Endometriosis: A Century of Unresolved Pathogenesis – It’s Time for Decisive Action

Endometriosis affects around 10% of reproductive-age women, causing severe pain, infertility, and various other symptoms. Traditional treatments, like hormonal therapies and surgeries, often provide temporary relief with significant side effects, The disease’s heterogeneity and varied responses to treatment necessitate a personalized approach. The leading hypothesis for endometriosis onset and recurrence is retrograde menstruation, influenced by factors like uterine position, tubal filtering function by its length and opening sizes, and specific uterine contractility profiles. This hypothesis suggests that only some women are predisposed due to these factors, leading to endometrial cell regurgitation into the pelvic cavity. Advances in biophysical and biochemical markers (proteomics and metabolomics) offer insights into disease activity and treatment response, enabling real-time monitoring and personalized care. Targeted therapies, including angiogenesis inhibitors and drugs/devices modulating hormonal and inflammatory pathways, and uterine content outflow through adequate cervical/ tubal openings and uterine contractions control, promise to enhance outcomes and quality of life.

Endometriosis; Pathogenesis; Theory; Epidemiology

Background Information Endometriosis is characterized by the growth of tissue resem - bling the lining of the uterus in areas outside the uterus, such as the ovaries, fallopian tubes, bladder, intestines, or peritoneum. It can less commonly affect areas outside the pelvis, like the diaphragm, pleura, abdominal wall, or nervous system [1,2]. This condition causes se - vere pelvic pain and can make it difficult to conceive. About 10% of women and girls of childbearing age worldwide, around 190 million people, are affected by endometriosis. The economic impact is signif- icant, with costs exceeding 80 billion USD annually [1-4]. It manifests as a chronic ailment with symptoms that can be debilitating, such as severe menstrual pain, discomfort during sex, difficulties with bow - el movements or urination, dysuria, ongoing pelvic pain, bloating, constipation, painful bowel movements, nausea, exhaustion, and in some cases, depression and anxiety [1,3,4]. Approximately 40-50% of women with infertility issues have endometriosis [3-5]. Although var- ious mechanisms have been suggested to explain infertility linked to endometriosis, there is no conclusive evidence of its association with endometrial receptivity. A recent study found a slight decrease in live birth rates among women with a history of endometriosis, suggesting that minor impairments in uterine receptivity might contribute to in- fertility in these women [6]. ARTICLE INFO Received: September 16, 2024 Published: September 26,2024 Citation: Francesco Maria Bulletti, Maurizio Guido, Antonio Palagiano, Maria Elisabetta Coccia and Carlo Bulletti. Endometriosis: A Century of Unresolved Pathogenesis – It’s Time for Decisive Action. Biomed J Sci & Tech Res 58(5)-2024. BJSTR. MS.ID.009214. Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 50903 On the other hand, the condition distorts pelvic anatomy, caus - es adhesions and fallopian tube scarring, and leads to local inflam - mation and hormonal regulation disruptions [3-5]. These symptoms can significantly affect a person’s quality of life, education, career, and relationships [1-5]. This article offers a comprehensive overview of the current understanding and recent advancements in the theories of endometriosis pathogenesis, with our opinion on the need for a few RCTs designed to confirm the pathogenesis. An extensive litera - ture search was performed using databases such as PubMed, Scopus, and Web of Science, employing keywords including “endometriosis,” “pathogenesis,” “theory,” and “epidemiology.” The aim of synthesizing these findings is to provide a wide-ranging perspective on endome - triosis pathogenesis, emphasizing potential areas for future research. Endometriosis can present a wide range of symptoms that sig - nificantly impact the quality of life and emotional well-being, includ - ing pain, fatigue, heavy menstrual bleeding, and mood swings. These symptoms can affect education, career, and intimate relationships [1- 8]. The condition can start with the first menstrual period and contin- ue in varying patterns until menopause. Starting menstruation after age 14 is significantly correlated with a lower risk of developing en - dometriosis. Currently, there is no known way to prevent the disease, and while it cannot be cured, symptoms can be managed through medication or surgery [4,9,10]. Endometriosis manifests in three main forms: superficial peritoneal endometriosis, ovarian endome - triomas, and deep infiltrating endometriosis (DIE) [1,2,4,10-12]. DIE penetrates organs in the pelvic area and often requires surgical treat- ment. The disease can progress in 37% of cases, remain stable in 50%, and regress in 17% (10). Surgery for DIE carries a risk of major com- plications (3-4%) and minor complications (10-15%) [12]. Gaining a full grasp of the complex processes behind endometriosis is essen - tial for advancing treatment options, which are presently inadequate [2,5,12]. A recent large-scale, web-based survey revealed that women with endometriosis endure a lengthy and challenging journey before receiving a diagnosis and effective treatment, highlighting the urgent need to reduce diagnostic delays. On average, seven years elapse be - tween the onset of symptoms (at 23.8 ± 10.2 years) and diagnosis (31.0 ± 8.9 years). Women reported an average of 4.6 ± 2.3 symptoms, with 82% experiencing severe pain (pain scores between 7 and 10). After diagnosis, 66% of women received medical treatment, primar - ily hormonal (45%), which significantly reduced pain intensity (VAS scores after treatment = 4.9 ± 2.7, p < 0.001). Additionally, 62% had undergone surgery, with 22% undergoing laparotomies. The survey highlighted significant impacts on daily life, particularly in sexual, psychological, and physical areas, with an overall quality of life score averaging 4.3 ± 2.6 out of 1013. Developing new interventions to prevent both the occurrence and recurrence of endometriosis is crucial. The exact cause of endometri- osis is not definitively known, but several theories offer insights into its potential origins and guide research toward innovative treatments [2,3,8,9,12]. These theories include metastatic dissemination, sur - gical transplantation, genetic factors, coelomic metaplasia, immune dysregulation, embryonic cell origin, endometrial stem cell involve - ment, hormonal imbalance, bone marrow stem cells, and retrograde menstruation [1-10]. Recent research also suggests the possible role of microbiota in the development of endometriosis, indicating that the role of infection in disease etiology should be further investigated14. Despite these theories, questions remain about why certain women are affected, the varied progression of the disease, and its resistance to progesterone treatment [1-8]. Literature Review While the Sampson theory on endometriosis is supported by nu - merous facts [1-4,8,9], it seems to leave some questions unanswered. However, a careful, deep analysis can provide answers to these ques- tions: Variability in Affected Women Endometriosis affects certain women and not others due to differ- ences in the amount and frequency of endometrial debris transported through the fallopian tubes and subsequently implanted in the pelvic cavity (Figure 1) [1-4]. Disease Progression The progression of endometriosis in some women, while remain- ing stable in others, is influenced by individual combinations of chem- ical-physical factors. These factors determine the capacity for leakage and accumulation of endometrial debris (Figures 1A-1C) [1-4,8,9]. Beyond Oversimplified Views Viewing endometriosis as merely a chronic, inflammatory, multi- faceted disease that resists progesterone treatment is an oversimpli - fication. The Sampson theory emphasizes that the chronic nature, in- flammation, and complexity of the disease result from the continued presence of endometrial tissue outside the uterus [1-4,8,9]. Mechanical Aspects Understanding the mechanical aspects of how endometriosis begins and advances is crucial. Detailed explanations are needed to guide the creation of targeted and effective treatments rather than relying on general theories [1-4,8,9]. Physical and chemical factors such as the size of the cervical canal, the dimensions of the tubal os - tia, the configuration of the tubal portion within the uterine wall, the length of the tubes, the functioning of the junction between the uterus and tubes, the volume of menstrual flow, the personal placement of the uterus, the size of its openings, and the frequency and intensity of myometrial contractions significantly contribute to the likelihood of developing endometriosis (Figures 1A-1C) [1-4,8,9]. These factors particularly affect individuals with obstructive Müllerian anoma - lies 25. The principles laid out by Bernoulli, Torricelli, and Laplace [8,13,14] underpin the variation in quantities from person to person (Figures 1A-1C). Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. 50904 Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 Figure 1: A. Endometrial Shedding: Debris exits through the cervix and tubes, with the tubes acting as filters. Uterine contractions and anatomy affect this process. The cumulative regurgitation of endometrial debris through the tubal opening into the pelvic cavity is governed by Bernoulli, Torricelli, and Laplace Laws, which is responsible for the progression and regression of the disease (Figure 1A). The individual length and internal size of cervical and tubal openings filter the endometrial debris from the lumen content to the pelvic cavity. B. Uterine Position: Normoverted, Anteverted, and Retroverted. Different uterine positions influence the flow of endometrial debris through the cervix and tubes. This may explain the varying occurrences of endometriosis (Figure 1B). C. Uterine Contractions: Contraction patterns influence the displacement of uterine content, with estrogen increasing and progesterone decreasing contraction frequency. This introduces three different patterns and related directions of displacement through the cervical os, tubal openings, or both (Figure 1C). A B Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 50905 Statement of Opinion The retrograde menstruation theory (Sampson)15,16suggests that during menstruation, some endometrial tissue may backflow through the fallopian tubes into the abdominal cavity, potentially leading to the formation of endometriotic lesions [12,15-18] (Figures 1A-1C). Recurrent endometrial accumulation infiltrates deeper struc- tures or appears outside the peritoneal cavity, where lymphatic dis - semination has been implicated 2-9. Risk factors such as short men - strual cycles, extended menstrual periods, and uterine obstructions are associated with the development of the disease in women with open fallopian tubes 1-4 A - Endometrial Shedding Debris exits through the cervix and tubes, with the tubes acting as filters. Uterine contractions and anatomy affect this process. The cumulative regurgitation of endometrial debris through the tubal opening into the pelvic cavity is governed by Bernoulli, Torricelli, and Laplace Laws, which is responsible for the progression and regres - sion of the disease (Figure 1A). The individual length and internal size of cervical and tubal openings filter the endometrial debris from the lumen content to the pelvic cavity. B - Uterine Position Normoverted, Anteverted, and Retroverted. Different uterine po- sitions influence the flow of endometrial debris through the cervix and tubes. This may explain the varying occurrences of endometriosis (Figure 1B). C - Uterine Contractions Contraction patterns influence the displacement of uterine con - tent, with estrogen increasing and progesterone decreasing contrac - tion frequency. This introduces three different patterns and related directions of displacement through the cervical os, tubal openings, or both (Figure 1C).

Endometriosis as a Systemic Disease? Endometriosis is considered a systemic disease, evidenced by the presence of extra-pelvic endometriosis, including thoracic endome - triosis. Retrograde menstruation is a potential mechanism but does not fully explain the disease’s pathophysiology [19]. There may be a genetically predisposed condition [20-23] that, when combined with retrograde menstruation, leads to endometriosis. Although most cas- es (>98%) are not hereditary, understanding disease risk according to subphenotypes could be promising. Retrograde menstruation is an intrinsic part of the overall predisposition, potentially influenced by abnormal myometrial contractions [4,10,24-26]. Adolescents with obstructive Müllerian anomalies are more prone to developing endo- metriosis and hematosalpinx [27]. Both endogenous and exogenous stem cells may also play a role, with bone marrow-derived stem cells potentially colonizing the endometrium [28,29]. Endometriosis is a chronic inflammatory disease, and while chronic inflammation has long-term consequences, the pathogenesis may still be rooted in ret - rograde menstruation. This condition allows blood and endometrial cells to pass through the fallopian tubes, causing persistent inflammation. Endometriosis has been linked to diseases such as atherosclerosis, migraines, and Raynaud’s syndrome, as well as a tendency towards a hypercoagu - lable state [30]. The inflammatory response affects cytokine cascade metabolites, increasing uterine contractions [13]. It remains unclear whether vascular endothelial damage [17] is a cause or consequence of the inflammation, and whether this is specific to endometriosis or common to general inflammation. Given these complexities, the question remains: how do we stop the disease? Should we slow down estrogen pressure or engage in radical surgeries, or can we engage in prevention? The inflammatory cells release cytokines and chemo - kines, causing further inflammation. Interestingly, progesterone acts not only as an antiproliferative agent but also as an immune modula- tor [31]. Chronic inflammation in endometriosis suggests it may also be an autoimmune disease. Traditional treatments often yield partial results. Interventions aimed at reversing key causal phenomena, such as retrograde menstruation, should be prioritized, alongside early di- agnostic tools [32,33]. Preventing the retrograde transit of endome - trial debris could reduce the disease’s incidence and complications. Sub-classifications of endometriosis that predict prognosis and en - hance treatment prioritization are essential [32,33]. Recent studies identifying genetic alterations, such as APOBEC3B deletion, might help in better diagnosing and treating endometriosis [20]. Theoretical Framework Retrograde menstruation can cause endometrial tissue to exit through the fallopian tubes [17,18,34] under specific conditions (Fig- ures 1A-1C). Ovarian hormones and chronic inflammation promote the adhesion and growth of endometrial tissue in the pelvic cavity [1- 4,7], where undifferentiated mesenchymal cells in the peritoneum act as progenitors of endometrial stromal cells. Supporting Evidence Recurrent menstrual cycles exacerbate inflammation and tissue damage, progressing endometriosis [1-4,8,9]. Genetic, hormonal, life- style [35], and environmental factors contribute to the disease. En - dometrial ablation and levonorgestrel IUDs can reduce recurrence and alleviate pain [8,9]. Postpartum cervical changes in parous wom- en decrease endometriosis risk by promoting cervical outflow [14]. Reduced periods of amenorrhea, due to fewer pregnancies and less frequent breastfeeding in modern times, may increase the risk of en - dometriosis and adenomyosis among young women. Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. 50906 Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 Interpretation of Facts Normally, inflammation from menstruation is temporary and non-damaging. However, repeated menstrual cycles may lead to ongoing inflammation [1,5] increased production of utero-con - tracted prostaglandins, sequential increases in tubal debris outflow [17,18,27,28] and scarring, potentially contributing to conditions like adenomyosis. Comparison with Existing Literature Recurrent menstrual cycles cause repeated stress on the uterine lining and may result in basal endometrium fragments being dis - lodged into the pelvic area [1-8] and myometrium. This could lead to damage from excess iron and resistance to cell death40, promoting lesion progression and fibrosis.

Despite the acceptance of this pathophysiological hypothesis, spe- cific randomized studies are lacking and therefore it remains the hy - pothesis with the highest presumption of correspondence to the real pathophysiology of its genesis but not yet included in the evidence.

Over a century since the initial pathogenetic hypothesis of en - dometriosis, the disease remains a significant challenge, affecting millions of women without a definitive cure. Despite numerous treat- ment strategies, the scientific community is at an impasse, partly due to the hesitation to invest in and validate the most credible theories. This hesitation has hindered progress in developing effective treat - ments. Symptom Variability and Impact Endometriosis significantly impairs quality of life, causing symp - toms such as pain, fatigue, heavy bleeding, and emotional distress. These symptoms can start from the first menstrual period and contin- ue until menopause, impacting education, career, and personal rela - tionships. Women who begin menstruating after age 14 have a lower risk of developing endometriosis. Types and Progression There are three main types of endometriosis: superficial perito - neal, ovarian endometriomas, and deep infiltrating endometriosis (DIE). DIE often invades pelvic organs and typically requires surgical intervention. Endometriosis can progress in 37% of cases, remain sta- ble in 50%, and regress in 17%. Surgery for DIE carries a 3-4% risk of major complications. Diagnostic Challenges Women with endometriosis often face long delays in diagnosis and treatment, averaging seven years from symptom onset to diag - nosis. Common symptoms include severe pain, with 82% of women reporting pain scores between 7 and 10. Post-diagnosis, 66% receive hormonal treatment, significantly reducing pain, and 62% undergo surgery. Need for New Interventions New interventions are urgently needed to prevent the occurrence and recurrence of endometriosis. Theories of Origin The exact cause of endometriosis remains unknown. Theories include metastatic dissemination, genetic factors, coelomic meta - plasia, immune dysregulation, embryonic cell origin, involvement of endometrial stem cells, hormonal imbalance, and retrograde men - struation. Recent research suggests a potential role for microbiota in disease development. Sampson Theory and Unanswered Questions While the Sampson theory of retrograde menstruation explains some aspects of endometriosis, it leaves several questions unan - swered, such as why some women develop the disease and others do not, and why the disease progresses in some cases but not others. This variability may be due to differences in the amount and frequen- cy of endometrial debris transported through the fallopian tubes and individual biochemical and biophysical factors [36-38]. Mechanical and Chemical Influences Factors such as the size of the cervical canal, the dimensions of the tubal ostia, the configuration of the tubal portion within the uter- ine wall, menstrual flow volume, uterine placement, and myometrial contractions significantly influence the development of endometrio - sis. These factors affect the volume of blood and endometrial cells re- gurgitate each cycle, contributing to the likelihood of developing the disease. Genetic and Mechanical Contributions Genetic predisposition and physical dynamics (such as princi - ples of Bernoulli, Torricelli, and Laplace) explain variations in dis - ease prevalence among individuals, especially those with obstructive Müllerian anomalies. While retrograde menstruation is common, not all women develop endometriosis or adenomyosis, suggesting protec- tive mechanisms are at play. Variations in the amount of endometrial debris, its passage through the cervix or fallopian tubes, uterine con - tractions, and the filtering ability of the tubes could explain discrep - ancies in disease development (Figures 1A-1C). Future Directions New strategies for prevention and relapse should include hor - monal changes, biochemical agents affecting uterine muscle move - ments, introducing uterine pacemakers [31,39] and altering retro - grade menstruation to flow through the cervical opening, potentially by enlarging its internal uterine opening [17]. Retrograde menstru - Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 50907 ation, stem cells, embryologic remnants, and/or metastases could occur in all women, yet endometriosis does not develop universally. Therefore, we need precise mechanistic explanations rather than simplistic “just-so” stories to understand why and how the disease begins and progresses, to identify effective therapeutic interventions. To achieve this goal, we must step out of our “comfort zone” and avoid complacency [36-38,40]. We require fundamental changes in our in - terpretation of clinical, imaging, surgical, and pathological data. In our opinion, if we do not alter our conceptualization of the disease, accumulating more data, regardless of how it is obtained, will contrib- ute little to our understanding. We must embark on a path of treat - ment experimentation based on the most credible pathogenetic theo- ry after 100 years. This is essential to prevent the onset, progression, and recurrence of the disease. This path is now obligatory [41,42] (Table 1). Table 1: The table reports the proposal of 4 RCTs aimed at strengthening the pathogenic hypothesis of endometriosis with more robust evi - dence that lays the foundation for treatments consistent with this physiopathology. Two of the four studies establish two potential intervention tools that are the result of this hypothesis.  Randomized Controlled Trials (RCT) Proposal Study Question 1: The Role of Endometrial Debris Tubal Outflow in Causing and Developing Endometriosis? Study Question 2: The Effectiveness of Reversing Tubal to Cervical Outflow of Endometrial Debris in Reducing Occurrence and Recurrence of Endometriosis. Study 1 Study 2 Study 3 Study 4 Endometriosis and Uterine Contractility Overview: This study aims to explore the relationship between uterine contractility and the occurrence and recurrence of en- dometriosis through a carefully designed randomized controlled trial. Uterine contractility, par- ticularly during menstruation, is believed to play a key role in the development and progres- sion of endometriosis, a chronic gynecological condition that affects a significant percentage of reproductive-age women. The trial will assess both clinical outcomes and physiological parameters related to uterine contractility. Study Population: 400 women of reproductive age will be enrolled and divided into two groups. Group 1: 200 women with adequate uterine contractility displacement during their men- strual period. Group 2: 200 women with inadequate uterine contractility, as measured by displacement during the menstrual period. Participants will be recruited based on well-defined inclusion and exclusion criteria ensuring proper classification into their respective groups. Primary Objective: Assess the Occurrence and Recurrence of Endometriosis and Family History Overview: This randomized con- trolled trial aims to investigate the relationship between family history, delivery method, and the occurrence and recurrence of endometriosis. Additionally, the study will explore the role of uterine contractility during menstruation and its cor- relation with endometriosis. The study will compare two groups of women: those with a family history of endometriosis and a control group without such history, further subdi- vided by mode of previous delivery (vaginal vs. cesarean section). Study Population: 400 women of reproductive age will be enrolled in two groups: Group 1: 200 women with a family history of endometriosis. Group 2 (Control Group): 200 women without a family history of endometriosis. These groups will be further strat- ified based on previous childbirth

vaginal deliveries versus cesarean sections. Primary Objective. Evaluate the Occurrence and Recurrence of Endo- metriosis: • The trial will examine the inci- dence and recurrence of endometri- osis, comparing the role of family history and the impact of previous delivery method (vaginal vs. cesar- ean). • The study will also utilize ultrasound measurements of the internal os of the cervix to assess any potential anatomical correlation with the occurrence and recurrence of endometriosis. Impact of Periodic Cervical Os Dilation on Endometrial Debris Outflow and Endometriosis Oc- currence Study Design: This is a dou- ble-blind, randomized controlled trial (RCT) aimed at investigating the impact of periodic cervical os dilation on the quantity of cervical endometrial debris outflow and its effect on the incidence and recur- rence of endometriosis. Participants will be randomly assigned to two groups: One undergoing regular cervical dilation, and A control group with no interven- tion. Participants: The study will include 400 women, aged 18–45, divided into two equal groups of 200 each: Intervention Group (n=200): Women will undergo periodic cer- vical os dilation at predetermined time intervals. The dilation will be performed by a trained clinician using a standardized protocol. Control Group (n=200): These women will receive no cervical os dilation or any related intervention. All participants will have a history of menstrual-related symptoms or risk factors for endometrial debris retention, but none will have a prior confirmed diagnosis of endometri- osis. Inclusion Criteria: Women aged 18-45 Regular menstrual cycles No prior diagnosis of endometriosis No history of cervical surgery or interventions Efficacy of a Physical Pacemaker in Managing Dysmenorrhea in Wom- en with Endometriosis: A Random- ized Controlled Trial Study Design: This is a random- ized controlled trial (RCT) aimed at evaluating the efficacy of a phtysical pacemaker implanted in the uterine fundus in reducing dysmenorrhea and managing endometriosis. The study will compare outcomes between women receiving the pace- maker and those who do not. Participants: The study will involve 400 women diagnosed with endometriosis, all of whom report severe dysmenorrhea (painful menstrual periods). The participants will be divided into two groups: Intervention Group (n=200): Women will have a physical pacemaker surgically implanted in the uterine fundus to induce fundus-to-cervix contractions during menstruation. Control Group (n=200): These wom- en will not receive a pacemaker but will be monitored under the same protocol as the intervention group. Inclusion Criteria: Women aged 18–45 with a con- firmed diagnosis of endometriosis Severe dysmenorrhea, measured using a validated pain scale. Regular menstrual cycles. No prior uterine surgeries. Exclusion Criteria: Pregnant or breastfeeding women. Previous uterine surgery or pace- maker implantations. Concurrent treatment for endome- triosis beyond standard medical management Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. 50908 Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 Endometriosis: The trial will primarily focus on evaluating the incidence of new endometriosis cases and the recurrence of previously diag- nosed endometriosis in the two groups over a defined follow-up period. Secondary Objectives: Evaluate Menstrual Cervical Outflow. Cervical outflow will be measured during menstrua- tion in both groups to investi- gate any potential correlation between contractility patterns and menstrual fluid expulsion through the cervix. Ultrasound Assessment of the Internal Os: High-resolution ultrasound will be employed to examine the in- ternal os of the cervix, assessing its structure, patency, and any potential abnormalities. This will help establish any relation- ship between cervical anatomy and uterine contractility. Examination of Liquid Collec- tion in the Douglas Pouch: The presence of fluid in the Douglas pouch (rectouterine pouch) will be evaluated via ul- trasound. Accumulation of fluid here could serve as an indicator of retrograde menstrual flow, which is a hypothesized contrib- uting factor to the development of endometriosis. Methodology: Baseline Assessment: All participants will undergo baseline screening, including a detailed gynecological history, pelvic examination, and ultra- sound imaging to assess uterine contractility and any pre-exist- ing endometriosis. Randomization: Participants will be randomized into two arms based on their uterine contractility displace- ment (adequate vs. inadequate) during menstruation. Intervention and Follow-Up: Both groups will be followed for a period of 12 to 24 months, with regular assessments of endome- triosis symptoms, recurrence, and ultrasound measurements. Secondary Objective. Establish the Pattern of Uterine Contractility During Menses: • This objective involves identify- ing patterns of uterine contractility during menstruation in both groups. By comparing contractility in wom- en with and without a family history of endometriosis, the study aims to identify potential predictive markers or risk factors for the development or recurrence of endometriosis. Methodology: Baseline Assessment: Participants will undergo a detailed medical history, physical examina- tion, and initial ultrasound assess- ment of the internal os of the cervix. Uterine contractility will be eval- uated using ultrasound during menstruation in both groups. Randomization and Stratification: Participants will be randomly as- signed to either the family history or control group. Each group will then be further divided into those who have had vaginal deliveries versus cesarean sections. Follow-Up and Data Collection: Participants will be followed over a period of 12-24 months, with assessments for the occurrence or recurrence of endometriosis. Ultrasound imaging will be per- formed at regular intervals to mon- itor changes in the internal os and uterine contractility patterns. Outcome Measures: Primary Outcome: Incidence and recurrence rates of endometriosis based on family history and mode of delivery. Secondary Outcomes: Contractility patterns during men- struation in both groups and their correlation with endometriosis. Anatomical variations in the internal os and their potential link to endo- metriosis. Exclusion Criteria: Pregnant or breastfeeding women History of cervical abnormalities Hormonal treatments affecting menstruation in the past six months Intervention: The intervention group will receive cervical os dilation at regular intervals throughout the menstrual cycle, timed to coincide with key phases of the cycle (e.g., pre-men- strual and post-menstrual). The dilation will be performed using a standardized dilator to a set dilation size, ensuring consistency across participants. Each participant will undergo dilation five times over a six-month period. The control group will receive standard care without any cervical dilation interventions but will be monitored on the same schedule for comparison. Primary Objectives: Cervical Endometrial Debris Out- flow: The primary aim is to measure the quantity of cervical endometrial debris expelled following each menstrual cycle. This will be quanti- tatively assessed through fluid and tissue samples collected at specific time intervals after menstruation. Incidence and Recurrence of Endo- metriosis: The study will also track the incidence of newly diagnosed endometriosis in both groups over the course of 12 months. In women with pre-existing symptoms, re- currence rates will be documented. Diagnosis of endometriosis will be confirmed through clinical evalua- tion and, if necessary, laparoscopic investigation. Outcome Measures: Primary Outcome: Quantity of endometrial debris out- flow, assessed through cytology and histology at specified intervals. Incidence and recurrence rates of endometriosis, as determined through clinical follow-up and imaging. Secondary Outcomes: Change in menstrual symptoms such as pain, flow, and duration. Quality of life as measured by vali- dated questionnaires (e.g., SF-36). Intervention: The intervention group will undergo a surgical procedure for the insertion of a physical pacemaker in the uterine fundus. The device will be programmed to generate rhythmic contractions of the uterus from the fundus to the cervix, mimicking natural contractions but enhancing outflow of menstrual contents. The goal is to reduce uterine congestion and improve the clearance of endo- metrial debris, potentially alleviating pain and lowering the risk of endo- metriosis recurrence. The control group will not receive any pacemaker but will be closely followed for comparison. Primary Objectives: Pain Intensity (Dysmenorrhea): The primary objective is to assess the intensity of dysmenorrhea using a validated pain score (e.g., Visual Analog Scale, VAS) before and after the intervention in both groups. Occurrence and Recurrence of Endometriosis: The secondary

is to evaluate the impact of pacemaker-induced contractions on the incidence of new or recurrent endometriosis. This will be tracked over a 12-month follow-up period using clinical evaluations, imaging, and potentially laparoscopy. Outcome Measures: Primary Outcome: Change in dysmenorrhea pain scores, assessed monthly over a 12-month period, using VAS or similar pain assessment tools. The occurrence and recurrence of endometriosis, measured by clinical symptoms and confirmed through imaging or surgical exploration. Secondary Outcomes: Menstrual flow characteristics (vol- ume and duration) ü Quality of life, measured by vali- dated questionnaires (e.g., SF-36) Adverse events related to pacemaker insertion or function Copyright@ : Carlo Bulletti | Biomed J Sci & Tech Res | BJSTR.MS.ID.009214. Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 50909 Recurrence of endometriosis will be confirmed through laparosco- py if clinically indicated. Outcome Measures: Primary Outcome: Incidence and recurrence rates of endometriosis in both groups. Secondary Outcomes: Quantitative and qualitative analysis of cervical outflow. Structural and functional assess- ment of the internal os. Presence and volume of fluid in the Douglas pouch. Significance of the Study: This randomized controlled trial will provide valuable insights into the potential role of uterine contractility in the pathogenesis and recurrence of endometriosis. The findings could pave the way for new therapeutic inter- ventions aimed at improving uterine contractility, potentially offering novel approaches to the management and prevention of this debilitating condition. The combination of clinical obser- vations with advanced imaging techniques (ultrasound) adds rigor and depth to the study, offering a comprehensive evalu- ation of the mechanisms behind endometriosis development.This format should clearly illustrate the proposed study design and its relevance, ensuring that the research objectives are presented in a structured and convincing manner. Significance of the Study: This study will provide insights into the role of family history and previous delivery method (vaginal vs. cesarean) in the development and recurrence of endometriosis. By investigating uterine contractility patterns and correlating them with the occurrence of endometriosis, the study could lead to improved under- standing of the underlying mecha- nisms and risk factors. Additionally, the use of ultrasound measurements of the internal os offers a novel approach to examining potential an- atomical contributions to endometri- osis. This research could ultimately contribute to better prediction, pre- vention, and management strategies for women at risk of endometriosis. This format clearly presents the

and design of the second study, providing a comprehensive and structured overview. Data Collection and Analysis: Baseline Assessments: All partici- pants will undergo a detailed base- line assessment, including a medical history, gynecological examination, and pelvic ultrasound. Follow-up Visits: Participants will attend follow-up visits at regular intervals for monitoring, sample collection, and assessments. Statistical Analysis: Data will be analyzed using appropriate statisti- cal methods (e.g., t-tests, chi-square tests) to compare the intervention and control groups for primary and secondary outcomes. A p-value of <0.05 will be considered statistically significant. Ethical Considerations: Informed consent will be obtained from all participants. The study will adhere to the ethical guidelines set forth by relevant regulatory authorities, ensuring participant safety and privacy. An independent Data Safe- ty Monitoring Board (DSMB) will oversee the trial.

This RCT will provide important insights into the role of periodic cervical os dilation in enhancing endometrial debris outflow and its potential in prevent- ing or reducing the recurrence of endometriosis. If successful, this in- tervention could represent a novel, non-invasive strategy for managing endometrial health and reducing the burden of endometriosis. Data Collection and Analysis: Baseline Assessments: All partic- ipants will undergo a baseline as- sessment including medical history, gynecological examination, and pain evaluation. Follow-up Visits: Monthly follow-up visits will be conducted for pain assessment, menstrual flow evaluation, and pacemaker performance (for the intervention group). Statistical Analysis: Data will be analyzed using ap- propriate statistical methods (e.g., paired t-tests, chi-square tests) to compare the two groups. A p-value of <0.05 will be considered statisti- cally significant. • Ethical Consid- erations: Informed consent will be obtained from all participants. The study will adhere to ethical guide- lines ensuring participant safety and privacy. A Data Safety Monitoring Board (DSMB) will oversee the trial, particularly in monitoring any adverse effects related to the pacemaker.

This RCT aims to determine whether the use of a physical pacemaker to induce fundus-to-cervix uterine contractions can effectively reduce dysmenorrhea and manage endome- triosis. The findings could poten- tially introduce a novel treatment approach for women suffering from severe pain and recurrent endome- triosis. Authors Contribution • Francesco Maria Bulletti and Carlo Bulletti contributed equally to this article in terms of conceptualization and the first draft of the manuscript. Francesco Maria Bulletti wrote the last version of the manuscript • Antonio Palagiano and Maurizio Guido provided to search and first selection of the studies required and remarked the more realistic pathogenetic concept reported • Maria Elisabetta Coccia revised the second and third draft • Ethical Considerations are not applicable.

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Volume 58- Issue 5 DOI: 10.26717/BJSTR.2024.58.009214 50911 Submission Link: https://biomedres.us/submit-manuscript.php Assets of Publishing with us • Global archiving of articles • Immediate, unrestricted online access • Rigorous Peer Review Process • Authors Retain Copyrights • Unique DOI for all articles https://biomedres.us/ This work is licensed under Creative Commons Attribution 4.0 License ISSN: 2574-1241 DOI: 10.26717/BJSTR.2024.58.009214 Carlo Bulletti. Biomed J Sci & Tech Res