The estrobolome and its emerging role in endometriosis pathogenesis: no guts, no story?

Hypothesis/aims of study. Endometriosis is a chronic recurrent disease that leads to a significant decrease in the quality of life. Despite the existing therapeutic methods, the prevalence of the disease is steadily increasing. The pathogenesis of endometriosis has not been studied enough, resulting in failure to achieve high efficiency in its treatment. Due to chronic pelvic pain, infertility, and dissatisfaction with the quality of life, women suffering from endometriosis present with various mental disorders of different degrees of severity. This study aims to summarize the literature discussing the possible role of oxytocin in the pathogenesis of both endometriosis and affective disorders.
 Study design, materials, and methods. Literature data for the period from 1986 to 2019.
 Conclusion. The role of oxytocin in the pathogenesis of endometriosis needs further study. Oxytocin receptor antagonists can be considered promising in the treatment of this medical condition, as well as in prevention and management of affective disorders in patients with endometriosis.

Increased activation of nuclear factor-kappa B (NF-κB) in isolated peritoneal macrophages of patients with endometriosis

In the structure of gynecological diseases, genital endometriosis takes the third place, and its frequency tends to increase. Endometriosis occurs in 510% of women of reproductive age, in 3550% of patients with infertility and in 7080% of women with chronic pelvic pain. The frequency of spontaneous abortion in endometriosis ranges from 10 to 50%. Noteworthy is the fact that the delay in diagnosing and starting treatment is 5 to 10 years. The disadvantages of surgical treatment are the high relapse rate (up to 50% after 5 years from the start of treatment). Hormonal treatments are effective, but they also have serious side effects that limit them in the long run. Naturally, the great practical and social importance of genital endometriosis induced numerous studies on the etiology and pathogenesis, which, however, have not yet been fully elucidated. The widespread prevalence of genital endometriosis necessitates the search and development of new effective methods of diagnosis and treatment. The article presents data on survivin, which is one of the members of the family of apoptosis inhibitors encoded by the BIRC5 gene. Survivin is involved in the pathogenesis of endometriosis and may be one of the early markers of the disease. Apoptosis is an important last step that determines the fate of the cell. Given recent developments in the search for targeted therapy for endometriosis, antagonists of apoptosis inhibitor proteins, including survivin, are considered as a potential target. Influence on the processes of programmed cell death can be a rather promising direction in the treatment of endometriosis. The purpose of this review is to evaluate the significance of surviving expression in the pathogenesis and diagnosis of endometriosis. 43 literature sources (domestic and foreign) were analyzed using various database (PubMed, PubMed central, Google Scholar, UpToDate).

Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases. It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.

Endometriosis is defined as the existence of endometrial tissue outside the uterine cavity, and it includes a chronic, inflammatory reaction associated with female infertility and pelvic pain. Endometriosis occurs in 7 to 10% of women. Although it has been studied for more than 50 years, the pathogenesis and development of endometriosis are still poorly understood. There is no curative therapy for endometriosis, which often recurs after surgical or medical treatment. There is a consensus that the adverse current of menstrual blood plays a crucial role in the development of endometriosis. This places a major limitation on research using rodent models of endometriosis, although these are still widely employed, because rodents do not menstruate and endometriosis does not occur spontaneously in these animals. In fact, menstruation and spontaneous endometriosis only occur in women and some non-human primates, making models that employ non-human primates the best animal models for research into the pathogenesis, pathophysiology, spontaneous onset, and treatment of endometriosis. This review assesses the effectiveness and potential of the non-human primate models of endometriosis. It also describes the current findings and theories on the pathogenesis of endometriosis that have been obtained by research using non-human primates.

Endometriosis is a common gynaecological disease that affects about 10% of women of reproductive age — approximately 200 million people worldwide. It is characterised by the presence of endometrium-like tissue outside the uterine cavity. Endometriosis predominantly causes reproductive dysfunction, pelvic pain, dyspareunia, infertility, reduced quality of life and is accompanied by combined hyperplastic processes — uterine myoma, adenomyosis and others. According to our studies, hyperestrogenism plays a significant role in the pathogenesis of endometriosis, which allows us to consider it a hyperproliferative disease. The role of oxidative stress in the pathogenesis of various forms of endometriosis is among the topical and insufficiently studied problems. Cyclic changes in endometriosis foci, their enlargement and inflammation create a microenvironment with high iron content, reactive oxygen species and free radicals that promote adhesion and growth of ectopic endometrial cells. Based on which we developed an experimental model of endometriosis to further investigate the role of iron metabolism in the development and maintenance of endometriosis. It is suggested that the primary defect of endometriosis is an abnormal eutopic endometrium characterised by resistance to ferroptosis, a process of iron-mediated non-apoptotic programmed cell death. Currently, the pathogenesis of endometriosis and the role of oxidative stress and iron metabolism requires further study, which is of high relevance, practical and theoretical importance.

Th e article presents analysis of relevant literature on risk factors and pathogenesis of endometriosis and adenomyosis. Despite of numerous studies, it has not been possible so far to formulate a unifi ed concept of the pathogenesis and etiology of endometriosis and adenomyosis. We discuss the role of cytokines, including chemokines, prostaglandins and matrix metalloproteinases, as well as disorders of steroid genesis in the pathogenesis of endometriosis. It has been shown that the main therapeutical approach for patients with endometriosis is the diff erentiated use of modern hormonal drugs, which depends on age and reproductive plans. According to the more recent European guidelines, progestogens are the drugs of the fi rst line

Effect of a Statin on an In Vitro Model of Endometriosis

Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells

Endometriosis is a benign gynaecological disease. Thus, it came as a complete surprise when it was reported recently that the majority of deep endometriosis lesions harbour somatic mutations and a sizeable portion of them contain known cancer-associated mutations (CAMs). Four more studies have since been published, all demonstrating the existence of CAMs in different subtypes of endometriosis. While the field is still evolving, the confirmation of CAMs has raised many questions that were previously overlooked. A comprehensive overview of CAMs in endometriosis has been produced. In addition, with the recently emerged understanding of the natural history of endometriotic lesions as well as CAMs in normal and apparently healthy tissues, this review attempts to address the following questions: Why has there been such a wild discrepancy in reported mutation frequencies? Why does ectopic endometrium have a higher mutation rate than that of eutopic endometrium? Would the presence of CAMs in endometriotic lesions increase the risk of cancer to the bearers? Why do endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart? What clinical implications, if any, do the CAMs have for the bearers? Do these CAMs tell us anything about the pathogenesis and/or pathophysiology of endometriosis? The PubMed database was searched, from its inception to September 2019, for all papers in English using the term 'endometriosis and CAM', 'endometriosis and cancer-driver mutation', 'somatic mutations', 'fibrosis', 'fibrosis and epigenetic', 'CAMs and tumorigenesis', 'somatic mutation and normal tissues', 'oestrogen receptor and fibrosis', 'oxidative stress and fibrosis', 'ARID1A mutation', and 'Kirsten rat sarcoma mutation and therapeutics'. All retrieved papers were read and, when relevant, incorporated into the review results. Seven papers that identified CAMs in endometriosis using various sequencing methods were retrieved, and their results were somewhat different. Yet, it is apparent that those using microdissection techniques and more accurate sequencing methods found more CAMs, echoing recent discoveries that apparently healthy tissues also harbour CAMs as a result of the replicative aging process. Hence endometriotic lesions, irrespective of subtype, if left intact, would generate CAMs as part of replicative aging, oxidative stress and perhaps other factors yet to be identified and, in some rare cases, develop cancer. The published data still are unable to paint a clear picture on pathogenesis of endometriosis. However, since endometriotic epithelial cells have a higher turnover than their stromal counterpart due to cyclic bleeding, and since the endometriotic stromal component can be formed by refresh influx of mesenchymal cells through epithelial-mesenchymal transition, endothelial-mesenchymal transition, mesothelial-mesenchymal transition and other processes as well as recruitment of bone-marrow-derived stem cells and outflow due to smooth muscle metaplasia, endometriotic epithelial cells have much higher mutation frequencies than their stromal counterpart. The epithelial and stromal cellular components develop in a dependent and co-evolving manner. Genes involved in CAMs are likely to be active players in lesional fibrogenesis, and hyperestrogenism and oxidative stress are likely drivers of both CAMs and fibrogenesis. Finally, endometriotic lesions harbouring CAMs would conceivably be more refractory to medical treatment, due, in no small part, to their high fibrotic content and reduced vascularity and cellularity. The accumulating data on CAMs in endometriosis have shed new light on the pathogenesis and pathophysiology of endometriosis. They also suggest new challenges in management. The distinct yet co-evolving developmental trajectories of endometriotic stroma and epithelium underscore the importance of the lesional microenvironment and ever-changing cellular identity. Mutational profiling of normal endometrium from women of different ages and reproductive history is needed in order to gain a deeper understanding of the pathogenesis. Moreover, one area that has conspicuously received scant attention is the epigenetic landscape of ectopic, eutopic and normal endometrium.

The etiology and pathogenesis of endometriosis are hotspots in the field of obstetrics and gynecology today.With the rapid development of experimental studies of endometriosis, the establishment of in vitro histological models is increasingly important.The establishment and application of in vitro histological model provides a new research platform for exploring the pathogenesis and treatment of endometriosis. It is an important method to study endometriosis. Recently a variety of models have been successfully constructed, but still have many deficiencies. Up to now, studies on in vitro histological models have been qualitative, and no studies have involved quantitative analysis. Whether peritoneal mesothelial defect is the cause or result of adhesion, that is, peritoneal mesothelial defect itself exists in the patient, or the damage of the mesothelial during operation, or the destruction of the mesothelial by some cytokines secreted by implanted endometrial tissue? These problems have not yet been decided. Therefore, the choice of appropriate histological model to establish a method is conducive to further reveal the etiology of endometriosis, pathogenesis and evaluation of treatment. This paper reviews the research progress about the development of endometriosis with establishment of in vitro histological models, to further explore the best and stable culture conditions of human endometriosis histological model, and to establish a good model basis for further study of endometriosis.

Introduction: Endometriosis is an enigmatic disease defined by the presence of endometrial-like glands and stroma out the uterine cavity. The pathogenesis of endometriosis was under intensive investigation throughout the last decades and many hypotheses were formulated. In this chapter, we provide a comprehensive review of the current knowledge that concerns the possible involvement of endometrial stem/progenitor cells in the pathogenesis of endometriosis. Methods: The PubMed/Medline database was searched using the search terms: “Stem, Progenitor, Stemness, Endometriosis, Pathogenesis”. All original articles and reviews discussing the role of the embryonic or adult stem cells in the pathogenesis of endometriosis were included. Results: Stem cells with aberrant stemness markers expression were identified within the ectopic endometrium. These cells exhibited highly proliferative, migratory, and invasive capabilities when cultured in vitro and in vivo. Much of these aggressive characteristics are attributed to the cancer-associated mutations often encountered in endometriosis. Additionally, many post-transcriptional factors could influence the ectopic endometrial stem cells behavior. Conclusions: The endometrial stem cells appear to have a pivotal role in the pathogenesis of endometriosis. The biological behavior of these cells is supposed to be influenced by genetic, epigenetic, and environmental factors that determine the severity and hormonal responsiveness of endometriosis. KeywordsEndometriosisPathogenesisProgenitor cellsStem cells

Endometriosis is a disease characterized by the development of endometrial tissue outside the uterus, but its cause remains largely unknown. Numerous genes have been studied and proposed to help explain its pathogenesis. However, the large number of these candidate genes has made functional validation through experimental methodologies nearly impossible. Computational methods could provide a useful alternative for prioritizing those most likely to be susceptibility genes. Using artificial intelligence applied to text mining, this study analyzed the genes involved in the pathogenesis, development, and progression of endometriosis. The data extraction by text mining of the endometriosis-related genes in the PubMed database was based on natural language processing, and the data were filtered to remove false positives. Using data from the text mining and gene network information as input for the web-based tool, 15,207 endometriosis-related genes were ranked according to their score in the database. Characterization of the filtered gene set through gene ontology, pathway, and network analysis provided information about the numerous mechanisms hypothesized to be responsible for the establishment of ectopic endometrial tissue, as well as the migration, implantation, survival, and proliferation of ectopic endometrial cells. Finally, the human genome was scanned through various databases using filtered genes as a seed to determine novel genes that might also be involved in the pathogenesis of endometriosis but which have not yet been characterized. These genes could be promising candidates to serve as useful diagnostic biomarkers and therapeutic targets in the management of endometriosis.

Since the first description about oxygen toxicity made by Joseph Priestley, the oxidative stress has been enrolled as a key factor in the pathogenesis of endometriosis. Our aim was to review oxidative stress biomarkers measured in patients with endometriosis. Relevant studies were identified by searches of the MEDLINE database from 1990 to March 2011 using endometriosis, free radical and oxidative stress as mesh terms. We only included manuscripts in English, and review articles were excluded. In addition, free radical chemistry and oxidative stress history were discussed. After inclusion and exclusion criteria, 19 articles were selected to be included in this systematic review. A total of 36 oxidative stress biomarkers (20 different markers) were measured in patients with endometriosis. Some of the markers were measured in more than one manuscript. They were arranged in five subgroups: Enzymatic activity (n = 3), Anions/free radicals (n = 5), Lipoperoxidation markers (n = 7), DNA Damage markers (n = 1), and Protein oxidation (n = 4). Of those 36 markers, 23 were found to be significantly higher in patients with endometriosis comparing with control patients. Oxidative stress plays an important role in the pathogenesis and progression of endometriosis.

Aim: Transfer RNA-derived fragments have been reported to play a vital role in disease progression, but their role in the pathogenesis of endometriosis remains unknown. Materials & methods: Small RNA sequencing was conducted in three paired ovarian endometriomas and eutopic endometria. The data from 22 paired samples were validated by quantitative real-time polymerase chain reaction (qPCR) and bioinformatic analysis was performed to establish the roles of these fragments in endometriosis pathogenesis. Results: We identified 19 upregulated and five downregulated tRNA-derived fragments, of which tiRNA-5 was the most common. Gene Ontology and pathway analyses revealed that these molecules could have roles in the pathogenesis of endometriosis. Conclusion: tRNA-derived fragments are dysregulated and could be involved in the pathogenesis and progression of ovarian endometriosis.