1 6796 107 [ENDOMETRIOSIS: A NEW APPROACH TO ETIOLOGY AND PATHOGENESIS (REVIEW)]. ENDOMETRIOSIS IS A DYSHORMONAL IMMUNE-DEPENDENT GENETICALLY DETERMINED DISEASE, WHICH APPEARS AS AN ENDOMETRIOID TISSUE THAT GROWS OUTSIDE THE UTERINE. ENDOMETRIOSIS IS ONE OF THE MOST URGENT PROBLEMS OF MEDICINE. TO DATE, NEW CONCEPTS OF THE ENDOMETRIOSIS ETIOLOGY AND PATHOGENESIS HAVE BEEN DEVELOPED, BUT, DESPITE THEIR ABUNDANCE, THERE IS NO UNIFIED THEORY. GENETIC AND EPIGENETIC FACTORS RESULT IN CHANGES IN AN EXPRESSION OF AROMATASE, STEROIDOGENIC FACTOR 1, AND ESTROGEN RECEPTORS ARE SUGGESTED TO BE THE MAIN CAUSE OF ENDOMETRIOSIS. THESE CHANGES LEAD TO AN ACTIVE SYNTHESIS OF VARIOUS PRO-INFLAMMATORY AGENTS AND A NERVE GROWTH FACTOR, THAT ARE IMPORTANT IN THE DEVELOPMENT OF PAIN SYNDROME. ALSO, CHANGES IN THE PROGESTERONE RECEPTOR FUNCTIONING AND THE LOCAL PROGESTERONE RESISTANCE DEVELOPMENT DECREASE THE ANTIPROLIFERATIVE ACTIVITY, APOPTOSIS, AND THE ANTI-INFLAMMATORY SUBSTANCES LEVEL, AS WELL AS INCREASE THE PROSTAGLANDIN, METALLOPROTEINASE ACTIVITY, AND LEVEL OF HYPOXIA FACTORS. IN ADDITION, THERE ARE SHREDS OF EVIDENCE THAT ENDOMETRIOSIS IS ASSOCIATED WITH THE RISK OF MALIGNANT TUMORS DEVELOPMENT, SO NEW CONCEPTS FOR UNDERSTANDING THESE MECHANISMS ARE ACTIVELY DEVELOPING. SOME OF THESE MECHANISMS ARE DISCUSSED IN THIS REVIEW. 2017 2 498 33 ASSOCIATION BETWEEN DIABETES AND CANCER. CURRENT MECHANISTIC INSIGHTS INTO THE ASSOCIATION AND FUTURE CHALLENGES. COMPELLING PIECES OF EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL RESEARCH HAVE DEMONSTRATED THAT DIABETES MELLITUS (DM) IS A MAJOR RISK FACTOR ASSOCIATED WITH INCREASED CANCER INCIDENCE AND MORTALITY IN MANY HUMAN NEOPLASMS. IN THE PATHOPHYSIOLOGY CONTEXT OF DM, MANY OF THE MAIN CLASSICAL ACTORS ARE RELEVANT ELEMENTS THAT CAN FUEL THE DIFFERENT STEPS OF THE CARCINOGENESIS PROCESS. HYPERGLYCEMIA, HYPERINSULINEMIA, METABOLIC INFLAMMATION, AND DYSLIPIDEMIA ARE AMONG THE CLASSIC CONTRIBUTORS TO THIS ASSOCIATION. FURTHERMORE, NEW EMERGING ACTORS HAVE RECEIVED PARTICULAR ATTENTION IN THE LAST FEW YEARS, AND COMPELLING DATA SUPPORT THAT THE MICROBIOME, THE EPIGENETIC CHANGES, THE RETICULUM ENDOPLASMIC STRESS, AND THE INCREASED GLYCOLYTIC INFLUX ALSO PLAY IMPORTANT ROLES IN PROMOTING THE DEVELOPMENT OF MANY CANCER TYPES. THE ARSENAL OF GLUCOSE-LOWERING THERAPEUTIC AGENTS USED FOR TREATING DIABETES IS WIDE AND DIVERSE, AND A GROWING BODY OF DATA RAISED DURING THE LAST TWO DECADES HAS TRIED TO CLARIFY THE CONTRIBUTION OF THERAPEUTIC AGENTS TO THIS ASSOCIATION. HOWEVER, THIS RESEARCH AREA REMAINS CONTROVERSIAL, BECAUSE SOME ANTI-DIABETIC DRUGS ARE NOW CONSIDERED AS EITHER PROMOTORS OR PROTECTING ELEMENTS. IN THE PRESENT REVIEW, WE INTEND TO HIGHLIGHT THE COMPELLING EPIDEMIOLOGICAL SHREDS OF EVIDENCE THAT SUPPORT THIS ASSOCIATION, AS WELL AS THE MECHANISTIC CONTRIBUTIONS OF MANY OF THESE POTENTIAL PATHOLOGICAL MECHANISMS, SOME CONTROVERSIAL POINTS AS WELL AS FUTURE CHALLENGES. 2023 3 3820 24 INTRODUCTION TO PRECLINICAL EVIDENCE FROM ANIMAL MODELS OF ENDOMETRIOSIS. ENDOMETRIOSIS, THE PRESENCE AND GROWTH OF UTERINE ENDOMETRIAL GLANDULAR EPITHELIAL AND STROMA CELLS OUTSIDE THE UTERINE CAVITY, CAUSES PAIN AND INFERTILITY IN WOMEN AND GIRLS OF REPRODUCTIVE AGE. AS RANDOMIZED, DOUBLE-BLINDED, CONTROLLED STUDIES OF ENDOMETRIOSIS IN WOMEN ARE IMPRACTICAL AND AT TIMES ETHICALLY PROHIBITIVE, ANIMAL MODELS FOR ENDOMETRIOSIS AROSE AS AN IMPORTANT ADJUNCT TO GAIN MECHANISTIC INSIGHTS INTO THE ETIOLOGY AND PATHOPHYSIOLOGICAL MECHANISMS OF THIS PERPLEXING DISORDER. A MORE THOROUGH UNDERSTANDING OF ENDOMETRIOSIS IN WOMEN MAY HELP DEVELOP NOVEL NONINVASIVE DIAGNOSTICS, CLASSIFICATION SYSTEMS, THERAPEUTIC REGIMES, AND EVEN PREVENTATIVE METHODS FOR THE MANAGEMENT OF ENDOMETRIOSIS. THIS CHAPTER IS INTENDED TO INTRODUCE A BRIEF HISTORICAL BACKGROUND, BIOLOGICAL AND EPIDEMIOLOGICAL ASPECTS, THE MAJOR SYMPTOMS, THE EFFECTS OF ENDOCRINE-DISRUPTING CHEMICALS, AND AN EXAMPLE OF AN EPIGENETIC FACTOR OF ENDOMETRIOSIS IN WOMEN. 2020 4 5241 34 PROGESTERONE RESISTANCE IN ENDOMETRIOSIS: CURRENT EVIDENCE AND PUTATIVE MECHANISMS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE THE UTERUS. PROGESTINS ARE CURRENTLY THE MOST COMMONLY USED TREATMENT FOR ENDOMETRIOSIS BECAUSE OF THEIR EXCELLENT THERAPEUTIC EFFECTS AND LIMITED SIDE EFFECTS. HOWEVER, PROGESTINS HAVE BEEN UNSUCCESSFUL IN SOME SYMPTOMATIC PATIENTS. THE INABILITY OF THE ENDOMETRIUM TO RESPOND PROPERLY TO PROGESTERONE IS KNOWN AS PROGESTERONE RESISTANCE. AN INCREASING BODY OF EVIDENCE SUGGESTS THE LOSS OF PROGESTERONE SIGNALING AND THE EXISTENCE OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE MECHANISMS OF PROGESTERONE RESISTANCE HAVE RECEIVED CONSIDERABLE SCHOLARLY ATTENTION IN RECENT YEARS. ABNORMAL PGR SIGNALING, CHRONIC INFLAMMATION, ABERRANT GENE EXPRESSION, EPIGENETIC ALTERATIONS, AND ENVIRONMENTAL TOXINS ARE CONSIDERED POTENTIAL MOLECULAR CAUSES OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE GENERAL OBJECTIVE OF THIS REVIEW WAS TO SUMMARIZE THE EVIDENCE AND MECHANISMS OF PROGESTERONE RESISTANCE. A DEEPER UNDERSTANDING OF HOW THESE MECHANISMS CONTRIBUTE TO PROGESTERONE RESISTANCE MAY HELP DEVELOP A NOVEL THERAPEUTIC REGIMEN FOR WOMEN WITH ENDOMETRIOSIS BY REVERSING PROGESTERONE RESISTANCE. 2023 5 4956 26 PATHOGENESIS OF ENDOMETRIOSIS: FOCUS ON ADENOGENESIS-RELATED FACTORS. ENDOMETRIOSIS CAN BE DEFINED AS THE PRESENCE OF THE ENDOMETRIUM OUTSIDE THE UTERINE CAVITY. IT AFFECTS APPROXIMATELY 10% OF WOMEN OF REPRODUCTIVE AGE AND CAUSES INFERTILITY, CHRONIC PAIN, AND DETERIORATION OF THE QUALITY OF LIFE. SINCE THE IDENTIFICATION OF THE DISEASE, VARIOUS PATHOGENETIC MECHANISMS HAVE BEEN PROPOSED, SUCH AS RETROGRADE MENSTRUATION, COELOMIC METAPLASIA, HORMONAL IMBALANCE, STEM CELL INVOLVEMENT, AND ALTERATIONS IN EPIGENETIC REGULATION. HOWEVER, THE UNDERLYING PATHOGENESIS OF ENDOMETRIOSIS REMAINS INADEQUATELY UNDERSTOOD. ELUCIDATION OF THE PRECISE MECHANISM OF THE DEVELOPMENT AND PROGRESSION OF ENDOMETRIOSIS IS CRUCIAL FOR EFFECTIVE TREATMENT. THIS REVIEW PRESENTS THE MAJOR PATHOGENETIC THEORIES OF ENDOMETRIOSIS BASED ON CURRENT RESEARCH STUDIES WITH A MAJOR FOCUS ON THE POTENTIAL ROLE OF UTERINE FACTORS. 2023 6 6649 24 UPDATE ON ENDOMETRIOSIS PATHOGENESIS. ENDOMETRIOSIS IS A CHRONIC, INFLAMMATORY, CONDITION OF HIGH INCIDENCE AND SERIOUS REPRODUCTIVE AND GENERAL HEALTH CONSEQUENCES. UNDERSTANDING THE PATHOGENESIS OF ENDOMETRIOSIS IS CRUCIAL FOR PROPER DIAGNOSTIC AND ORDERING THE MOST EFFECTIVE TREATMENT. EVEN THOUGH THERE IS A LARGE BODY OF DATA REGARDING THIS PATHOLOGY OUR UNDERSTANDING OF THE PATHOGENESIS OF THIS DISEASE REMAINS INCOMPLETE. THE AIM OF THIS REVIEW IS TO SUMMARIZE CONTEMPORARY DATA REGARDING PATHOGENESIS OF ENDOMETRIOSIS. CURRENT DATA REGARDING ENDOMETRIAL ORIGIN, METAPLASTIC AND MULLERIAN EMBRYONIC RESTS THEORY WILL BE REVIEWED HERE. ALSO GENETIC, EPIGENETIC, ENVIRONMENTAL FACTORS AND IMMUNOLOGICAL DYSFUNCTION ROLE IN ENDOMETRIOSIS WILL BE SUMMARIZED. TO CONCLUDE, A LOT OF EFFORT MUST BE PUT TO INTEGRATE THE ABUNDANT DATA FROM GENETIC, EPIGENETIC AND IMMUNOLOGICAL STUDIES TO PROPOSE ONE COHERENT THEORY FOR THE PATHOGENESIS OF ENDOMETRIOSIS. 2017 7 4310 36 MICRORNAS AND PROGESTERONE RECEPTOR SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY. ENDOMETRIOSIS IS A SIGNIFICANT DISEASE CHARACTERIZED BY INFERTILITY AND PELVIC PAIN IN WHICH ENDOMETRIAL STROMAL AND GLANDULAR TISSUE GROW IN ECTOPIC LOCATIONS. ALTERED RESPONSIVENESS TO PROGESTERONE IS A CONTRIBUTING FACTOR TO ENDOMETRIOSIS PATHOPHYSIOLOGY, BUT THE PRECISE MECHANISMS ARE POORLY UNDERSTOOD. PROGESTERONE RESISTANCE INFLUENCES BOTH THE EUTOPIC AND ECTOPIC (ENDOMETRIOTIC LESION) ENDOMETRIUM. AN INABILITY OF THE EUTOPIC ENDOMETRIUM TO PROPERLY RESPOND TO PROGESTERONE IS BELIEVED TO CONTRIBUTE TO THE INFERTILITY ASSOCIATED WITH THE DISEASE, WHILE AN ALTERED RESPONSIVENESS OF ENDOMETRIOTIC LESION TISSUE MAY CONTRIBUTE TO THE SURVIVAL OF THE ECTOPIC TISSUE AND ASSOCIATED SYMPTOMS. WOMEN WITH ENDOMETRIOSIS EXPRESS ALTERED LEVELS OF SEVERAL ENDOMETRIAL PROGESTERONE TARGET GENES WHICH MAY BE DUE TO THE ABNORMAL EXPRESSION AND/OR FUNCTION OF PROGESTERONE RECEPTORS AND/OR CHAPERONE PROTEINS, AS WELL AS INFLAMMATION, GENETICS, AND EPIGENETICS. MIRNAS ARE A CLASS OF EPIGENETIC MODULATORS PROPOSED TO PLAY A ROLE IN ENDOMETRIOSIS PATHOPHYSIOLOGY, INCLUDING THE MODULATION OF PROGESTERONE SIGNALING. IN THIS PAPER, WE SUMMARIZE THE ROLE OF PROGESTERONE RECEPTORS AND PROGESTERONE SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY, REVIEW MIRNAS, WHICH ARE OVER-EXPRESSED IN ENDOMETRIOSIS TISSUES AND FLUIDS, AND FOLLOW THIS WITH A DISCUSSION ON THE POTENTIAL REGULATION OF KEY PROGESTERONE SIGNALING COMPONENTS BY THESE MIRNAS, CONCLUDING WITH SUGGESTIONS FOR FUTURE RESEARCH ENDEAVORS IN THIS AREA. 2022 8 1889 34 ENDOMETRIOSIS MALIGNANT TRANSFORMATION: EPIGENETICS AS A PROBABLE MECHANISM IN OVARIAN TUMORIGENESIS. ENDOMETRIOSIS, DEFINED AS THE PRESENCE OF ECTOPIC ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY, IS A CHRONIC, HORMONE-DEPENDENT GYNECOLOGIC DISEASE AFFECTING MILLIONS OF WOMEN ACROSS THE WORLD, WITH SYMPTOMS INCLUDING CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, DYSURIA, AND SUBFERTILITY. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION, WITH THE INVOLVEMENT OF VARIOUS MECHANISMS OF DEVELOPMENT. MORE AND MORE EVIDENCE REVEALS AN IMPORTANT CONTRIBUTION OF EPIGENETIC MODIFICATION NOT ONLY IN ENDOMETRIOSIS BUT ALSO IN MECHANISMS OF ENDOMETRIOSIS MALIGNANT TRANSFORMATION, INCLUDING DNA METHYLATION AND DEMETHYLATION, HISTONE MODIFICATIONS, AND MIRNA ABERRANT EXPRESSIONS. IN THIS PRESENT REVIEW, WE MAINLY SUMMARIZE THE RESEARCH PROGRESS ABOUT THE CURRENT KNOWLEDGE REGARDING THE EPIGENETIC MODIFICATIONS OF THE RELATIONS BETWEEN ENDOMETRIOSIS MALIGNANT TRANSFORMATION AND OVARIAN CANCER IN AN EFFORT TO IDENTIFY SOME RISK FACTORS PROBABLY ASSOCIATED WITH ECTOPIC ENDOMETRIUM TRANSFORMATION. 2018 9 2669 40 ESTROGEN- AND PROGESTERONE (P4)-MEDIATED EPIGENETIC MODIFICATIONS OF ENDOMETRIAL STROMAL CELLS (ENSCS) AND/OR MESENCHYMAL STEM/STROMAL CELLS (MSCS) IN THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMMON CHRONIC INFLAMMATORY CONDITION IN WHICH ENDOMETRIAL TISSUE APPEARS OUTSIDE THE UTERINE CAVITY. BECAUSE ECTOPIC ENDOMETRIOSIS CELLS EXPRESS BOTH ESTROGEN AND PROGESTERONE (P4) RECEPTORS, THEY GROW AND UNDERGO CYCLIC PROLIFERATION AND BREAKDOWN SIMILAR TO THE ENDOMETRIUM. THIS DEBILITATING GYNECOLOGICAL DISEASE AFFECTS UP TO 15% OF REPRODUCTIVE AGED WOMEN. DESPITE MANY YEARS OF RESEARCH, THE ETIOPATHOGENESIS OF ENDOMETRIAL LESIONS REMAINS UNCLEAR. RETROGRADE TRANSPORT OF THE VIABLE MENSTRUAL ENDOMETRIAL CELLS WITH RETAINED ABILITY FOR ATTACHMENT WITHIN THE PELVIC CAVITY, PROLIFERATION, DIFFERENTIATION AND SUBSEQUENT INVASION INTO THE SURROUNDING TISSUE CONSTITUTES THE RATIONALE FOR WIDELY ACCEPTED IMPLANTATION THEORY. ACCORDINGLY, THE MOST ABUNDANT CELLS IN THE ENDOMETRIUM ARE ENDOMETRIAL STROMAL CELLS (ENSCS). THESE CELLS CONSTITUTE A PARTICULAR POPULATION WITH CLONOGENIC ACTIVITY THAT RESEMBLES PROPERTIES OF MESENCHYMAL STEM/STROMAL CELLS (MSCS). THUS, A SIGNIFICANT ROLE OF STEM CELL-BASED DYSFUNCTION IN FORMATION OF THE INITIAL ENDOMETRIAL LESIONS IS SUSPECTED. THERE IS INCREASING EVIDENCE THAT THE ROLE OF EPIGENETIC MECHANISMS AND PROCESSES IN ENDOMETRIOSIS HAVE BEEN UNDERESTIMATED. THE IMPORTANCE OF EXCESS ESTROGEN EXPOSURE AND P4 RESISTANCE IN EPIGENETIC HOMEOSTASIS FAILURE IN THE ENDOMETRIAL/ENDOMETRIOTIC TISSUE ARE CRUCIAL. EPIGENETIC ALTERATIONS REGARDING TRANSCRIPTION FACTORS OF ESTROGEN AND P4 SIGNALING PATHWAYS IN MSCS ARE ROBUST IN ENDOMETRIOTIC TISSUE. THUS, PERSPECTIVES FOR THE FUTURE MAY INCLUDE MSCS AND ENSCS AS THE TARGETS OF EPIGENETIC THERAPIES IN THE PREVENTION AND TREATMENT OF ENDOMETRIOSIS. HERE, WE REVIEWED THE CURRENT KNOWN CHANGES IN THE EPIGENETIC BACKGROUND OF ENSCS AND MSCS DUE TO ESTROGEN/P4 IMBALANCES IN THE CONTEXT OF ETIOPATHOGENESIS OF ENDOMETRIOSIS. GRAPHICAL ABSTRACT. 2021 10 4950 28 PATHOGENESIS OF ADENOMYOSIS: AN UPDATE ON MOLECULAR MECHANISMS. ADENOMYOSIS IS A UTERINE DISORDER BECOMING MORE COMMONLY DIAGNOSED IN WOMEN OF REPRODUCTIVE AGE BECAUSE OF DIAGNOSTIC IMAGING ADVANCEMENTS. THE NEW EPIDEMIOLOGICAL SCENARIO AND THE CLINICAL EVIDENCE OF PELVIC PAIN, ABNORMAL UTERINE BLEEDING AND INFERTILITY ARE CHANGING THE CLASSIC PERSPECTIVE OF ADENOMYOSIS AS A PREMENOPAUSAL DISEASE. IN THE LAST DECADE, THE EVALUATION OF MULTIPLE MOLECULAR MEDIATORS HAS IMPROVED OUR KNOWLEDGE OF PATHOGENIC MECHANISMS OF ADENOMYOSIS, SUPPORTING THAT THIS IS AN INDEPENDENT DISEASE FROM ENDOMETRIOSIS. ALTHOUGH THEY SHARE COMMON GENETIC MUTATIONS AND EPIGENETIC CHANGES IN SEX STEROID HORMONE RECEPTORS AND SIMILAR INFLAMMATORY MEDIATORS, AN INCREASING NUMBER OF RECENT STUDIES HAVE SHOWN PATHOGENIC PATHWAYS SPECIFIC FOR ADENOMYOSIS. A PUBMED SEARCH UP TO OCTOBER 2016 SUMMARIZES THE KEY MEDIATORS OF PAIN, ABNORMAL UTERINE BLEEDING AND INFERTILITY IN ADENOMYOSIS, INCLUDING SEX STEROID HORMONE RECEPTORS, INFLAMMATORY MOLECULES, EXTRACELLULAR MATRIX ENZYMES, GROWTH FACTORS AND NEUROANGIOGENIC FACTORS. 2017 11 4966 30 PATHOGENOMICS OF ENDOMETRIOSIS DEVELOPMENT. FOR OVER 100 YEARS, ENDOMETRIOSIS, AS A CHRONIC, ESTROGEN-DEPENDENT, INFLAMMATORY, HERITABLE DISEASE AFFECTING APPROXIMATELY 5(-)10% OF WOMEN IN REPRODUCTIVE AGE HAS BEEN THE FOCUS OF CLINICIANS AND SCIENTISTS. IN SPITE OF NUMEROUS ENVIRONMENTAL, GENETIC, EPIGENETIC, ENDOCRINE, AND IMMUNOLOGICAL STUDIES, OUR KNOWLEDGE OF ENDOMETRIOSIS IS STILL FRAGMENTARY, AND ITS PRECISE PATHOPHYSIOLOGY AND PATHOGENOMICS REMAIN A MYSTERY. THE IMPLEMENTATION OF NEW TECHNOLOGIES HAS PROVIDED TREMENDOUS PROGRESS IN UNDERSTANDING THE MANY INTRINSIC MOLECULAR MECHANISMS IN THE DEVELOPMENT OF ENDOMETRIOSIS, WITH PROGENITOR AND STEM CELLS (SCS) OF THE EUTOPIC ENDOMETRIUM AS THE STARTING PLAYERS AND ENDOMETRIOTIC LESIONS AS THE FINAL PATHOMORPHOLOGICAL TRAIT. NOVEL DATA ON THE MOLECULAR, GENETIC, AND EPIGENETIC MECHANISMS OF THE DISEASE ARE BRIEFLY OUTLINED. WE HYPOTHESIZE THE EXISTENCE OF AN ENDOMETRIOSIS DEVELOPMENT GENETIC PROGRAM (EMDP) THAT GOVERNS THE ORIGIN OF ENDOMETRIUM STEM CELLS PROGRAMMED FOR ENDOMETRIOSIS (1), THEIR TRANSITION (METAPLASIA) INTO MESENCHYMAL SCS (2), AND THEIR INVASION OF THE PERITONEUM AND PROGRESSION TO ENDOMETRIOTIC LESIONS (3). THE PROS AND CONS OF THE RECENT UNIFYING THEORY OF ENDOMETRIOSIS ARE ALSO DISCUSSED. COMPLEX GENOMIC AND EPIGENETIC INTERACTIONS AT DIFFERENT STAGES OF THE ENDOMETRIOSIS PROCESS RESULT IN DIFFERENT FORMS OF THE DISEASE, WITH SPECIFIC FEATURES AND CLINICAL MANIFESTATIONS. THE SIGNIFICANCE OF THE EMDP IN ELABORATING A NEW STRATEGY FOR ENDOMETRIOSIS PREDICTION, PREVENTION, AND TREATMENT IS DISCUSSED. 2018 12 6272 27 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS. 2020 13 6237 26 THE MAIN THEORIES ON THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMPLEX DISEASE, WHICH IS DEFINED BY ABNORMAL GROWTH OF ENDOMETRIAL TISSUE OUTSIDE THE UTERUS. IT AFFECTS ABOUT 10% OF WOMEN OF REPRODUCTIVE AGE ALL OVER THE WORLD. ENDOMETRIOSIS CAUSES SYMPTOMS THAT NOTABLY WORSEN PATIENT'S WELL-BEING-SUCH AS SEVERE PELVIC PAIN, DYSFUNCTION OF THE ORGANS OF PELVIC CAVITY, INFERTILITY AND SECONDARY MENTAL ISSUES. THE DIAGNOSIS OF ENDOMETRIOSIS IS QUITE OFTEN DELAYED BECAUSE OF NONSPECIFIC MANIFESTATIONS. SINCE THE DISEASE WAS DEFINED, SEVERAL DIFFERENT PATHOGENETIC PATHWAYS HAVE BEEN CONSIDERED, INCLUDING RETROGRADE MENSTRUATION, BENIGN METASTASIS, IMMUNE DYSREGULATION, COELOMIC METAPLASIA, HORMONAL DISBALANCE, INVOLVEMENT OF STEM CELLS AND ALTERATIONS IN EPIGENETIC REGULATION, BUT THE TRUE PATHOGENESIS OF ENDOMETRIOSIS REMAINS POORLY UNDERSTOOD. THE KNOWLEDGE OF THE EXACT MECHANISM OF THE ORIGIN AND PROGRESSION OF THIS DISEASE IS SIGNIFICANT FOR THE APPROPRIATE TREATMENT. THEREFORE, THIS REVIEW REPORTS THE MAIN PATHOGENETIC THEORIES OF ENDOMETRIOSIS BASED ON CURRENT STUDIES. 2023 14 2602 38 EPIGENETICS, ENDOMETRIOSIS AND SEX STEROID RECEPTORS: AN UPDATE ON THE EPIGENETIC REGULATORY MECHANISMS OF ESTROGEN AND PROGESTERONE RECEPTORS IN PATIENTS WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS A BENIGN GYNECOLOGICAL DISEASE AFFECTING APPROXIMATELY 10% OF REPRODUCTIVE-AGED WOMEN AND IS DEFINED AS THE PRESENCE OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. ENDOMETRIOSIS CAN CAUSE A VARIETY OF HEALTH PROBLEMS, FROM PELVIC DISCOMFORT TO CATAMENIAL PNEUMOTHORAX, BUT IT'S MAINLY LINKED WITH SEVERE AND CHRONIC PELVIC PAIN, DYSMENORRHEA, AND DEEP DYSPAREUNIA, AS WELL AS REPRODUCTIVE ISSUES. THE PATHOGENESIS OF ENDOMETRIOSIS INVOLVES AN ENDOCRINE DYSFUNCTION, WITH ESTROGEN DEPENDENCY AND PROGESTERONE RESISTANCE, AND INFLAMMATORY MECHANISM ACTIVATION, TOGETHER WITH IMPAIRED CELL PROLIFERATION AND NEUROANGIOGENESIS. THE PRESENT CHAPTER AIMS TO DISCUSS THE MAIN EPIGENETIC MECHANISMS RELATED TO ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS. THERE ARE NUMEROUS EPIGENETIC MECHANISMS PARTICIPATING IN ENDOMETRIOSIS, REGULATING THE EXPRESSION OF THE GENES ENCODING THESE RECEPTORS BOTH INDIRECTLY, THROUGH THE REGULATION OF TRANSCRIPTION FACTORS, AND DIRECTLY, THROUGH DNA METHYLATION, HISTONE MODIFICATIONS, MICRO RNAS AND LONG NONCODING RNAS. THIS REPRESENTS AN OPEN FIELD OF INVESTIGATION, WHICH MAY LEAD TO IMPORTANT CLINICAL IMPLICATIONS SUCH AS THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF ENDOMETRIOSIS AND THE IDENTIFICATION OF SPECIFIC AND EARLY BIOMARKERS FOR THE DISEASE. 2023 15 5242 29 PROGESTERONE RESISTANCE IN ENDOMETRIOSIS: ORIGINS, CONSEQUENCES AND INTERVENTIONS. ENDOMETRIOSIS IS A COMMON CAUSE OF PELVIC PAIN AND AFFECTS UP TO 10% OF WOMEN OF REPRODUCTIVE AGE. ABERRANT PROGESTERONE SIGNALING IN THE ENDOMETRIUM PLAYS A SIGNIFICANT ROLE IN IMPAIRED DECIDUALIZATION AND ESTABLISHMENT OF ECTOPIC ENDOMETRIAL IMPLANTS. EUTOPIC ENDOMETRIAL CELLS FROM WOMEN WITH ENDOMETRIOSIS FAIL TO DOWNREGULATE GENES NEEDED FOR DECIDUALIZATION, SUCH AS THOSE INVOLVED IN CELL CYCLE REGULATION, LEADING TO UNBRIDLED PROLIFERATION. SEVERAL CAUSES OF PROGESTERONE RESISTANCE IN THE ENDOMETRIUM HAVE BEEN POSTULATED, INCLUDING CONGENITAL "PRECONDITIONING", WHEREBY THE IN UTERO ENVIRONMENT RENDERS INFANTS SUSCEPTIBLE TO NEONATAL UTERINE BLEEDING AND ENDOMETRIOSIS. PROGESTERONE ACTION IS CRUCIAL TO DECREASING INFLAMMATION IN THE ENDOMETRIUM, AND DEVIANT PROGESTERONE SIGNALING RESULTS IN A PROINFLAMMATORY PHENOTYPE. CONVERSELY, CHRONIC INFLAMMATION CAN INDUCE A PROGESTERONE-RESISTANT STATE. REPETITIVE RETROGRADE ENDOMETRIAL SHEDDING BEGETS CHRONIC PERITONEAL INFLAMMATION, WHICH FURTHER EXACERBATES PROGESTERONE RESISTANCE. GENETIC CAUSES OF PROGESTERONE RESISTANCE INCLUDE PROGESTERONE RECEPTOR GENE POLYMORPHISMS, ALTERED MICRORNA EXPRESSION, AND EPIGENETIC MODIFICATIONS TO PROGESTERONE RECEPTORS AND THEIR TARGETS. ENVIRONMENTAL TOXINS SUCH AS DIOXIN PLAY A POSSIBLE ROLE IN THE GENESIS OF ENDOMETRIOSIS BY PERMITTING AN INFLAMMATORY MILIEU. A CONSEQUENCE OF IMPAIRED PROGESTERONE ACTION IS THAT HORMONAL THERAPY IS RENDERED INEFFECTIVE FOR A SUBSET OF WOMEN WITH ENDOMETRIOSIS. SYNTHETIC PROGESTINS, SUCH AS DIENOGEST, MAY OVERCOME THIS PHENOMENON BY INCREASING PROGESTERONE RECEPTOR EXPRESSION AND DECREASING PROINFLAMMATORY CYTOKINES. OTHER MODALITIES INCLUDE HIGH DOSE DEPOT FORMULATIONS OF PROGESTINS, MEDICATED INTRAUTERINE DEVICES AND THE LIKELY ADVENT OF ORAL GNRH ANTAGONISTS. UNEARTHING ROOT CAUSES OF PROGESTERONE INACTION IN ENDOMETRIOSIS WILL AID IN THE DEVELOPMENT OF NOVEL THERAPEUTICS GEARED TOWARD PREVENTION AND TREATMENT. 2017 16 3821 27 INTRODUCTION: FROM PATHOGENESIS TO THERAPY, DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. A NUMBER OF THEORIES MAY EXPLAIN ITS PATHOGENESIS AND MANY ARGUMENTS SUPPORT THE HYPOTHESIS THAT GENETIC OR EPIGENETIC CHANGES ARE A PREREQUISITE FOR DEVELOPMENT OF LESIONS INTO DEEP ENDOMETRIOSIS. DEEP ENDOMETRIOSIS IS FREQUENTLY RESPONSIBLE FOR PELVIC PAIN, DYSMENORRHEA, AND/OR DEEP DYSPAREUNIA, BUT CAN ALSO CAUSE OBSTETRICAL COMPLICATIONS. DIAGNOSIS MAY BE IMPROVED BY HIGH-QUALITY IMAGING. THERAPEUTIC APPROACHES ARE A SOURCE OF CONTENTION AS WELL. IN THIS ISSUE'S VIEWS AND REVIEWS, MEDICAL AND SURGICAL STRATEGIES ARE DISCUSSED, AND IT IS EMPHASIZED THAT TREATMENT SHOULD BE DESIGNED ACCORDING TO A PATIENT'S SYMPTOMS AND INDIVIDUAL NEEDS. IT IS ALSO VITAL THAT REFERRAL CENTERS HAVE THE KNOWLEDGE AND EXPERIENCE TO TREAT DEEP ENDOMETRIOSIS MEDICALLY AND/OR SURGICALLY. THE DEBATE MUST CONTINUE BECAUSE EMERGING TRENDS IN THERAPY NEED TO BE FOLLOWED AND INVESTIGATED FOR OPTIMAL MANAGEMENT. 2017 17 6254 30 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY. 2019 18 1114 31 COMMONALITIES AND DISPARITIES BETWEEN ENDOMETRIOSIS AND CHRONIC ENDOMETRITIS: THERAPEUTIC POTENTIAL OF NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ECTOPIC ENDOMETRIUM. CHRONIC ENDOMETRITIS (CE) IS A LOCAL MUCOSAL INFLAMMATORY DISORDER OF THE UTERINE LINING, WHICH IS HISTOPATHOLOGICALLY RECOGNIZED AS THE UNUSUAL INFILTRATION OF CD138(+) PLASMACYTES INTO THE ENDOMETRIAL STROMAL COMPARTMENT. ACCUMULATING BODY OF RESEARCH DOCUMENTED THAT CE IS ASSOCIATED WITH FEMALE INFERTILITY AND SEVERAL OBSTETRIC/NEONATAL COMPLICATIONS. THE MAJOR CAUSE OF CE IS THOUGHT TO BE INTRAUTERINE INFECTION REPRESENTED BY COMMON BACTERIA (ESCHERICHIA COLI, ENTEROCOCCUS FAECALIS, STREPTOCOCCUS, AND STAPHYLOCOCCUS), MYCOPLASMA/UREAPLASMA, AND MYCOBACTERIUM. ADDITIONALLY, LOCAL DYSBIOSIS IN THE FEMALE REPRODUCTIVE TRACT MAY BE INVOLVED IN THE ONSET AND DEVELOPMENT OF CE. ANTIBIOTIC TREATMENTS AGAINST THESE MICROORGANISMS ARE EFFECTIVE IN THE ELIMINATION OF ENDOMETRIAL STROMAL PLASMACYTES IN THE AFFECTED PATIENTS. MEANWHILE, ENDOMETRIOSIS IS A COMMON FEMALE REPRODUCTIVE TRACT DISEASE CHARACTERIZED BY ENDOMETRIOTIC TISSUES (ECTOPIC ENDOMETRIUM) GROWING OUTSIDE THE UTERUS AND POTENTIALLY CAUSES CHRONIC PELVIC SYMPTOMS (DYSMENORRHEA, DYSPAREUNIA, DYSCHEZIA, AND DYSURIA), INFERTILITY, AND OVARIAN CANCERS. ENDOMETRIOSIS INVOLVES ENDOCRINOLOGICAL, GENETIC, AND EPIGENETIC FACTORS IN ITS ETIOLOGY AND PATHOGENESIS. RECENT STUDIES FOCUS ON IMMUNOLOGICAL, INFLAMMATORY, AND INFECTIOUS ASPECTS OF ENDOMETRIOSIS AND DEMONSTRATE SEVERAL COMMON CHARACTERISTICS BETWEEN ENDOMETRIOSIS AND CE. THIS REVIEW AIMED TO BETTER UNDERSTAND THE IMMUNOLOGICAL AND MICROBIAL BACKGROUNDS UNDERLYING ENDOMETRIOSIS AND CE AND LOOK INTO THE THERAPEUTIC POTENTIAL OF THE NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ENDOMETRIOSIS IN LIGHT OF ENDOMETRIAL INFECTIOUS DISEASE. 2023 19 1891 35 ENDOMETRIOSIS. PELVIC ENDOMETRIOSIS IS A COMPLEX SYNDROME CHARACTERIZED BY AN ESTROGEN-DEPENDENT CHRONIC INFLAMMATORY PROCESS THAT AFFECTS PRIMARILY PELVIC TISSUES, INCLUDING THE OVARIES. IT IS CAUSED WHEN SHED ENDOMETRIAL TISSUE TRAVELS RETROGRADE INTO THE LOWER ABDOMINAL CAVITY. ENDOMETRIOSIS IS THE MOST COMMON CAUSE OF CHRONIC PELVIC PAIN IN WOMEN AND IS ASSOCIATED WITH INFERTILITY. THE UNDERLYING PATHOLOGIC MECHANISMS IN THE INTRACAVITARY ENDOMETRIUM AND EXTRAUTERINE ENDOMETRIOTIC TISSUE INVOLVE DEFECTIVELY PROGRAMMED ENDOMETRIAL MESENCHYMAL PROGENITOR/STEM CELLS. ALTHOUGH ENDOMETRIOTIC STROMAL CELLS, WHICH COMPOSE THE BULK OF ENDOMETRIOTIC LESIONS, DO NOT CARRY SOMATIC MUTATIONS, THEY DEMONSTRATE SPECIFIC EPIGENETIC ABNORMALITIES THAT ALTER EXPRESSION OF KEY TRANSCRIPTION FACTORS. FOR EXAMPLE, GATA-BINDING FACTOR-6 OVEREXPRESSION TRANSFORMS AN ENDOMETRIAL STROMAL CELL TO AN ENDOMETRIOTIC PHENOTYPE, AND STEROIDOGENIC FACTOR-1 OVEREXPRESSION CAUSES EXCESSIVE PRODUCTION OF ESTROGEN, WHICH DRIVES INFLAMMATION VIA PATHOLOGICALLY HIGH LEVELS OF ESTROGEN RECEPTOR-BETA. PROGESTERONE RECEPTOR DEFICIENCY CAUSES PROGESTERONE RESISTANCE. POPULATIONS OF ENDOMETRIAL AND ENDOMETRIOTIC EPITHELIAL CELLS ALSO HARBOR MULTIPLE CANCER DRIVER MUTATIONS, SUCH AS KRAS, WHICH MAY BE ASSOCIATED WITH THE ESTABLISHMENT OF PELVIC ENDOMETRIOSIS OR OVARIAN CANCER. IT IS NOT KNOWN HOW INTERACTIONS BETWEEN EPIGENOMICALLY DEFECTIVE STROMAL CELLS AND THE MUTATED GENES IN EPITHELIAL CELLS CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN IS MANAGED BY SUPPRESSION OF OVULATORY MENSES AND ESTROGEN PRODUCTION, CYCLOOXYGENASE INHIBITORS, AND SURGICAL REMOVAL OF PELVIC LESIONS, AND IN VITRO FERTILIZATION IS FREQUENTLY USED TO OVERCOME INFERTILITY. ALTHOUGH NOVEL TARGETED TREATMENTS ARE BECOMING AVAILABLE, AS ENDOMETRIOSIS PATHOPHYSIOLOGY IS BETTER UNDERSTOOD, PREVENTIVE APPROACHES SUCH AS LONG-TERM OVULATION SUPPRESSION MAY PLAY A CRITICAL ROLE IN THE FUTURE. 2019 20 1892 23 ENDOMETRIOSIS: EPIDEMIOLOGY, CLASSIFICATION, PATHOGENESIS, TREATMENT AND GENETICS (REVIEW OF LITERATURE). ENDOMETRIOSIS IS A "MYSTERIOUS" DISEASE AND ITS EXACT CAUSE HAS NOT YET BEEN ESTABLISHED. AMONG THE ETIOLOGICAL FACTORS, CONGENITAL, ENVIRONMENTAL, EPIGENETIC, AUTOIMMUNE AND ALLERGIC FACTORS ARE LISTED. IT IS BELIEVED THAT THE PRIMARY MECHANISM OF THE FORMATION OF ENDOMETRIOSIS FOCI IS RETROGRADE MENSTRUATION, I.E., THE PASSAGE OF MENSTRUAL BLOOD THROUGH THE FALLOPIAN TUBES INTO THE PERITONEAL CAVITY AND IMPLANTATION OF EXFOLIATED ENDOMETRIAL CELLS. HOWEVER, SINCE THIS MECHANISM IS ALSO OBSERVED IN HEALTHY WOMEN, OTHER FACTORS MUST ALSO BE INVOLVED IN THE FORMATION OF ENDOMETRIOSIS FOCI. ENDOMETRIOSIS IS IN MANY WOMEN THE CAUSE OF INFERTILITY, CHRONIC PAIN AND THE DETERIORATION OF THE QUALITY OF LIFE. IT ALSO REPRESENTS A SIGNIFICANT FINANCIAL BURDEN ON HEALTH SYSTEMS. THE ARTICLE PRESENTS A REVIEW OF THE LITERATURE ON ENDOMETRIOSIS-A DISEASE AFFECTING WOMEN THROUGHOUT THE WORLD. 2021