1 1114 123 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 2 1889 32 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 3 3741 37 INSIGHT INTO THE POTENTIAL MECHANISMS OF ENDOCRINE DISRUPTION BY DIETARY PHYTOESTROGENS IN THE CONTEXT OF THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. PHYTOESTROGENS (PES) ARE ESTROGEN-LIKE NONSTEROIDAL COMPOUNDS DERIVED FROM PLANTS (E.G., NUTS, SEEDS, FRUITS, AND VEGETABLES) AND FUNGI THAT ARE STRUCTURALLY SIMILAR TO 17BETA-ESTRADIOL. PES BIND TO ALL TYPES OF ESTROGEN RECEPTORS, INCLUDING ERALPHA AND ERBETA RECEPTORS, NUCLEAR RECEPTORS, AND A MEMBRANE-BOUND ESTROGEN RECEPTOR KNOWN AS THE G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER). AS ENDOCRINE-DISRUPTING CHEMICALS (EDCS) WITH PRO- OR ANTIESTROGENIC PROPERTIES, PES CAN POTENTIALLY DISRUPT THE HORMONAL REGULATION OF HOMEOSTASIS, RESULTING IN DEVELOPMENTAL AND REPRODUCTIVE ABNORMALITIES. HOWEVER, A LACK OF PES IN THE DIET DOES NOT RESULT IN THE DEVELOPMENT OF DEFICIENCY SYMPTOMS. TO PROPERLY ASSESS THE BENEFITS AND RISKS ASSOCIATED WITH THE USE OF A PE-RICH DIET, IT IS NECESSARY TO DISTINGUISH BETWEEN ENDOCRINE DISRUPTION (ENDOCRINE-MEDIATED ADVERSE EFFECTS) AND NONSPECIFIC EFFECTS ON THE ENDOCRINE SYSTEM. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE OF UNKNOWN ETIOPATHOGENESIS, IN WHICH TISSUE SIMILAR TO THE LINING OF THE UTERUS (THE ENDOMETRIUM) GROWS OUTSIDE OF THE UTERUS WITH SUBSEQUENT COMPLICATIONS BEING MANIFESTED AS A RESULT OF LOCAL INFLAMMATORY REACTIONS. ENDOMETRIOSIS AFFECTS 10-15% OF WOMEN OF REPRODUCTIVE AGE AND IS ASSOCIATED WITH CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, AND INFERTILITY. IN THIS REVIEW, THE ENDOCRINE-DISRUPTIVE ACTIONS OF PES ARE REVIEWED IN THE CONTEXT OF ENDOMETRIOSIS TO DETERMINE WHETHER A PE-RICH DIET HAS A POSITIVE OR NEGATIVE EFFECT ON THE RISK AND COURSE OF ENDOMETRIOSIS. 2023 4 2602 35 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 5 3821 32 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 6 6237 30 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 7 4956 34 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 8 2668 34 ESTROGEN RECEPTORS AND ENDOMETRIOSIS. ENDOMETRIOSIS IS A FREQUENT AND CHRONIC INFLAMMATORY DISEASE WITH IMPACTS ON REPRODUCTION, HEALTH AND QUALITY OF LIFE. THIS DISORDER IS HIGHLY ESTROGEN-DEPENDENT AND THE PURPOSE OF HORMONAL TREATMENTS IS TO DECREASE THE ENDOGENOUS OVARIAN PRODUCTION OF ESTROGENS. HIGH ESTROGEN PRODUCTION IS A CONSISTENTLY OBSERVED ENDOCRINE FEATURE OF ENDOMETRIOSIS. MRNA AND PROTEIN LEVELS OF ESTROGEN RECEPTORS (ER) ARE DIFFERENT BETWEEN A NORMAL HEALTHY ENDOMETRIUM AND ECTOPIC/EUTOPIC ENDOMETRIAL LESIONS: ENDOMETRIOTIC STROMAL CELLS EXPRESS EXTRAORDINARILY HIGHER ERBETA AND SIGNIFICANTLY LOWER ERALPHA LEVELS COMPARED WITH ENDOMETRIAL STROMAL CELLS. ABERRANT EPIGENETIC REGULATION SUCH AS DNA METHYLATION IN ENDOMETRIOTIC CELLS IS ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF ENDOMETRIOSIS. ALTHOUGH THERE IS A LARGE BODY OF DATA REGARDING ERS IN ENDOMETRIOSIS, OUR UNDERSTANDING OF THE ROLES OF ERALPHA AND ERBETA IN THE PATHOGENESIS OF ENDOMETRIOSIS REMAINS INCOMPLETE. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE LINKS BETWEEN ENDOMETRIOSIS, ERS AND THE RECENT ADVANCES OF TREATMENT STRATEGIES BASED ON ERS MODULATION. WE WILL ALSO ATTEMPT TO SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF ERS AND HOW THIS COULD PAVE THE WAY TO NEW THERAPEUTIC STRATEGIES. 2020 9 3820 30 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 10 236 38 ADENOMYOSIS: MECHANISMS AND PATHOGENESIS. ADENOMYOSIS IS A COMMON DISORDER OF THE UTERUS, AND IS ASSOCIATED WITH AN ENLARGED UTERUS, HEAVY MENSTRUAL BLEEDING (HMB), PELVIC PAIN, AND INFERTILITY. IT IS CHARACTERIZED BY ENDOMETRIAL EPITHELIAL CELLS AND STROMAL FIBROBLASTS ABNORMALLY FOUND IN THE MYOMETRIUM WHERE THEY ELICIT HYPERPLASIA AND HYPERTROPHY OF SURROUNDING SMOOTH MUSCLE CELLS. WHILE BOTH THE MECHANISTIC PROCESSES AND THE PATHOGENESIS OF ADENOMYOSIS ARE UNCERTAIN, SEVERAL THEORIES HAVE BEEN PUT FORWARD ADDRESSING HOW THIS DISEASE DEVELOPS. THESE INCLUDE INTRINSIC OR INDUCED (1) MICROTRAUMA OF THE ENDOMETRIAL-MYOMETRIAL INTERFACE; (2) ENHANCED INVASION OF ENDOMETRIUM INTO MYOMETRIUM; (3) METAPLASIA OF STEM CELLS IN MYOMETRIUM; (4) INFILTRATION OF ENDOMETRIAL CELLS IN RETROGRADE MENSTRUAL EFFLUENT INTO THE UTERINE WALL FROM THE SEROSAL SIDE; (5) INDUCTION OF ADENOMYOTIC LESIONS BY ABERRANT LOCAL STEROID AND PITUITARY HORMONES; AND (6) ABNORMAL UTERINE DEVELOPMENT IN RESPONSE TO GENETIC AND EPIGENETIC MODIFICATIONS. DYSMENORRHEA, HMB, AND INFERTILITY ARE LIKELY RESULTS OF INFLAMMATION, NEUROGENESIS, ANGIOGENESIS, AND CONTRACTILE ABNORMALITIES IN THE ENDOMETRIAL AND MYOMETRIAL COMPONENTS. ELUCIDATING MECHANISMS UNDERLYING THE PATHOGENESIS OF ADENOMYOSIS RAISE POSSIBILITIES TO DEVELOP TARGETED THERAPIES TO AMELIORATE SYMPTOMS BEYOND THE CURRENT AGENTS THAT ARE LARGELY INEFFECTIVE. HEREIN, WE ADDRESS THESE POSSIBLE ETIOLOGIES AND DATA THAT SUPPORT UNDERLYING MECHANISMS. 2020 11 2669 34 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 12 5242 33 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 13 1891 39 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 14 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 15 1892 26 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 16 4310 34 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 17 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 18 4435 42 MOLECULAR DYSREGULATIONS UNDERLYING THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CRIPPLING DISEASE CHARACTERIZED BY THE PRESENCE OF ENDOMETRIUM-LIKE TISSUE OR SCAR OUTSIDE THE UTERINE CAVITY, COMMONLY CONFINED TO THE PERITONEAL AND SEROSAL SURFACES OF THE PELVIC ORGANS. 10-15% OF WOMEN IN REPRODUCTIVE AGE ARE ESTIMATED TO BE AFFECTED BY ENDOMETRIOSIS. MOST OF THESE PATIENTS PRESENT WITH INFERTILITY AND SUFFER FROM PELVIC PAIN. THE BENIGN DISEASE RARELY PROGRESSES TO MALIGNANCY. REGARDLESS OF ITS HIGH PREVALENCE, THE PATHOGENESIS OF THE DISEASE IS NOT FULLY UNDERSTOOD. TREATMENT OPTIONS FOR ENDOMETRIOSIS ARE LIMITED AND ARE OFTEN BASED ON A SYMPTOMATIC APPROACH. THE UNAVAILABILITY OF PROPER DIAGNOSTIC APPROACHES, FEWER THERAPEUTIC OPTIONS, AND SPARSE UNDERSTANDING OF MOLECULAR ALTERATIONS ARE RESPONSIBLE FOR THE CONTINUED DISEASE BURDEN. EXPLORING THE MOLECULAR ELEMENTS CAUSING THE PATHOGENESIS OF ENDOMETRIOSIS MAY LEAD TO A NUMBER OF BREAKTHROUGHS IN THE TREATMENT OF THE ILLNESS, SUCH AS THE DISCOVERY OF NEW BIOMARKERS FOR DIAGNOSIS AND THERAPEUTIC TARGETS THAT CAN BE A GUIDE TO BETTER PROGNOSIS AND REDUCED RECURRENCE. THE GOAL OF THIS REVIEW IS TO PROVIDE THE READER A CRITICAL UNDERSTANDING OF THE DISEASE BY SUMMARIZING THE GENETIC, IMMUNOLOGICAL, HORMONAL, AND EPIGENETIC DEREGULATIONS THAT SUPPORT THE MOLECULAR BASIS FOR DEVELOPMENT OF ENDOMETRIOTIC CYST, WITH A SPECIAL FOCUS ON THE STUDY MODELS NEEDED TO ANALYZE THESE CHANGES IN THE ENDOMETRIOTIC MICROENVIRONMENT. 2021 19 2575 25 EPIGENETICS OF ESTROGEN AND PROGESTERONE RECEPTORS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY GYNECOLOGICAL DISEASE. INCREASED ESTROGEN ACTIVITY AND PROGESTERONE RESISTANCE ARE THE MAIN HORMONAL SUBSTRATE OF THIS DISEASE AND ARE ASSOCIATED WITH INFLAMMATORY RESPONSE AND DEBILITATING SYMPTOMS, INCLUDING PAIN AND INFERTILITY. ESTROGENS AND PROGESTERONE ACT VIA THEIR SPECIFIC NUCLEAR RECEPTORS. THE REGULATION OF RECEPTOR EXPRESSION BY EPIGENETICS MAYBE A CRITICAL FACTOR FOR ENDOMETRIOSIS. THE PRESENT REVIEW AIMS TO DISCUSS THE EPIGENETIC MECHANISMS RELATED TO THE EXPRESSION OF ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS, INCLUDING TWO CLASSIC EPIGENETIC MECHANISMS: DNA METHYLATION AND HISTONE MODIFICATION, AND, OTHER NON-CLASSIC MECHANISMS: MIRNAS AND LNCRNA. SEVERAL IN VITRO AND IN VIVO STUDIES SUPPORT THE KEY ROLE OF EPIGENETICS IN THE REGULATION OF THE EXPRESSION OF ERS AND PRS, WHICH MAY PROVIDE NEW MOLECULES AND TARGETS FOR THE DIAGNOSIS AND TREATMENT OF ENDOMETRIOSIS. 2020 20 5697 40 SIMILARITIES IN PATHOGENETIC MECHANISMS UNDERLYING THE BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PELVIC INFLAMMATORY DISEASE. BACKGROUND: ENDOMETRIOSIS IS A COMMON INFLAMMATORY DISEASE CHARACTERIZED BY THE PRESENCE OF ENDOMETRIAL CELLS OUTSIDE OF THE UTERINE CAVITY. ENDOMETRIOSIS AFFECTS 10% OF WOMEN OF REPRODUCTIVE AGE AND SIGNIFICANTLY REDUCES THEIR QUALITY OF LIFE AS A RESULT OF CHRONIC PELVIC PAIN AND INFERTILITY. BIOLOGIC MECHANISMS, INCLUDING PERSISTENT INFLAMMATION, IMMUNE DYSFUNCTION, AND EPIGENETIC MODIFICATIONS, HAVE BEEN PROPOSED AS THE PATHOGENESIS OF ENDOMETRIOSIS. IN ADDITION, ENDOMETRIOSIS CAN POTENTIALLY BE ASSOCIATED WITH AN INCREASED RISK OF PELVIC INFLAMMATORY DISEASE (PID). CHANGES IN THE VAGINAL MICROBIOTA ASSOCIATED WITH BACTERIAL VAGINOSIS (BV) RESULT IN PID OR A SEVERE FORM OF ABSCESS FORMATION, TUBO-OVARIAN ABSCESS (TOA). THIS REVIEW AIMS TO SUMMARIZE THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS AND PID AND TO DISCUSS WHETHER ENDOMETRIOSIS MAY PREDISPOSE TO PID AND VICE VERSA. METHODS: PAPERS PUBLISHED BETWEEN 2000 AND 2022 IN THE PUBMED AND GOOGLE SCHOLAR DATABASES WERE INCLUDED. RESULTS: AVAILABLE EVIDENCE SUPPORTS THAT WOMEN WITH ENDOMETRIOSIS ARE AT INCREASED RISK OF COMORBID PID AND VICE VERSA, SUPPORTING THAT ENDOMETRIOSIS AND PID ARE LIKELY TO COEXIST. THERE IS A BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PID THAT SHARES A SIMILAR PATHOPHYSIOLOGY, WHICH INCLUDES THE DISTORTED ANATOMY FAVORABLE TO BACTERIA PROLIFERATION, HEMORRHAGE FROM ENDOMETRIOTIC LESIONS, ALTERATIONS TO THE REPRODUCTIVE TRACT MICROBIOME, AND IMPAIRED IMMUNE RESPONSE MODULATED BY ABERRANT EPIGENETIC PROCESSES. HOWEVER, WHETHER ENDOMETRIOSIS PREDISPOSES TO PID OR VICE VERSA HAS NOT BEEN IDENTIFIED. CONCLUSIONS: THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE PATHOGENESIS OF ENDOMETRIOSIS AND PID AND DISCUSSES THE SIMILARITIES BETWEEN THEM. 2023