konrad L, Dietze R, Kudipudi PK, et al. Endometriosis in MRKH cases as a proof for the coelomic metaplasia hypothesis? Reproduction. \n2019; 158:R41-7. https://doi.org/10.1530/REP-19-0106\n3. Wang Y , Nicholes K, Shih I-M. The origin and pathogenesis of endometriosis. Annu Rev Pathol. 2020; 15:71-95. https://doi.org/10.1146/\nannurev-pathmechdis-012419-032654\n4. Hayashi S, Nakamura T, Motooka Y , Ito F, Jiang L, Akatsuka S, Iwase A, Kajiyama H, Kikkawa F, Toyokuni S. Novel ovarian \nendometriosis model causes of infertility via iron-mediated oxidative stress in mice. 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