{"paper_id":"7927c874-f7cd-4339-b5ec-f48be70642dc","body_text":"Review Article\nISSN: 2574 -1241              DOI: 10.26717/BJSTR.2024.58.009214\nEndometriosis: A Century of Unresolved Pathogenesis – \nIt’s Time for Decisive Action\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. 50902\nFrancesco Maria Bulletti1, Maurizio Guido2, Antonio Palagiano3, Maria Elisabetta Coccia4 and Carlo Bulletti5*\n1CHUV Lausanne - Département D’hôpital Maternité / Gynécologie et obstétrique, Switzerland\n2Full Professor Obstetrics and Gynecology, MeSVA department, University of L ’ Aquila, Italy\n3Chief Consultant in Fertility and Sterility – CSA, Italy\n4Associate Professor SSD: MEDS-21/A – University of Florence, Italy - Ginecologia e Ostetricia Dipartimento di Scienze Biomediche, Sperimentali \ne Cliniche ‘Mario Serio, Italy\n5Associate Professor Adjunct, Department Obstetrics, Gynecology and Reproductive Science, Yale University New Haven (Ct) USA, and Director \nof Help Me Doctor a Worldwide Platform for 1st and 2nd medical Opinions. Cattolica (Rn), Italy\n*Corresponding author: Carlo Bulletti, Associate Professor Adjunct, Department Obstetrics, Gynecology and Reproductive Science, Yale \nUniversity New Haven (Ct) USA, and Director of Help Me Doctor a Worldwide Platform for 1st and 2nd medical Opinions. Cattolica (Rn), Italy\nABSTRACT\nEndometriosis affects around 10% of reproductive-age women, causing severe pain, infertility, and various other \nsymptoms. Traditional treatments, like hormonal therapies and surgeries, often provide temporary relief with \nsignificant side effects, The disease’s heterogeneity and varied responses to treatment necessitate a personalized \napproach. The leading hypothesis for endometriosis onset and recurrence is retrograde menstruation, influenced \nby factors like uterine position, tubal filtering function by its length and opening sizes, and specific uterine \ncontractility profiles. This hypothesis suggests that only some women are predisposed due to these factors, \nleading to endometrial cell regurgitation into the pelvic cavity. Advances in biophysical and biochemical markers \n(proteomics and metabolomics) offer insights into disease activity and treatment response, enabling real-time \nmonitoring and personalized care. Targeted therapies, including angiogenesis inhibitors and drugs/devices \nmodulating hormonal and inflammatory pathways, and uterine content outflow through adequate cervical/\ntubal openings and uterine contractions control, promise to enhance outcomes and quality of life.\nKeywords: Endometriosis; Pathogenesis; Theory; Epidemiology\nIntroduction \nBackground Information\nEndometriosis is characterized by the growth of tissue resem -\nbling the lining of the uterus in areas outside the uterus, such as the \novaries, fallopian tubes, bladder, intestines, or peritoneum. It can less \ncommonly affect areas outside the pelvis, like the diaphragm, pleura, \nabdominal wall, or nervous system [1,2]. This condition causes se -\nvere pelvic pain and can make it difficult to conceive. About 10% of \nwomen and girls of childbearing age worldwide, around 190 million \npeople, are affected by endometriosis. The economic impact is signif-\nicant, with costs exceeding 80 billion USD annually [1-4]. It manifests \nas a chronic ailment with symptoms that can be debilitating, such as \nsevere menstrual pain, discomfort during sex, difficulties with bow -\nel movements or urination, dysuria, ongoing pelvic pain, bloating, \nconstipation, painful bowel movements, nausea, exhaustion, and in \nsome cases, depression and anxiety [1,3,4]. Approximately 40-50% of \nwomen with infertility issues have endometriosis [3-5]. Although var-\nious mechanisms have been suggested to explain infertility linked to \nendometriosis, there is no conclusive evidence of its association with \nendometrial receptivity. A recent study found a slight decrease in live \nbirth rates among women with a history of endometriosis, suggesting \nthat minor impairments in uterine receptivity might contribute to in-\nfertility in these women [6].\nARTICLE INFO\nReceived: \n   September 16, 2024\nPublished: \n  September 26,2024\nCitation: Francesco Maria Bulletti, \nMaurizio Guido, Antonio Palagiano, \nMaria Elisabetta Coccia and Carlo \nBulletti. Endometriosis: A Century \nof Unresolved Pathogenesis – It’s \nTime for Decisive Action. Biomed J \nSci & Tech Res 58(5)-2024. BJSTR. \nMS.ID.009214.\n\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\n50903\nOn the other hand, the condition distorts pelvic anatomy, caus -\nes adhesions and fallopian tube scarring, and leads to local inflam -\nmation and hormonal regulation disruptions [3-5]. These symptoms \ncan significantly affect a person’s quality of life, education, career, and \nrelationships [1-5]. This article offers a comprehensive overview of \nthe current understanding and recent advancements in the theories \nof endometriosis pathogenesis, with our opinion on the need for a \nfew RCTs designed to confirm the pathogenesis. An extensive litera -\nture search was performed using databases such as PubMed, Scopus, \nand Web of Science, employing keywords including “endometriosis,” \n“pathogenesis,” “theory,” and “epidemiology.” The aim of synthesizing \nthese findings is to provide a wide-ranging perspective on endome -\ntriosis pathogenesis, emphasizing potential areas for future research.\nEndometriosis can present a wide range of symptoms that sig -\nnificantly impact the quality of life and emotional well-being, includ -\ning pain, fatigue, heavy menstrual bleeding, and mood swings. These \nsymptoms can affect education, career, and intimate relationships [1-\n8]. The condition can start with the first menstrual period and contin-\nue in varying patterns until menopause. Starting menstruation after \nage 14 is significantly correlated with a lower risk of developing en -\ndometriosis. Currently, there is no known way to prevent the disease, \nand while it cannot be cured, symptoms can be managed through \nmedication or surgery [4,9,10]. Endometriosis manifests in three \nmain forms: superficial peritoneal endometriosis, ovarian endome -\ntriomas, and deep infiltrating endometriosis (DIE) [1,2,4,10-12]. DIE \npenetrates organs in the pelvic area and often requires surgical treat-\nment. The disease can progress in 37% of cases, remain stable in 50%, \nand regress in 17% (10). Surgery for DIE carries a risk of major com-\nplications (3-4%) and minor complications (10-15%) [12]. Gaining \na full grasp of the complex processes behind endometriosis is essen -\ntial for advancing treatment options, which are presently inadequate \n[2,5,12]. A recent large-scale, web-based survey revealed that women \nwith endometriosis endure a lengthy and challenging journey before \nreceiving a diagnosis and effective treatment, highlighting the urgent \nneed to reduce diagnostic delays. On average, seven years elapse be -\ntween the onset of symptoms (at 23.8 ± 10.2 years) and diagnosis \n(31.0 ± 8.9 years). Women reported an average of 4.6 ± 2.3 symptoms, \nwith 82% experiencing severe pain (pain scores between 7 and 10). \nAfter diagnosis, 66% of women received medical treatment, primar -\nily hormonal (45%), which significantly reduced pain intensity (VAS \nscores after treatment = 4.9 ± 2.7, p < 0.001). Additionally, 62% had \nundergone surgery, with 22% undergoing laparotomies. The survey \nhighlighted significant impacts on daily life, particularly in sexual, \npsychological, and physical areas, with an overall quality of life score \naveraging 4.3 ± 2.6 out of 1013. \nDeveloping new interventions to prevent both the occurrence and \nrecurrence of endometriosis is crucial. The exact cause of endometri-\nosis is not definitively known, but several theories offer insights into \nits potential origins and guide research toward innovative treatments \n[2,3,8,9,12]. These theories include metastatic dissemination, sur -\ngical transplantation, genetic factors, coelomic metaplasia, immune \ndysregulation, embryonic cell origin, endometrial stem cell involve -\nment, hormonal imbalance, bone marrow stem cells, and retrograde \nmenstruation [1-10]. Recent research also suggests the possible role \nof microbiota in the development of endometriosis, indicating that the \nrole of infection in disease etiology should be further investigated14. \nDespite these theories, questions remain about why certain women \nare affected, the varied progression of the disease, and its resistance \nto progesterone treatment [1-8].\nLiterature Review\nWhile the Sampson theory on endometriosis is supported by nu -\nmerous facts [1-4,8,9], it seems to leave some questions unanswered. \nHowever, a careful, deep analysis can provide answers to these ques-\ntions:\nVariability in Affected Women\nEndometriosis affects certain women and not others due to differ-\nences in the amount and frequency of endometrial debris transported \nthrough the fallopian tubes and subsequently implanted in the pelvic \ncavity (Figure 1) [1-4].\nDisease Progression\nThe progression of endometriosis in some women, while remain-\ning stable in others, is influenced by individual combinations of chem-\nical-physical factors. These factors determine the capacity for leakage \nand accumulation of endometrial debris (Figures 1A-1C) [1-4,8,9].\nBeyond Oversimplified Views\nViewing endometriosis as merely a chronic, inflammatory, multi-\nfaceted disease that resists progesterone treatment is an oversimpli -\nfication. The Sampson theory emphasizes that the chronic nature, in-\nflammation, and complexity of the disease result from the continued \npresence of endometrial tissue outside the uterus [1-4,8,9].\nMechanical Aspects\nUnderstanding the mechanical aspects of how endometriosis \nbegins and advances is crucial. Detailed explanations are needed to \nguide the creation of targeted and effective treatments rather than \nrelying on general theories [1-4,8,9]. Physical and chemical factors \nsuch as the size of the cervical canal, the dimensions of the tubal os -\ntia, the configuration of the tubal portion within the uterine wall, the \nlength of the tubes, the functioning of the junction between the uterus \nand tubes, the volume of menstrual flow, the personal placement of \nthe uterus, the size of its openings, and the frequency and intensity \nof myometrial contractions significantly contribute to the likelihood \nof developing endometriosis (Figures 1A-1C) [1-4,8,9]. These factors \nparticularly affect individuals with obstructive Müllerian anoma -\nlies 25. The principles laid out by Bernoulli, Torricelli, and Laplace \n[8,13,14] underpin the variation in quantities from person to person \n(Figures 1A-1C).\n\nCopyright@ :   Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\n50904\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\nFigure 1: \nA.\t Endometrial\t Shedding:\tDebris\texits\tthrough\tthe\tcervix\tand\ttubes,\twith\tthe\ttubes\tacting\tas\tfilters.\tUterine\tcontractions\tand\tanatomy\taffect\t\nthis\t process.\t The\t cumulative\t regurgitation\t of\t endometrial\t debris\t through\t the\t tubal\t opening\t into\t the\t pelvic\t cavity\t is\t governed\t by\t Bernoulli,\t\nTorricelli,\tand\tLaplace\tLaws,\twhich\tis\tresponsible\tfor\tthe\tprogression\tand\tregression\tof\tthe\tdisease\t(Figure\t1A).\tThe\tindividual\tlength\tand\tinternal\t\nsize\tof\tcervical\tand\ttubal\topenings\tfilter\tthe\tendometrial\tdebris\tfrom\tthe\tlumen\tcontent\tto\tthe\tpelvic\tcavity.\nB.\t Uterine\t Position:\tNormoverted,\tAnteverted,\tand\tRetroverted.\tDifferent\tuterine\tpositions\tinfluence\tthe\tflow\tof\tendometrial\tdebris\tthrough\t\nthe\tcervix\tand\ttubes.\tThis\tmay\texplain\tthe\tvarying\toccurrences\tof\tendometriosis\t(Figure\t1B).\nC.\t Uterine\t Contractions:\t Contraction\t patterns\t influence\t the\t displacement\t of\t uterine\t content,\t with\t estrogen\t increasing\t and\t progesterone\t\ndecreasing\tcontraction\tfrequency.\tThis\tintroduces\tthree\tdifferent\tpatterns\tand\trelated\tdirections\tof\tdisplacement\tthrough\tthe\tcervical\tos,\ttubal\t\nopenings,\tor\tboth\t(Figure\t1C).\nA B\n\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\n50905\nStatement of Opinion\nThe retrograde menstruation theory (Sampson)15,16suggests \nthat during menstruation, some endometrial tissue may backflow \nthrough the fallopian tubes into the abdominal cavity, potentially \nleading to the formation of endometriotic lesions [12,15-18] (Figures \n1A-1C). Recurrent endometrial accumulation infiltrates deeper struc-\ntures or appears outside the peritoneal cavity, where lymphatic dis -\nsemination has been implicated 2-9. Risk factors such as short men -\nstrual cycles, extended menstrual periods, and uterine obstructions \nare associated with the development of the disease in women with \nopen fallopian tubes 1-4\nA - Endometrial Shedding\nDebris exits through the cervix and tubes, with the tubes acting \nas filters. Uterine contractions and anatomy affect this process. The \ncumulative regurgitation of endometrial debris through the tubal \nopening into the pelvic cavity is governed by Bernoulli, Torricelli, and \nLaplace Laws, which is responsible for the progression and regres -\nsion of the disease (Figure 1A). The individual length and internal size \nof cervical and tubal openings filter the endometrial debris from the \nlumen content to the pelvic cavity.\nB - Uterine Position\nNormoverted, Anteverted, and Retroverted. Different uterine po-\nsitions influence the flow of endometrial debris through the cervix \nand tubes. This may explain the varying occurrences of endometriosis \n(Figure 1B).\nC - Uterine Contractions\nContraction patterns influence the displacement of uterine con -\ntent, with estrogen increasing and progesterone decreasing contrac -\ntion frequency. This introduces three different patterns and related \ndirections of displacement through the cervical os, tubal openings, or \nboth (Figure 1C).\nDiscussion\nEndometriosis as a Systemic Disease?\nEndometriosis is considered a systemic disease, evidenced by the \npresence of extra-pelvic endometriosis, including thoracic endome -\ntriosis. Retrograde menstruation is a potential mechanism but does \nnot fully explain the disease’s pathophysiology [19]. There may be a \ngenetically predisposed condition [20-23] that, when combined with \nretrograde menstruation, leads to endometriosis. Although most cas-\nes (>98%) are not hereditary, understanding disease risk according \nto subphenotypes could be promising. Retrograde menstruation is \nan intrinsic part of the overall predisposition, potentially influenced \nby abnormal myometrial contractions [4,10,24-26]. Adolescents with \nobstructive Müllerian anomalies are more prone to developing endo-\nmetriosis and hematosalpinx [27]. Both endogenous and exogenous \nstem cells may also play a role, with bone marrow-derived stem cells \npotentially colonizing the endometrium [28,29]. Endometriosis is a \nchronic inflammatory disease, and while chronic inflammation has \nlong-term consequences, the pathogenesis may still be rooted in ret -\nrograde menstruation.\nThis condition allows blood and endometrial cells to pass through \nthe fallopian tubes, causing persistent inflammation. Endometriosis \nhas been linked to diseases such as atherosclerosis, migraines, and \nRaynaud’s syndrome, as well as a tendency towards a hypercoagu -\nlable state [30]. The inflammatory response affects cytokine cascade \nmetabolites, increasing uterine contractions [13]. It remains unclear \nwhether vascular endothelial damage [17] is a cause or consequence \nof the inflammation, and whether this is specific to endometriosis \nor common to general inflammation. Given these complexities, the \nquestion remains: how do we stop the disease? Should we slow down \nestrogen pressure or engage in radical surgeries, or can we engage \nin prevention? The inflammatory cells release cytokines and chemo -\nkines, causing further inflammation. Interestingly, progesterone acts \nnot only as an antiproliferative agent but also as an immune modula-\ntor [31]. Chronic inflammation in endometriosis suggests it may also \nbe an autoimmune disease. Traditional treatments often yield partial \nresults. Interventions aimed at reversing key causal phenomena, such \nas retrograde menstruation, should be prioritized, alongside early di-\nagnostic tools [32,33]. Preventing the retrograde transit of endome -\ntrial debris could reduce the disease’s incidence and complications. \nSub-classifications of endometriosis that predict prognosis and en -\nhance treatment prioritization are essential [32,33]. Recent studies \nidentifying genetic alterations, such as APOBEC3B deletion, might \nhelp in better diagnosing and treating endometriosis [20].\nTheoretical Framework\nRetrograde menstruation can cause endometrial tissue to exit \nthrough the fallopian tubes [17,18,34] under specific conditions (Fig-\nures 1A-1C). Ovarian hormones and chronic inflammation promote \nthe adhesion and growth of endometrial tissue in the pelvic cavity [1-\n4,7], where undifferentiated mesenchymal cells in the peritoneum act \nas progenitors of endometrial stromal cells.\nSupporting Evidence\nRecurrent menstrual cycles exacerbate inflammation and tissue \ndamage, progressing endometriosis [1-4,8,9]. Genetic, hormonal, life-\nstyle [35], and environmental factors contribute to the disease. En -\ndometrial ablation and levonorgestrel IUDs can reduce recurrence \nand alleviate pain [8,9]. Postpartum cervical changes in parous wom-\nen decrease endometriosis risk by promoting cervical outflow [14]. \nReduced periods of amenorrhea, due to fewer pregnancies and less \nfrequent breastfeeding in modern times, may increase the risk of en -\ndometriosis and adenomyosis among young women.\n\nCopyright@ :   Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\n50906\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\nInterpretation of Facts\nNormally, inflammation from menstruation is temporary and \nnon-damaging. However, repeated menstrual cycles may lead to \nongoing inflammation [1,5] increased production of utero-con -\ntracted prostaglandins, sequential increases in tubal debris outflow \n[17,18,27,28] and scarring, potentially contributing to conditions like \nadenomyosis.\nComparison with Existing Literature\nRecurrent menstrual cycles cause repeated stress on the uterine \nlining and may result in basal endometrium fragments being dis -\nlodged into the pelvic area [1-8] and myometrium. This could lead to \ndamage from excess iron and resistance to cell death40, promoting \nlesion progression and fibrosis.\nLimitations\nDespite the acceptance of this pathophysiological hypothesis, spe-\ncific randomized studies are lacking and therefore it remains the hy -\npothesis with the highest presumption of correspondence to the real \npathophysiology of its genesis but not yet included in the evidence.\nConclusion\nOver a century since the initial pathogenetic hypothesis of en -\ndometriosis, the disease remains a significant challenge, affecting \nmillions of women without a definitive cure. Despite numerous treat-\nment strategies, the scientific community is at an impasse, partly due \nto the hesitation to invest in and validate the most credible theories. \nThis hesitation has hindered progress in developing effective treat -\nments.\nSymptom Variability and Impact\nEndometriosis significantly impairs quality of life, causing symp -\ntoms such as pain, fatigue, heavy bleeding, and emotional distress. \nThese symptoms can start from the first menstrual period and contin-\nue until menopause, impacting education, career, and personal rela -\ntionships. Women who begin menstruating after age 14 have a lower \nrisk of developing endometriosis.\nTypes and Progression\nThere are three main types of endometriosis: superficial perito -\nneal, ovarian endometriomas, and deep infiltrating endometriosis \n(DIE). DIE often invades pelvic organs and typically requires surgical \nintervention. Endometriosis can progress in 37% of cases, remain sta-\nble in 50%, and regress in 17%. Surgery for DIE carries a 3-4% risk of \nmajor complications.\nDiagnostic Challenges\nWomen with endometriosis often face long delays in diagnosis \nand treatment, averaging seven years from symptom onset to diag -\nnosis. Common symptoms include severe pain, with 82% of women \nreporting pain scores between 7 and 10. Post-diagnosis, 66% receive \nhormonal treatment, significantly reducing pain, and 62% undergo \nsurgery.\nNeed for New Interventions\nNew interventions are urgently needed to prevent the occurrence \nand recurrence of endometriosis.\nTheories of Origin\nThe exact cause of endometriosis remains unknown. Theories \ninclude metastatic dissemination, genetic factors, coelomic meta -\nplasia, immune dysregulation, embryonic cell origin, involvement of \nendometrial stem cells, hormonal imbalance, and retrograde men -\nstruation. Recent research suggests a potential role for microbiota in \ndisease development.\nSampson Theory and Unanswered Questions\nWhile the Sampson theory of retrograde menstruation explains \nsome aspects of endometriosis, it leaves several questions unan -\nswered, such as why some women develop the disease and others \ndo not, and why the disease progresses in some cases but not others. \nThis variability may be due to differences in the amount and frequen-\ncy of endometrial debris transported through the fallopian tubes and \nindividual biochemical and biophysical factors [36-38].\nMechanical and Chemical Influences\nFactors such as the size of the cervical canal, the dimensions of \nthe tubal ostia, the configuration of the tubal portion within the uter-\nine wall, menstrual flow volume, uterine placement, and myometrial \ncontractions significantly influence the development of endometrio -\nsis. These factors affect the volume of blood and endometrial cells re-\ngurgitate each cycle, contributing to the likelihood of developing the \ndisease.\nGenetic and Mechanical Contributions\nGenetic predisposition and physical dynamics (such as princi -\nples of Bernoulli, Torricelli, and Laplace) explain variations in dis -\nease prevalence among individuals, especially those with obstructive \nMüllerian anomalies. While retrograde menstruation is common, not \nall women develop endometriosis or adenomyosis, suggesting protec-\ntive mechanisms are at play. Variations in the amount of endometrial \ndebris, its passage through the cervix or fallopian tubes, uterine con -\ntractions, and the filtering ability of the tubes could explain discrep -\nancies in disease development (Figures 1A-1C).\nFuture Directions\nNew strategies for prevention and relapse should include hor -\nmonal changes, biochemical agents affecting uterine muscle move -\nments, introducing uterine pacemakers [31,39] and altering retro -\ngrade menstruation to flow through the cervical opening, potentially \nby enlarging its internal uterine opening [17]. Retrograde menstru -\n\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\n50907\nation, stem cells, embryologic remnants, and/or metastases could \noccur in all women, yet endometriosis does not develop universally. \nTherefore, we need precise mechanistic explanations rather than \nsimplistic “just-so” stories to understand why and how the disease \nbegins and progresses, to identify effective therapeutic interventions. \nTo achieve this goal, we must step out of our “comfort zone” and avoid \ncomplacency [36-38,40]. We require fundamental changes in our in -\nterpretation of clinical, imaging, surgical, and pathological data. In \nour opinion, if we do not alter our conceptualization of the disease, \naccumulating more data, regardless of how it is obtained, will contrib-\nute little to our understanding. We must embark on a path of treat -\nment experimentation based on the most credible pathogenetic theo-\nry after 100 years. This is essential to prevent the onset, progression, \nand recurrence of the disease. This path is now obligatory [41,42]  \n(Table 1).\nTable 1: The table reports the proposal of 4 RCTs aimed at strengthening the pathogenic hypothesis of endometriosis with more robust evi -\ndence that lays the foundation for treatments consistent with this physiopathology. Two of the four studies establish two potential intervention \ntools that are the result of this hypothesis. \nRandomized Controlled Trials (RCT) Proposal \nStudy Question 1: The Role of Endometrial Debris Tubal Outflow in \nCausing and Developing Endometriosis?\nStudy Question 2: The Effectiveness of Reversing Tubal to Cervical \nOutflow of Endometrial Debris in Reducing Occurrence and Recurrence \nof Endometriosis.\nStudy 1 Study 2 Study 3 Study 4\nEndometriosis and Uterine \nContractility\nOverview:\tThis\tstudy\taims\tto\t\nexplore the relationship between \nuterine\tcontractility\tand\tthe\t\noccurrence\tand\trecurrence\tof\ten-\ndometriosis\tthrough\ta\tcarefully\t\ndesigned randomized controlled \ntrial.\tUterine\tcontractility,\tpar-\nticularly\tduring\tmenstruation,\t\nis\tbelieved\tto\tplay\ta\tkey\trole\tin\t\nthe development and progres-\nsion\tof\tendometriosis,\ta\tchronic\t\ngynecological\tcondition\tthat\t\naffects\ta\tsignificant\tpercentage\t\nof\treproductive-age\twomen.\t\nThe trial will assess both clinical \noutcomes\tand\tphysiological\t\nparameters related to uterine \ncontractility. \nStudy Population: 400 women \nof\treproductive\tage\twill\tbe\t\nenrolled and divided into two \ngroups.\nGroup\t1:\t200\twomen\twith\t\nadequate\tuterine\tcontractility\t\ndisplacement during their men-\nstrual period.\nGroup\t2:\t200\twomen\twith\t\ninadequate\tuterine\tcontractility,\t\nas\tmeasured\tby\tdisplacement\t\nduring the menstrual period. \nParticipants\twill\tbe\trecruited\t\nbased\ton\twell-defined\tinclusion\t\nand exclusion criteria ensuring \nproper\tclassification\tinto\ttheir\t\nrespective groups.\nPrimary Objective: Assess the \nOccurrence\tand\tRecurrence\tof\nEndometriosis and Family History \nOverview: This randomized con-\ntrolled trial aims to investigate the \nrelationship\tbetween\tfamily\thistory,\t\ndelivery\tmethod,\tand\tthe\toccurrence\t\nand\trecurrence\tof\tendometriosis.\t\nAdditionally,\tthe\tstudy\twill\texplore\t\nthe\trole\tof\tuterine\tcontractility\t\nduring menstruation and its cor-\nrelation with endometriosis. The \nstudy\twill\tcompare\ttwo\tgroups\tof\t\nwomen:\tthose\twith\ta\tfamily\thistory\t\nof\tendometriosis\tand\ta\tcontrol\tgroup\t\nwithout\tsuch\thistory,\tfurther\tsubdi-\nvided\tby\tmode\tof\tprevious\tdelivery\t\n(vaginal\tvs.\tcesarean\tsection). \nStudy Population: \n400\twomen\tof\treproductive\tage\twill\t\nbe enrolled in two groups: \nGroup 1:\t200\twomen\twith\ta\tfamily\t\nhistory\tof\tendometriosis.\nGroup 2 (Control Group):\t200\t\nwomen\twithout\ta\tfamily\thistory\tof\t\nendometriosis. \nThese\tgroups\twill\tbe\tfurther\tstrat-\nified\tbased\ton\tprevious\tchildbirth\t\nmethod: vaginal deliveries versus \ncesarean sections. \nPrimary Objective. Evaluate the \nOccurrence\tand\tRecurrence\tof\tEndo-\nmetriosis: \n• The trial will examine the inci-\ndence\tand\trecurrence\tof\tendometri-\nosis,\tcomparing\tthe\trole\tof\tfamily\t\nhistory\tand\tthe\timpact\tof\tprevious\t\ndelivery\tmethod\t(vaginal\tvs.\tcesar-\nean). \n•\tThe\tstudy\twill\talso\tutilize\t\nultrasound\tmeasurements\tof\tthe\t\ninternal\tos\tof\tthe\tcervix\tto\tassess\tany\t\npotential anatomical correlation with \nthe\toccurrence\tand\trecurrence\tof\t\nendometriosis. \nImpact of Periodic Cervical Os \nDilation on Endometrial Debris \nOutflow and Endometriosis Oc-\ncurrence \nStudy Design: This is a dou-\nble-blind, randomized controlled \ntrial\t(RCT)\taimed\tat\tinvestigating\t\nthe\timpact\tof\tperiodic\tcervical\tos\t\ndilation\ton\tthe\tquantity\tof\tcervical\t\nendometrial\tdebris\toutflow\tand\tits\t\neffect\ton\tthe\tincidence\tand\trecur-\nrence\tof\tendometriosis.\tParticipants \nwill be randomly assigned to two \ngroups:  \nOne undergoing regular cervical \ndilation, and  \nA control group with no interven-\ntion. \nParticipants: \nThe\tstudy\twill\tinclude\t400\twomen,\t\naged\t18–45,\tdivided\tinto\ttwo\tequal\t\ngroups\tof\t200\teach: \nIntervention Group (n=200): \nWomen will undergo periodic cer-\nvical os dilation at predetermined \ntime intervals. The dilation will be \nperformed\tby\ta\ttrained\tclinician\t\nusing a standardized protocol. \nControl Group (n=200): These \nwomen will receive no cervical os \ndilation\tor\tany\trelated\tintervention. \nAll\tparticipants\twill\thave\ta\thistory\t\nof\tmenstrual-related\tsymptoms\tor\t\nrisk\tfactors\tfor\tendometrial\tdebris\t\nretention, but none will have a prior \nconfirmed\tdiagnosis\tof\tendometri-\nosis.\nInclusion Criteria: \nWomen\taged\t18-45 \nRegular\tmenstrual\tcycles \nNo\tprior\tdiagnosis\tof\tendometriosis \nNo\thistory\tof\tcervical\tsurgery\tor\t\ninterventions \nEfficacy of a Physical Pacemaker in \nManaging Dysmenorrhea in Wom-\nen with Endometriosis: A Random-\nized Controlled Trial\nStudy Design: This is a random-\nized\tcontrolled\ttrial\t(RCT)\taimed\tat\t\nevaluating\tthe\tefficacy\tof\ta\tphtysical\t\npacemaker\timplanted\tin\tthe\tuterine\t\nfundus\tin\treducing\tdysmenorrhea\t\nand managing endometriosis. \nThe\tstudy\twill\tcompare\toutcomes\t\nbetween women receiving the pace-\nmaker\tand\tthose\twho\tdo\tnot.\nParticipants: \nThe\tstudy\twill\tinvolve\t400\twomen\t\ndiagnosed\twith\tendometriosis,\tall\tof\t\nwhom\treport\tsevere\tdysmenorrhea\t\n(painful menstrual\tperiods).\tThe\t\nparticipants will be divided into two \ngroups: \nIntervention\tGroup\t(n=200): Women \nwill\thave\ta\tphysical\tpacemaker\t\nsurgically\timplanted\tin\tthe\tuterine\t\nfundus\tto\tinduce\tfundus-to-cervix\t\ncontractions during menstruation. \nControl\tGroup\t(n=200): These wom-\nen\twill\tnot\treceive\ta\tpacemaker\tbut\t\nwill be monitored under the same \nprotocol as the intervention group. \nInclusion Criteria:\nWomen\taged\t18–45\twith\ta\tcon-\nfirmed\tdiagnosis\tof\tendometriosis \nSevere\tdysmenorrhea,\tmeasured\t\nusing a validated pain scale. \nRegular\tmenstrual\tcycles. \nNo\tprior\tuterine\tsurgeries. \nExclusion Criteria: \nPregnant\tor\tbreastfeeding\twomen. \nPrevious\tuterine\tsurgery\tor\tpace-\nmaker\timplantations. \nConcurrent\ttreatment\tfor\tendome-\ntriosis\tbeyond\tstandard\tmedical\t\nmanagement\n\nCopyright@ :   Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\n50908\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\nEndometriosis: \nThe\ttrial\twill\tprimarily\tfocus\t\non\tevaluating\tthe\tincidence\tof\t\nnew endometriosis cases and the \nrecurrence\tof\tpreviously\tdiag-\nnosed endometriosis in the two \ngroups\tover\ta\tdefined\tfollow-up\t\nperiod.\nSecondary Objectives:\nEvaluate Menstrual Cervical \nOutflow.\tCervical\toutflow\twill\t\nbe measured during menstrua-\ntion in both groups to investi-\ngate\tany\tpotential\tcorrelation\t\nbetween\tcontractility\tpatterns\t\nand\tmenstrual\tfluid\texpulsion\t\nthrough the cervix. \nUltrasound Assessment of the \nInternal Os: \nHigh-resolution ultrasound will \nbe\temployed\tto\texamine\tthe\tin-\nternal\tos\tof\tthe\tcervix,\tassessing\t\nits\tstructure,\tpatency,\tand\tany\t\npotential abnormalities. This \nwill\thelp\testablish\tany\trelation-\nship\tbetween\tcervical\tanatomy\t\nand\tuterine\tcontractility. \nExamination of Liquid Collec-\ntion in the Douglas Pouch:\nThe\tpresence\tof\tfluid\tin\tthe\t\nDouglas\tpouch\t(rectouterine\t\npouch)\twill\tbe\tevaluated\tvia\tul-\ntrasound.\tAccumulation\tof\tfluid\t\nhere could serve as an indicator \nof\tretrograde\tmenstrual\tflow,\t\nwhich\tis\ta\thypothesized\tcontrib-\nuting\tfactor\tto\tthe\tdevelopment\t\nof\tendometriosis. \nMethodology: \nBaseline Assessment: \nAll participants will undergo \nbaseline screening, including a \ndetailed\tgynecological\thistory,\t\npelvic examination, and ultra-\nsound imaging to assess uterine \ncontractility\tand\tany\tpre-exist-\ning endometriosis.\nRandomization:\nParticipants\twill\tbe\trandomized\t\ninto two arms based on their \nuterine\tcontractility\tdisplace-\nment\t(adequate\tvs.\tinadequate)\t\nduring menstruation. \nIntervention and Follow-Up: \nBoth\tgroups\twill\tbe\tfollowed\tfor\t\na\tperiod\tof\t12\tto\t24\tmonths,\twith\t\nregular\tassessments\tof\tendome-\ntriosis\tsymptoms,\trecurrence,\t\nand ultrasound measurements. \nSecondary Objective. \nEstablish\tthe\tPattern\tof\tUterine\t\nContractility\tDuring\tMenses: \n•\tThis\tobjective\tinvolves\tidentify-\ning\tpatterns\tof\tuterine\tcontractility\t\nduring menstruation in both groups. \nBy\tcomparing\tcontractility\tin\twom-\nen\twith\tand\twithout\ta\tfamily\thistory\t\nof\tendometriosis,\tthe\tstudy\taims\tto\t\nidentify\tpotential\tpredictive\tmarkers\t\nor\trisk\tfactors\tfor\tthe\tdevelopment\t\nor\trecurrence\tof\tendometriosis. \nMethodology: \nBaseline Assessment: \nParticipants\twill\tundergo\ta\tdetailed\t\nmedical\thistory,\tphysical\texamina-\ntion, and initial ultrasound assess-\nment\tof\tthe\tinternal\tos\tof\tthe\tcervix. \nUterine\tcontractility\twill\tbe\teval-\nuated using ultrasound during \nmenstruation in both groups. \nRandomization and Stratification: \nParticipants\twill\tbe\trandomly\tas-\nsigned\tto\teither\tthe\tfamily\thistory\tor\t\ncontrol group. Each group will then \nbe\tfurther\tdivided\tinto\tthose\twho\t\nhave had vaginal deliveries versus \ncesarean sections. \nFollow-Up and Data Collection: \nParticipants\twill\tbe\tfollowed\tover\t\na\tperiod\tof\t12-24\tmonths,\twith\t\nassessments\tfor\tthe\toccurrence\tor\t\nrecurrence\tof\tendometriosis. \nUltrasound\timaging\twill\tbe\tper-\nformed\tat\tregular\tintervals\tto\tmon-\nitor changes in the internal os and \nuterine\tcontractility\tpatterns.\t\nOutcome Measures: \nPrimary Outcome: Incidence and \nrecurrence\trates\tof\tendometriosis\t\nbased\ton\tfamily\thistory\tand\tmode\tof\t\ndelivery. \nSecondary Outcomes: \nContractility\tpatterns\tduring\tmen-\nstruation in both groups and their \ncorrelation with endometriosis. \nAnatomical variations in the internal \nos\tand\ttheir\tpotential\tlink\tto\tendo-\nmetriosis. \nExclusion Criteria: \nPregnant\tor\tbreastfeeding\twomen\nHistory\tof\tcervical\tabnormalities \nHormonal\ttreatments\taffecting\t\nmenstruation in the past six months \nIntervention: \nThe intervention group will receive \ncervical os dilation at regular \nintervals throughout the menstrual \ncycle,\ttimed\tto\tcoincide\twith\tkey\t\nphases\tof\tthe\tcycle\t(e.g.,\tpre-men-\nstrual\tand\tpost-menstrual).\t \nThe\tdilation\twill\tbe\tperformed\t\nusing a standardized dilator to a set \ndilation\tsize,\tensuring\tconsistency\t\nacross participants. Each participant \nwill\tundergo\tdilation\tfive\ttimes\t\nover a six-month period. \nThe control group will receive \nstandard\tcare\twithout\tany\tcervical\t\ndilation interventions but will be \nmonitored\ton\tthe\tsame\tschedule\tfor\t\ncomparison. \nPrimary Objectives: \nCervical Endometrial Debris Out-\nflow: The\tprimary\taim\tis\tto\tmeasure\t\nthe\tquantity\tof\tcervical\tendometrial\t\ndebris\texpelled\tfollowing\teach\t\nmenstrual\tcycle.\tThis\twill\tbe\tquanti-\ntatively\tassessed\tthrough\tfluid\tand\t\ntissue\tsamples\tcollected\tat\tspecific\t\ntime\tintervals\tafter\tmenstruation. \nIncidence and Recurrence of Endo-\nmetriosis: The\tstudy\twill\talso\ttrack\t\nthe\tincidence\tof\tnewly\tdiagnosed\t\nendometriosis in both groups over \nthe\tcourse\tof\t12\tmonths.\tIn\twomen\t\nwith\tpre-existing\tsymptoms,\tre-\ncurrence rates will be documented. \nDiagnosis\tof\tendometriosis\twill\tbe\t\nconfirmed\tthrough\tclinical\tevalua-\ntion\tand,\tif\tnecessary,\tlaparoscopic\t\ninvestigation.\nOutcome Measures:\nPrimary Outcome: \nQuantity\tof\tendometrial\tdebris\tout-\nflow,\tassessed\tthrough\tcytology\tand\t\nhistology\tat\tspecified\tintervals. \nIncidence and recurrence rates \nof\tendometriosis,\tas\tdetermined\t\nthrough\tclinical\tfollow-up\tand\t\nimaging. \nSecondary Outcomes: \nChange\tin\tmenstrual\tsymptoms\t\nsuch\tas\tpain,\tflow,\tand\tduration. \nQuality\tof\tlife\tas\tmeasured\tby\tvali-\ndated\tquestionnaires\t(e.g.,\tSF-36).\nIntervention: \nThe intervention group will undergo \na\tsurgical\tprocedure\tfor\tthe\tinsertion\t\nof\ta\tphysical\tpacemaker\tin\tthe\t\nuterine\tfundus.\tThe\tdevice\twill\tbe \nprogrammed\tto\tgenerate\trhythmic\t\ncontractions\tof\tthe\tuterus\tfrom\tthe\t\nfundus\tto\tthe\tcervix,\tmimicking\t\nnatural contractions but enhancing \noutflow\tof\tmenstrual\tcontents.\tThe\t\ngoal is to reduce uterine congestion \nand\timprove\tthe\tclearance\tof\tendo-\nmetrial\tdebris,\tpotentially\talleviating\t\npain\tand\tlowering\tthe\trisk\tof\tendo-\nmetriosis recurrence. \nThe control group will not receive \nany\tpacemaker\tbut\twill\tbe\tclosely\t\nfollowed\tfor comparison.\nPrimary Objectives:\nPain Intensity (Dysmenorrhea): \nThe\tprimary\tobjective\tis\tto\tassess\t\nthe\tintensity\tof\tdysmenorrhea\tusing\t\na\tvalidated\tpain\tscore\t(e.g.,\tVisual\t\nAnalog\tScale,\tVAS)\tbefore\tand\tafter\t\nthe intervention in both groups.\nOccurrence and Recurrence of \nEndometriosis: The\tsecondary\t\nobjective is to evaluate the impact \nof\tpacemaker-induced\tcontractions\t\non\tthe\tincidence\tof\tnew\tor\trecurrent\t\nendometriosis. This\twill\tbe\ttracked\t\nover\ta\t12-month\tfollow-up\tperiod\t\nusing clinical evaluations, imaging, \nand\tpotentially\tlaparoscopy.\nOutcome Measures: \nPrimary Outcome: \nChange\tin\tdysmenorrhea\tpain\t\nscores,\tassessed\tmonthly\tover\ta\t\n12-month\tperiod,\tusing\tVAS\tor\t\nsimilar pain assessment tools. \nThe\toccurrence\tand\trecurrence\tof\t\nendometriosis,\tmeasured\tby\tclinical\t\nsymptoms\tand\tconfirmed\tthrough\t\nimaging or surgical exploration. \nSecondary Outcomes: \nMenstrual\tflow\tcharacteristics\t(vol-\nume\tand\tduration) \nü\tQuality\tof\tlife,\tmeasured\tby\tvali-\ndated\tquestionnaires\t(e.g.,\tSF-36) \nAdverse\tevents\trelated\tto\tpacemaker\t\ninsertion\tor\tfunction \n\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\n50909\n \nRecurrence\tof\tendometriosis\twill\t\nbe\tconfirmed\tthrough\tlaparosco-\npy\tif\tclinically\tindicated. \nOutcome Measures: \nPrimary Outcome:  \nIncidence and recurrence rates \nof\tendometriosis\tin\tboth\tgroups. \nSecondary Outcomes: \nQuantitative\tand\tqualitative\t\nanalysis\tof\tcervical\toutflow. \nStructural\tand\tfunctional\tassess-\nment\tof\tthe\tinternal\tos. \nPresence\tand\tvolume\tof\tfluid\tin\t\nthe Douglas pouch. \nSignificance of the Study: \nThis randomized controlled trial \nwill provide valuable insights \ninto\tthe\tpotential\trole\tof\tuterine\t\ncontractility\tin\tthe\tpathogenesis\t\nand\trecurrence\tof\tendometriosis.\t\nThe\tfindings\tcould\tpave\tthe\t\nway\tfor\tnew\ttherapeutic\tinter-\nventions aimed at improving \nuterine\tcontractility,\tpotentially\t\noffering\tnovel\tapproaches\tto\tthe\t\nmanagement\tand\tprevention\tof\t\nthis debilitating condition. The \ncombination\tof\tclinical\tobser-\nvations with advanced imaging \ntechniques\t(ultrasound)\tadds\t\nrigor\tand\tdepth\tto\tthe\tstudy,\t\noffering\ta\tcomprehensive\tevalu-\nation\tof\tthe\tmechanisms\tbehind\t\nendometriosis development.This \nformat\tshould\tclearly\tillustrate\t\nthe\tproposed\tstudy\tdesign\tand\t\nits relevance, ensuring that the \nresearch objectives are presented \nin a structured and convincing \nmanner.\nSignificance of the Study: \nThis\tstudy\twill\tprovide\tinsights\t\ninto\tthe\trole\tof\tfamily\thistory\tand\t\nprevious\tdelivery\tmethod\t(vaginal\t\nvs.\tcesarean)\tin\tthe\tdevelopment\t\nand\trecurrence\tof\tendometriosis.\tBy\t\ninvestigating\tuterine\tcontractility\t\npatterns and correlating them with \nthe\toccurrence\tof\tendometriosis,\tthe\t\nstudy\tcould\tlead\tto\timproved\tunder-\nstanding\tof\tthe\tunderlying\tmecha-\nnisms\tand\trisk\tfactors.\tAdditionally,\t\nthe\tuse\tof\tultrasound\tmeasurements\t\nof\tthe\tinternal\tos\toffers\ta\tnovel\t\napproach to examining potential an-\natomical contributions to endometri-\nosis.\tThis\tresearch\tcould\tultimately\t\ncontribute to better prediction, pre-\nvention, and management strategies \nfor\twomen\tat\trisk\tof\tendometriosis.\t\nThis\tformat\tclearly\tpresents\tthe\t\nobjectives\tand\tdesign\tof\tthe\tsecond\t\nstudy,\tproviding\ta\tcomprehensive\t\nand structured overview.\nData Collection and Analysis: \nBaseline Assessments: All partici-\npants will undergo a detailed base-\nline assessment, including a medical \nhistory,\tgynecological\texamination,\t\nand pelvic ultrasound. \nFollow-up Visits:\tParticipants\twill\t\nattend\tfollow-up\tvisits\tat\tregular\t\nintervals\tfor\tmonitoring,\tsample\t\ncollection, and assessments. \nStatistical Analysis: Data will be \nanalyzed\tusing\tappropriate\tstatisti-\ncal\tmethods\t(e.g.,\tt-tests,\tchi-square\t\ntests)\tto\tcompare\tthe\tintervention\t\nand\tcontrol\tgroups\tfor\tprimary\tand\t\nsecondary\toutcomes.\tA\tp-value\tof\t\n<0.05\twill\tbe\tconsidered\tstatistically\t\nsignificant.\nEthical Considerations:\tInformed\t\nconsent\twill\tbe\tobtained\tfrom\tall\t\nparticipants.\tThe\tstudy\twill\tadhere\t\nto\tthe\tethical\tguidelines\tset\tforth\t\nby\trelevant\tregulatory\tauthorities,\t\nensuring\tparticipant\tsafety\tand\t\nprivacy.\tAn\tindependent\tData\tSafe-\nty\tMonitoring\tBoard\t(DSMB)\twill\t\noversee the trial.\nConclusion:\tThis\tRCT\twill\tprovide\t\nimportant insights into the role \nof\tperiodic\tcervical\tos\tdilation\t\nin enhancing endometrial debris \noutflow\tand\tits\tpotential\tin\tprevent-\ning\tor\treducing\tthe\trecurrence\tof\t\nendometriosis.\tIf\tsuccessful,\tthis\tin-\ntervention could represent a novel, \nnon-invasive\tstrategy\tfor\tmanaging\t\nendometrial health and reducing \nthe\tburden\tof\tendometriosis.\nData Collection and Analysis: \nBaseline Assessments: All partic-\nipants will undergo a baseline as-\nsessment\tincluding\tmedical\thistory,\t\ngynecological\texamination,\tand\tpain \nevaluation. \nFollow-up Visits: \nMonthly\tfollow-up\tvisits\twill\tbe\t\nconducted\tfor\tpain\tassessment,\t\nmenstrual\tflow\tevaluation,\tand\t\npacemaker\tperformance\t(for\tthe\t\nintervention\tgroup). \nStatistical Analysis: \nData\twill\tbe\tanalyzed\tusing\tap-\npropriate\tstatistical\tmethods\t(e.g.,\t\npaired\tt-tests,\tchi-square\ttests)\tto\t\ncompare the two groups. A p-value \nof\t<0.05\twill\tbe\tconsidered\tstatisti-\ncally significant. • Ethical Consid-\nerations: Informed\tconsent\twill\tbe\t\nobtained\tfrom\tall\tparticipants.\tThe\t\nstudy\twill\tadhere\tto\tethical\tguide-\nlines\tensuring\tparticipant\tsafety\tand\t\nprivacy.\tA\tData\tSafety\tMonitoring\t\nBoard\t(DSMB)\twill\toversee\tthe\t\ntrial,\tparticularly\tin\tmonitoring\t\nany\tadverse\teffects\trelated\tto\tthe \npacemaker.\nConclusion: \nThis\tRCT\taims\tto\tdetermine\twhether\t\nthe\tuse\tof\ta\tphysical\tpacemaker\tto\t\ninduce\tfundus-to-cervix\tuterine\t\ncontractions\tcan\teffectively\treduce \ndysmenorrhea\tand\tmanage\tendome-\ntriosis.\tThe\tfindings\tcould\tpoten-\ntially\tintroduce\ta\tnovel\ttreatment\t\napproach\tfor\twomen\tsuffering\tfrom\t\nsevere pain and recurrent endome-\ntriosis. \nAuthors Contribution\n• Francesco Maria Bulletti and Carlo Bulletti contributed \nequally to this article in terms of conceptualization and the \nfirst draft of the manuscript. Francesco Maria Bulletti wrote \nthe last version of the manuscript\n• Antonio Palagiano and Maurizio Guido provided to search \nand first selection of the studies required and remarked the \nmore realistic pathogenetic concept reported\n• Maria Elisabetta Coccia revised the second and third draft\n• Ethical Considerations are not applicable.\nReferences\n1. Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, et al. (2022) ESH-\nRE guideline: endometriosis. Hum Reprod Open.\n2. Horne AW, Missmer SA (2022) Pathophysiology, diagnosis, and manage -\nment of endometriosis. BMJ, pp. 379.\n3. De Ziegler D, Borghese B, Chapron C (2010) Endometriosis and infertility: \npathophysiology and management. Lancet 376(9742): 730-738. \n4. Vercellini P , Bandini V, Viganò P , Di Stefano G, Merli CEM, et al. (2024) Pro-\nposal for targeted, neo-evolutionary-oriented secondary prevention of \nearly-onset endometriosis and adenomyosis. Part I: pathogenic aspects. \nHum Reprod 39: 1-17. \n5. 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(2018) \nTime to redefine endometriosis including its pro-fibrotic nature, Human \nReproduction 33(3): 347-352.\n\nCopyright@ :  Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214.\nVolume 58- Issue 5\nDOI: 10.26717/BJSTR.2024.58.009214\n50911\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.2024.58.009214\nCarlo Bulletti. Biomed J Sci & Tech Res","source_license":"CC0","license_restricted":false}