Theory Of Retrograde Menstruation Research Articles

Fibrosis signaling in endometrial cells and endometriosis development

In endometriosis, the tissues similar to the endometrial tissue attaches outside the uterine cavity, causing inflammation and fibrosis. The retrograde menstruation theory is the most plausible mechanism, though the detailed pathogenesis remains unclear. Our observations suggest that endometriosis-like lesions occur more often at sites of ovarian excision causing bleeding in mouse models. Additionally, prostaglandin E2 (PGE2) and thrombin, a protease-activated receptor (PAR) agonist in menstrual blood exacerbate inflammation in these lesions. Focusing on the hypoxic conditions of menstrual blood, we investigated the effects of PGE2/thrombin on inflammation and fibrosis using primary cultured endometrial stromal cells (ESCs) and glandular epithelial cells (EECs) under low oxygen conditions. Chemokine CXCL12 secreted by endometrial stromal cells under hypoxia acts on CXCR4 receptors on glandular epithelial cells, inducing epithelial-mesenchymal transition (EMT), suggesting a possible role in endometriosis progression. RNA-seq analysis of PGE2/thrombin effects on endometrial stromal cells revealed activation of the transforming growth factor (TGF)-β pathway, particularly increased production and secretion of activin A, a member of the TGFβ family. Activin A, via increased connective tissue growth factor (CTGF) expression, promotes differentiation of endometrial stromal cells from fibroblast-like to myofibroblast transdifferentiation (FMT) of ESCs. In conclusion, targeting the CXCL12/CXCR4 and activin A/CTGF signaling pathways holds promise for improving fibrosis in endometriosis lesions.

Urinary Tract Endometriosis: A Review of Literature

Objective: Deep endometriosis (DE) is the most severe form of endometriosis. Bowel and urinary tract are the most common sites of intrapelvic DE. Urinary tract endometriosis (UTE) mainly involves the bladder and the ureters. The two mostly accepted theories explaining the pathophysiology of UTE are the “Retrograde Menstruation Theory” and the “Müllerian Remnants Theory”. The purpose of this paper is to provide a review of literature on the UTE, a rare form, affecting only 1–6% of patients with endometriosis. Mechanism: A literature review was conducted using keywords specific to UTE and DE to identify peer-reviewed, original research articles published between 1996 and 2024. Findings in Brief: When the bladder is involved, the patient presents lower urinary tract symptoms. Ureteral endometriosis is usually asymptomatic, thus delaying early diagnosis and efficient treatment leading to cases of chronic ureteral stricture. Clinical history and examination as well as questionnaires play an important role in guiding the clinician. Diagnostic modalities include conventional imaging such as ultrasonography and magnetic resonance imaging (MRI) as well as invasive techniques such as cystoscopy. As for all endometriotic lesions, definitive diagnosis should be confirmed by histopathology. Treatment modalities include medical hormonal treatments or surgical treatment. There are a multitude of surgical techniques that are more or less invasive depending on the location and the extent of the lesion. Conclusions: UTE, is an underdiagnosed form of endometriosis, and specialists should be aware of this important entity, due to the serious health implications for women.

Selection of reference miRNAs for RT-qPCR assays in endometriosis menstrual blood-derived mesenchymal stem cells.

Choosing appropriate reference genes or internal controls to normalize RT-qPCR data is mandatory for the interexperimental reproducibility of gene expression data obtained by RT-qPCR in most studies, including those on endometriosis. Particularly for miRNAs, the choice for reference genes is challenging because of their physicochemical and biological characteristics. Moreover, the retrograde menstruation theory, mesenchymal stem cells in menstrual blood (MenSCs), and changes in post-transcriptional regulatory processes through miRNAs have gained prominence in the scientific community as important players in endometriosis. Therefore, we originally explored the stability of 10 miRNAs expressions as internal control candidates in conditions involving the two-dimensional culture of MenSCs from healthy women and patients with endometriosis. Here, we applied multiple algorithms (geNorm, NormFinder, Bestkeeper, and delta Ct) to screen reference genes and assessed the comprehensive stability classification of miRNAs using RefFinder. Pairwise variation calculated using geNorm identified three miRNAs as a sufficient number of reference genes for accurate normalization. MiR-191-5p, miR-24-3p, and miR-103a-3p were the best combination for suitable gene expression normalization. This study will benefit similar research, but is also attractive for regenerative medicine and clinics that use MenSCs, miRNA expression, and RT-qPCR.

P-324 Finding on the gut microbiome impact on non-reproductive pathologies of the uterus: an endometriosis perspective

Abstract Study question Is there any link between intestinal microbiome and endometriosis? Summary answer The aetiopathogenesis of endometriosis might be linked to intestinal dysbiosis. Microorganisms could be used as potential microbiota-mediated metabolites therapy to target the estrobolome in endometriosis. What is known already Endometriosis (EMs) is a chronic estrogenic-dependent gynaecological condition with a complex and multifactorial aetiology, characterized by the presence of endometrial glands and endometrial-like tissue outside the uterus, accompanied by a severe inflammatory process. Sampson’s theory of retrograde menstruation is considered one of the most convincing hypotheses for the origin of EMs. Recently, the human microbiome has been linked to its pathogenesis, and exits some evidence that it might modulate the immune system from the gut, therefore the generation of a dysfunctional immune response caused by intestinal dysbiosis might play an important role in the initiation and progression of EMs. Study design, size, duration A case-control study was designed to analyse intestinal microbiome from EMs patients and age-matched healthy women. Herein, we aim to investigate for potential intestinal biomarkers related to the pathology. The recruitment was through health questionnaires such as EHP-5 setting the initial cohort at 243 women. This initial cohort was screened according to inclusion and exclusion criteria. Participants/materials, setting, methods Seventy-seven women met eligibility criteria and were enrolled in the study. Stool samples from the controls group (n = 43) and patients with a positive diagnosis of EMs (n = 34) were collected and subjected to 16S rRNA gene sequencing using the V3-V4 regions. Various multivariate analysis approaches were used to assess diversity, composition and abundance of intestinal microbiota. Main results and the role of chance The number of significantly different taxa between healthy controls and EMs patients were 18 (p-value<0.05). Among these 18 taxa, we found 3 families: Bacteroidaceae, Lactobacillaceae and Desulfovibrionaceae; 3 genera: Blautia, Anaerostipes and Lachnospira; and 12 species: Roseburia intestinalis, Bacteroides uniformis, Anaerobutyricum hallii, among others), with a higher diversity of families and genera in the patient group, while the control group had a higher diversity of species, according to the results of Shannon and Simpsońs indexes. This suggests that EMs is dominated by a few species belonging to a wide variety of families and genera, while in the control group there is a greater variability of intestinal species belonging to a smaller number of families and genera. These taxa were related with molecular routes implied in the management of inflammation and estrogens signalling. Additionally, the data were correlated with clinical parameters through the Endometriosis Health Profile-5 questionnaire (EHP-5). This correlation shows significant differences specifically into the «self-image» variable and the total score with the genus diversity (positive and negative correlations were reported), with a strong positive correlations between the variable “Infertility” and the genus Anaerostipes. Limitations, reasons for caution Pronacera develops molecular tests for several conditions that involve the analysis of genes, proteins, and microbes in human samples. Neither the patients nor the healthcare professionals participating in this study have been paid or influenced whatsoever. Hence, the authors report no other potential conflicts of interest. Wider implications of the findings The aetiopathogenesis of EMs might be linked to intestinal dysbiosis. In this sense, the taxa identified in this study and its estrobolome-related metabolite could play a key role in the initiation of the disease, proposing themselves as potential prognostic, diagnostic and therapeutic targets for the future. Trial registration number not applicable

Müllerian anomalies and endometriosis as potential explanatory models for the retrograde menstruation/implantation and the embryonic remnants/celomic metaplasia pathogenic theories: a systematic review and meta-analysis.

Does endometriosis prevalence differ in patients with obstructive Müllerian anomalies (OMA) versus those with nonobstructive Müllerian anomalies (NOMA), and in patients with NOMA versus those without Müllerian anomalies? The quantitative synthesis of published data demonstrates a substantially increased prevalence of endometriosis in patients with OMA compared with those with NOMA, and a similar prevalence in patients with NOMA and those without Müllerian anomalies. The pathogenesis of endometriosis has not been definitively clarified yet. A higher prevalence of endometriosis in patients with OMA than in those with NOMA would support the retrograde menstruation (RM)/implantation theory, whereas a higher prevalence of endometriosis in the NOMA group than in the group without Müllerian anomalies would support the embryonic remnants/celomic metaplasia hypothesis. This systematic review with meta-analysis was restricted to full-length, English-language articles published in peer-reviewed journals between 1980 and 2023. The PubMed and EMBASE databases were searched using the keyword 'endometriosis' in combination with 'Müllerian anomalies', 'obstructive Müllerian anomalies', 'female genital malformations', 'retrograde menstruation', 'infertility', 'pelvic pain', and 'classification'. References from relevant publications were screened, and PubMed's 'similar articles' and 'cited by' functions were used. Studies were selected if they reported the prevalence of surgically confirmed endometriosis in either individuals with OMA compared to those with NOMA, or patients with NOMA compared to those without Müllerian anomalies. Cohort and case-control studies and case series were deemed eligible for inclusion. Noncomparative studies, studies not reporting both the number of individuals with endometriosis and the total number of those with Müllerian anomalies or with other gynecological conditions, those including exclusively data on patients with absent or uncertain menstrual function (e.g. complete Müllerian agenesis category), or with imperforate hymen were excluded. Two reviewers independently abstracted data. The risk of bias was assessed with the Risk of Bias In Non-randomized Studies of Exposures tool. The overall certainty of the evidence was graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. Seven retrospective studies were included. The overall mean estimate of endometriosis prevalence was 47% (95% CI, 36-58%) in patients with OMA, and 19% (95% CI, 15-24%) in patients with NOMA, with a common odds ratio (OR) of 4.72 (95% CI, 2.54-8.77). The overall mean estimate of endometriosis prevalence in patients with NOMA was 23% (95% CI, 20-27%), and that in patients without Müllerian anomalies was 21% (95% CI, 20-22%), with a common OR of 0.95 (95% CI, 0.57-1.58). The overall certainty of the evidence according to GRADE guidelines was judged as low for both comparisons. Some NOMA subtypes may create a partial obstacle to menstrual efflux and/or generate dysfunctional myometrial contractions that favor transtubal reflux, thus increasing the risk of endometriosis and limiting the difference between OMA and NOMA. As infertility and pelvic pain are strongly associated with endometriosis, women with these symptoms are inappropriate controls. Confounding by indication could explain the lack of difference in endometriosis prevalence between patients with NOMA and those without Müllerian anomalies. The results of this meta-analysis support the validity of the RM theory but do not definitively rule out alternative hypotheses. Thus, RM may be considered the initiator for the development of endometriotic lesions, while not excluding the contribution of both inheritable and tissue-specific genetic and epigenetic modifications as disease-promoting factors. No funding was received for this review. P.Ve. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynecological practice. E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. N/A.

The Antigen-Processing Pathway via Major Histocompatibility Complex I as a New Perspective in the Diagnosis and Treatment of Endometriosis.

Endometriosis is a debilitating gynecological disease defined as the presence of endometrium-like epithelium and/or stroma outside the uterine cavity. The most commonly affected sites are the pelvic peritoneum, ovaries, uterosacral ligaments, and the rectovaginal septum. The aberrant tissue responds to hormonal stimulation, undergoing cyclical growth and shedding similar to appropriately located endometrial tissue in the uterus. Common symptoms of endometriosis are painful periods and ovulation, severe pelvic cramping, heavy bleeding, pain during sex, urination and bowel pain, bleeding, and pain between periods. Numerous theories have been proposed to explain the pathogenesis of endometriosis. Sampson's theory of retrograde menstruation is considered to be the most accepted. This theory assumes that endometriosis occurs due to the retrograde flow of endometrial cells through the fallopian tubes during menstruation. However, it has been shown that this process takes place in 90% of women, while endometriosis is diagnosed in only 10% of them. This means that there must be a mechanism that blocks the immune system from removing endometrial cells and interferes with its function, leading to implantation of the ectopic endometrium and the formation of lesions. In this review, we consider the contribution of components of the Major Histocompatibility Complex (MHC)-I-mediated antigen-processing pathway, such as the ERAP, TAP, LMP, LNPEP, and tapasin, to the susceptibility, onset, and severity of endometriosis. These elements can induce significant changes in MHC-I-bound peptidomes that may influence the response of immune cells to ectopic endometrial cells.

How do women get endometriosis?

How do women get endometriosis? This question has baffled investigators for nearly a century, and the pathogenesis of endometriosis still remains to this day an “enigma”. While Sampson's retrograde menstruation theory is widely accepted, the gapping divide between the ubiquity of retrograde menstruation and the moderate prevalence has been difficult to explain. Now, Drs. Mumusoglu and Hsueh have provided some much-needed clues by proposing that endometriosis is likely a result of maladaptation of the evolutionary baggage to dramatically changed societies and cultures. These changes are profound, sweeping and across the board, resulting in myriad mismatches between the evolutionary legacy and the changed societies, which, in turn, generated many potential risk factors for endometriosis that were completely absent in hunter-gatherer societies. These innumerable risk factors could conceivably account for the glaring gap between the ubiquity of retrograde menstruation and the moderate prevalence. This perspective may force us to view endometriosis from a fresh angle, provides a roadmap for future epidemiological studies, and may provide the prospect of developing novel ways for disease prevention and treatment.

Huayu Jiedu Fang Protects Ovarian Function in Mouse with Endometriosis Iron Overload by Inhibiting Ferroptosis.

Endometriosis (EM) is a common chronic inflammatory disease in women. Sampson's retrograde menstruation theory is the most widely accepted theory of EM pathogenesis. The periodic bleeding of ectopic lesions is an important pathological feature of this disease, and the occurrence and progression of EM are closely associated with the iron overload caused by ectopic lesions. However, animal models that simulate menstrual-blood reflux and hemorrhage from EM lesions are lacking. In this study, we performed intraperitoneal injection of endometrial fragments and periodic intraperitoneal blood injection to simulate the real cause and disease state of EM and successfully constructed a mouse model of EM iron overload. Our research found that the number, size, and degree of adhesion of EM lesions in the iron-overload model mouse were significantly higher than those in the model mouse. Moreover, the iron concentration in the abdominal fluid and ovary significantly increased, and the level of malondialdehyde (MDA) in the ovary increased. Conversely, GPX4, GSH, and other anti-ferroptosis-related proteins were downregulated, proving the occurrence of ferroptosis. Huayu Jiedu Fang (HYJDF) is an empirical prescription for EM treatment. This study combined animal experiments, UHPLC-QE-MS analysis, and network pharmacology to analyze whether HYJDF can inhibit ferroptosis to slow down the progression of EM and protect ovarian function. Based on the constructed iron-overload model, HYJDF can reduce the volume of EM lesions and the degree of adhesion, downregulate the total iron concentration in the peritoneal fluid and ovary, upregulate GPX4 expression and GSSG in the ovary, downregulate the level of MDA in the ovary, and promote the development of follicles. We further confirmed that HYJDF can inhibit the progression of EM disease and improve the ovarian function of the model mouse by inhibiting ferroptosis. Finally, through UHPLC-QE-MS and network pharmacology analysis, the natural compounds in HYJDF were identified and verified and the regulatory effect of HYJDF on the EM ferroptosis pathway through the IL-6/hepcidin pathway was preliminarily elucidated.

The importance of vitamin D in the diagnosis and treatment of adenomyosis.

There is still no unified theory of the occurrence of adenomyosis. The theories of retrograde menstruation, metaplasia, activation of Mullerian residues, lymphatic and vascular dissemination, iatrogenic dissemination, immunological changes, genetic predisposition, etc. are discussed. The theory of retrograde menstruation is the most relevant among all these theories. The aim is to study the content of folic acid, vitamins B1, D, E, ferritin in the blood, zinc, copper, calcium in the blood and removed uterine tissues, to assess the hormonal status in women with combined uterine pathology leiomyoma and adenomyosis. 150 women underwent a health examination, residents of the cities of Pavlodar and Nur-Sultan, aged 18 to 49years with benign dishormonal diseases of reproductive organs (the main group). The control group consisted of 40 women without gynaecological pathology. The study of the somatic status, objective general somatic, clinical and laboratory, gynaecological examination was carried out by routine methods. Ultrasound examination was performed for mammary glands, thyroid gland, pelvic organs in a real-time mode according to standard methods.

Laparoscopic Management of Innumerable Diaphragmatic Fenestrations

A 50-year-old woman known to have severe endometriosis was referred with cyclic pelvic pain, right shoulder pain, and recurring bilateral pleural effusions necessitating near-monthly thoracentesis of up to one liter of fluid. Gonadotrophin-releasing hormone agonism produced incomplete success. Diaphragmatic endometriosis is a condition affecting 1.5% of patients with endometriosis [1]. The mechanism postulated combines Sampson's theory of retrograde menstruation with clockwise transport of endometrial cells into the right subdiaphragmatic space via peritoneal fluid [1].

Chronic pelvic pain in a patient with Mayer-Rokitansky-Küster-Hauser syndrome: An unusual presentation

Introduction: MRKH syndrome, is a spectrum of congenital anomalies of unknown aetiology characterised by a variable degree of utero-vaginal agenesis in women with normal secondary sexual characteristics and a 46, XX karyotype. Case report: A 16 year old unmarried presented with absence of menses and chronic pelvic pain. MRKH with endometrioma was diagnosed on MRI. Laparoscopic removal of the Mullerian mass with endometriotic cyst was done. The diagnosis was subsequently confirmed on histology. Conclusion: This case highlights the atypical presentation of MRKH and reinforce the Sampsons theory of retrograde menstruation in the development of endometriosis. Patient with chronic pelvic pain and MRKH syndrome should be evaluated for endometriosis.

Menstruation Dysregulation and Endometriosis Development.

Endometriosis is a common gynecological condition characterized by the growth of endometrial-like tissue outside of the uterus which may cause symptoms such as chronic pelvic pain or subfertility. Several surgical and medical therapies are available to manage symptoms, but a cure has yet to be determined which can be attributed to the incomplete understanding of disease pathogenesis. Sampson's theory of retrograde menstruation is a widely accepted theory describing how shed endometrial tissue can enter the peritoneal cavity, but other factors are likely at play to facilitate the establishment of endometriosis lesions. This review summarizes literature that has explored how dysregulation of menstruation can contribute to the pathogenesis of endometriosis such as dysregulation of inflammatory mediators, aberrant endometrial matrix metalloproteinase expression, hypoxic stress, and reduced apoptosis. Overall, many of these factors have overlapping pathways which can prolong the survival of shed endometrial debris, increase tissue migration, and facilitate implantation of endometrial tissue at ectopic sites. Moreover, some of these changes are also implicated in abnormal uterine bleeding and endometrial diseases. More research is needed to better understand the underlying mechanisms driving dysregulation of menstruation in endometriosis specifically and identifying specific pathways could introduce new treatment targets. Analyzing menstrual fluid from women with endometriosis for inflammatory markers and other biomarkers may also be beneficial for earlier diagnosis and disease staging.

Surgical Correction and Rehabilitation of Patients with Congenital Uterovaginal Anomalies and Concomitant Genital Endometriosis

Study Objective To evaluate the results of surgical treatment and rehabilitation in patients with uterovaginal anomalies and concomitant external genital endometriosis. Design Prospective cohort study. Level II-1. Setting Federal State Budget Institution «Research Center for Obstetrics, Gynecology and Perinatology» Ministry of Healthcare of the Russian Federation. Patients or Participants Since 2013 to 2019 we examined 198 patients with various uterovaginal anomalies. The 1st group included 105 patients with concomitant endometriosis, the 2d consisted of 93 patients without endometriosis. Interventions Surgical treatment of uterovaginal anomalies was made according to the anatomical type of malformation, clinical manifestations and reproductive outcomes. In cases with concomitant endometriosis we made excision and coagulation of endometriotic lesions. Measurements and Main Results The prevalence of primary infertility was significantly higher in 1st group- 55.5%, compared with the 2d group - 25.3% (p = 0.0057). The index of dysmenorrhea was significantly higher in 1-st group - 53.3%, compared with the control group -36, 6% (p = 0.0179). The frequency of external genital endometriosis was 53%. In 20% of patients with aplasia of the uterus and vagina without functional rudimental horns endometriotic lesions were visualized on pelvic peritoneum. Conclusion The laparoscopy revealed no significant differences in the incidence of endometriosis among patients with and without outflow obstruction of menstrual blood. Sampson's theory of retrograde menstruation doesn't explain the development of endometriosis in all patients with uterovaginal anomalies. Comprehensive treatment, including surgical correction of the anatomic type of malformation, with incision and coagulation of endometriotic lesions helped to get pregnancy in 60% of patients.

Focal Adhesion Kinase-Mediated Sequences, Including Cell Adhesion, Inflammatory Response, and Fibrosis, as a Therapeutic Target in Endometriosis.

Endometriosis has several distinguishing features in the ectopic endometrium, including chronic inflammation and fibrosis. According to the retrograde menstruation theory, endometriotic cells are derived from eutopic endometrial cells, and adhesion of endometrial cells to the extracellular matrix can be the initial step in the development of endometriosis. Therefore, we hypothesized that cell adhesion, which mediates a sequence of events in the development of endometriosis triggering inflammatory responses and tissue fibrosis could be a possible therapeutic target for endometriosis. We found co-upregulation of focal adhesion kinase (FAK) and monocyte chemoattractant protein-1 (MCP-1) in the endometriotic tissues compared with that in the normal endometrium. MCP-1 secretion was significantly higher in the endometriotic stromal cells than in the eutopic endometrial stromal cells. Furthermore, co-culture of U937 cells and endometriotic stromal cells upregulated secretion of transforming growth factor-β1 (TGF-β1). A FAK inhibitor significantly inhibited the secretion of MCP-1 in the endometriotic stromal cells and TGF-β1 in the co-culture with macrophages. FAK inhibitor treatment in the murine endometriosis model demonstrated a decrease in the formation of endometriotic lesions as well as the expression of MCP-1 and TGF-β1. Our results suggest that the FAK-mediated sequential development of endometriosis, including inflammatory response and tissue fibrosis, can be a new therapeutic target in endometriosis.

Müllerian duct anomalies coincident with endometriosis: a review.

The association between obstructed müllerian duct anomalies and endometriosis has been well established and the pathogenesis is attributed to the theory of retrograde menstruation. However, this relationship with endometriosis is less clear in women with unobstructed müllerian duct anomalies and in those with rudimentary uterine structures that lack functioning endometrial tissue. This article reviews the embryology, genetics, pathophysiology, and American Society for Reproductive Medicine (ASRM) classification for müllerian duct anomalies together with the genetics and pathophysiology of endometriosis to provide a framework for understanding the complex relationship between these two entities. Available published data examining the coexistence of endometriosis in relationship to müllerian duct anomalies, including studies that stratify this relationship according to specific classes of anomalies, are reviewed and organized. Awareness of the increased prevalence of endometriosis among patients with uterine anomalies, particularly those with outflow obstruction, may facilitate early diagnosis of endometriosis and subsequent intervention, with the potential to reverse disease symptoms and arrest disease progression.

Ureaplasma Urealyticum Infection Contributes to the Development of Pelvic Endometriosis Through Toll-Like Receptor 2.

Endometriosis is a chronic gynecological disorder, characterized by the presence of ectopic endometrial tissue outside the uterine cavity. Among several hypotheses, Sampson's theory of retrograde menstruation is still applicable. Recent studies have reported the importance of inflammation among endometrial tissue, the peritoneum, and immune cells. However, less is known regarding the role of bacterial infection in the pathophysiology of endometriosis. We hypothesized that Ureaplasma urealyticum infection might contribute to the development of endometriosis by inducing the production of inflammatory mediators by peritoneal mesothelial cells (PMCs), possibly through TLR2. Hence, our objective was to reveal whether PMC infection by U. urealyticum is associated with endometriosis. Moreover, we aimed to demonstrate the molecular mechanism involved in this relationship. We developed a new infection-induced mouse model of endometriosis with wild type and Tlr2-deficient mice. Based on the in vivo mouse model, U. urealyticum-infected mice showed significantly increased numbers and sizes of ectopic endometriotic lesions. U. urealyticum upregulated not only the production of IL-6, CXCL1, and CCL2, but also the expression of ICAM-1, VCAM-1, and MMP2 in murine PMCs. Similarly, endometrial stromal cells dose-dependently produced IL-6, CXCL1, and CCL2 in response to U. urealyticum infection. The series of inflammatory responses in PMCs was mediated mainly through TLR2. The phosphorylation of ERK and JNK was observed when U. urealyticum was added to PMCs and knock out of Tlr2 inhibited these MAPKs phosphorylation. Based on our co-culture study, U. urealyticum-infected PMCs exhibited significantly increased attachment to ESCs compared with uninfected PMCs. Collectively, U. urealyticum infection promotes the development of endometriosis by increasing inflammatory mediators, adhesion molecules, and MMP-2 expression in PMCs through TLR2 signaling. Through our results, we present a theory that infection-induced pelvic inflammation contributes to the initiation and progression of endometriosis. Appropriate treatment of reproductive tract infection may decrease the prevalence of endometriosis.

Endometriosis Is a Cause of Infertility. Does Reactive Oxygen Damage to Gametes and Embryos Play a Key Role in the Pathogenesis of Infertility Caused by Endometriosis?

Approximately, 10–15% of women of reproductive age are affected by endometriosis, which often leads to infertility. Endometriosis often has an inherited component, and several causative predisposing factors are hypothesized to underlie the pathogenesis of endometriosis. One working hypothesis is the theory of retrograde menstruation. According to the theory of retrograde menstruation, components of refluxed blood, including apoptotic endometrial tissue, desquamated menstrual cells, lysed erythrocytes, and released iron, induce inflammation in the peritoneal cavity. This in turn activates macrophage release of reactive oxygen species (ROS), leading to oxidative stress via the respiratory burst. Refluxed blood promotes the Fenton reaction, terminating in the production of hydroxyl radical, the most potently destructive ROS. In this article, we review the papers that demonstrate decreased quantity and quality of oocytes and embryos retrieved from IVF/ICSI patients with endometriosis. We discuss literature data demonstrating that ROS are generated in endometriotic tissues that have physical proximity to gametes and embryos, and demonstrating adverse impacts on oocyte, sperm and embryo microtubule apparatus, chromosomes, and DNA. Data that addresses the notions that endometriosis causes oocyte and fetal aneuploidy and that these events are mediated by ROS species are also discussed. Literature data are also discussed that employ use of anti-oxidant molecules to evaluate the importance of ROS-mediated oxidative damage in the pathogenesis of endometriosis. Studies are discussed that have employed anti-oxidants compounds as therapeutics to improve oocyte and embryo quality in infertile subjects, and improve fertility in patients with endometriosis.

Endometriosis: aetiopathogenetic basis

Endometriosis, defined by the presence of endometrial tissue outside the uterine cavity, is a common condition affecting 10% of women in the reproductive age. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. The theory of retrograde menstruation with implantation of endometrial fragments, in conjunction with peritoneal factors to stimulate cell growth is the most widely accepted. There is a growing body of evidence that immunological factors and angiogenesis play a key role in the pathogenesis of endometriosis. In women with endometriosis, there appears to be an alteration in the function of peritoneal macrophages, natural killer cells and lymphocytes, with production of growth factors and inflammatory mediators in the peritoneal fluid. Survival, adhesion, proliferation, invasion and vascularization of endometrial tissue in abdominal cavity may be the consequence of retrograde menstruation and referred to as implantation theory.

Of Mice and Women: A Laparoscopic Mouse Model for Endometriosis

Study ObjectiveTo demonstrate how a novel laparoscopic approach allows the development of a mouse model for endometriosis after seeding menstrual endometrium from donor mice into the abdominal cavity of syngeneic recipient mice. DesignA step-by-step video description of the techniques used to adapt the estrous cycle of mice towards a menstrual cycle and to subsequently induce endometriosis via laparoscopic seeding of menstrual endometrium. SettingUniversity research institute. EthicsAll animal experiments were ethically approved by KU Leuven, Belgium (ethical approval number: P031/2013). Interventions, Measurements, and Main ResultsOophorectomized female C57BL/6JRj mice received a series of estrogen injections. Next, a progesterone pellet was administered, together with a second series of estrogen injections. In addition, decidualization of the endometrium was induced with an intrauterine sesame oil stimulus. Four days later the progesterone pellet was removed and menstruation started [1]. Five hours after the progesterone pellet was removal the uterus was harvested, and the menstrual endometrium was dissected and seeded into the abdominal cavity of syngeneic recipient mice to induce endometriosis [2] using a laparoscopic approach [3]. Uterus and lesions were removed from the recipient mice 1 week after induction, and tissues were immunohistochemically stained for H&E, vimentin, and cytokeratin. ConclusionIn this video we show a novel methodology to induce endometriosis in mice using laparoscopic inoculation of syngeneic menstrual endometrium, mimicking Sampson's theory of retrograde menstruation [4]. Compared with currently available rodent models, our model offers a less invasive and more physiologic way for fundamental and preclinical endometriosis research, with a high endometriosis incidence and lesion take rate.

PreImplantation Factor in endometriosis: A potential role in inducing immune privilege for ectopic endometrium.

Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial epithelial and stromal cells outside the uterine cavity. In addition to Sampson’s theory of retrograde menstruation, endometriosis pathogenesis is facilitated by a privileged inflammatory microenvironment, with T regulatory FoxP3+ expressing T cells (Tregs) being a significant factor. PreImplantation Factor (PIF) is a peptide essential for pregnancy recognition and development. An immune modulatory function of the synthetic PIF analog (sPIF) has been successfully confirmed in multiple animal models. We report that PIF is expressed in the epithelial ectopic cells in close proximity to FoxP3+ stromal cells. We provide evidence that PIF interacts with FoxP3+ cells and modulates cell viability, dependent on cell source and presence of inflammatory mediators. Our finding represent a novel PIF-based mechanism in endometriosis that has potential for novel therapeutics.