1 4957 132 PATHOGENESIS OF ENDOMETRIOSIS: THE GENETIC/EPIGENETIC THEORY. OBJECTIVE: TO STUDY THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. DESIGN: OVERVIEW OF OBSERVATIONS ON ENDOMETRIOSIS. SETTING: NOT APPLICABLE. PATIENT(S): NONE. INTERVENTIONS(S): NONE. MAIN OUTCOME MEASURE(S): THE HYPOTHESIS IS COMPATIBLE WITH ALL OBSERVATIONS. RESULT(S): ENDOMETRIOSIS, ENDOMETRIUM-LIKE TISSUE OUTSIDE THE UTERUS, HAS A VARIABLE MACROSCOPIC APPEARANCE AND A POORLY UNDERSTOOD NATURAL HISTORY. IT IS A HEREDITARY AND HETEROGENEOUS DISEASE WITH MANY BIOCHEMICAL CHANGES IN THE LESIONS, WHICH ARE CLONAL IN ORIGIN. IT IS ASSOCIATED WITH PAIN, INFERTILITY, ADENOMYOSIS, AND CHANGES IN THE JUNCTIONAL ZONE, PLACENTATION, IMMUNOLOGY, PLASMA, PERITONEAL FLUID, AND CHRONIC INFLAMMATION OF THE PERITONEAL CAVITY. THE SAMPSON HYPOTHESIS OF IMPLANTED ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION, ANGIOGENIC SPREAD, LYMPHOGENIC SPREAD, OR THE METAPLASIA THEORY CANNOT EXPLAIN ALL OBSERVATIONS IF METAPLASIA IS DEFINED AS CELLS WITH REVERSIBLE CHANGES AND AN ABNORMAL BEHAVIOR/MORPHOLOGY DUE TO THE ABNORMAL ENVIRONMENT. WE PROPOSE A POLYGENETIC/POLYEPIGENETIC MECHANISM. THE SET OF GENETIC AND EPIGENETIC INCIDENTS TRANSMITTED AT BIRTH COULD EXPLAIN THE HEREDITARY ASPECTS, THE PREDISPOSITION, AND THE ENDOMETRIOSIS-ASSOCIATED CHANGES IN THE ENDOMETRIUM, IMMUNOLOGY, AND PLACENTATION. TO DEVELOP TYPICAL, CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS, A VARIABLE SERIES OF ADDITIONAL TRANSMISSIBLE GENETIC AND EPIGENETIC INCIDENTS ARE REQUIRED TO OCCUR IN A CELL WHICH MAY VARY FROM ENDOMETRIAL TO STEM CELLS. SUBTLE LESIONS ARE VIEWED AS ENDOMETRIUM IN A DIFFERENT ENVIRONMENT UNTIL ADDITIONAL INCIDENTS OCCUR. TYPICAL CYSTIC OVARIAN OR DEEP ENDOMETRIOSIS LESIONS ARE HETEROGENEOUS AND REPRESENT THREE DIFFERENT DISEASES. CONCLUSION(S): THE GENETIC EPIGENETIC THEORY IS COMPATIBLE WITH ALL OBSERVATIONS ON ENDOMETRIOSIS. IMPLICATIONS FOR TREATMENT AND PREVENTION ARE DISCUSSED. 2019 2 1891 38 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 3 5239 39 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 4 236 36 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 5 5242 30 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 6 1892 31 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 7 1893 37 ENDOMETRIOSIS: NEW PERSPECTIVE FOR THE DIAGNOSIS OF CERTAIN CYTOKINES IN WOMEN AND ADOLESCENT GIRLS, AS WELL AS THE PROGRESSION OF DISEASE OUTGROWTH: A SYSTEMATIC REVIEW. ENDOMETRIOSIS IS A COMMON CHRONIC GYNECOLOGICAL DISORDER THAT UNDOUBTEDLY IMPACTS ON QUALITY OF LIFE, AND IS ONE OF THE MORE COMPLEX AND MYSTERIOUS ILLNESSES OF OUR CENTURY, WHICH IS ASSOCIATED WITH THE IMPROPER GROWTH OF ENDOMETRIAL TISSUE OUTSIDE OF THE UTERINE CAVITY. THIS PATHOLOGICALLY IMPLANTED TISSUE CAN BE FOUND MOST FREQUENTLY IN THE MINOR PELVIS, BUT ALSO IN THE PERITONEAL CAVITY, AND CAN AFFECT MANY ORGANS, LEADING TO CHRONIC PELVIC PAIN SYNDROME, INFERTILITY, AND DYSMENORRHEA. ENDOMETRIAL TISSUE IS A PARTICULARLY DYNAMIC TISSUE THAT HAS A DIRECT IMPACT ON THE PROGRESSION OF THE DISEASE, WITH ALTERED IMMUNITY, AS WELL AS CYTOKINE STORMS WITHIN THE METAPLASTIC ENDOMETRIOTIC SITE, AS POSSIBLE KEY FACTORS. CURRENTLY, DIAGNOSIS OF THIS MYSTERIOUS CHRONIC ILLNESS RELIES ON PERFORMING A LAPAROSCOPIC PROCEDURE WITH TISSUE SAMPLING. ONE OF THE MOST TROUBLESOME OUTCOMES OF THIS UNINTENDED PROGRESSION IS THAT WE LACK ANY SPECIFIC, SENSITIVE, NON-INVASIVE DIAGNOSTIC TOOLS. CURRENTLY, THE VAST MAJORITY OF REGIME STEWARDSHIP OPTIONS RELY ON ANTI-CONTRACEPTIVE DRUGS, OR OTHER REMEDIES THAT SUPPRESS THE RELEASE OF ESTROGEN THROUGH THE GONADS-ALTHOUGH IN MOST CLINICAL TRIALS, ENDOMETRIOSIS IS A CHRONIC PROGRESSIVE DISORDER THAT DEPENDS MOSTLY ON THE HIGH CONCENTRATION OF ESTROGEN. MOREOVER, MANY SPECIFIC TRIALS HAVE DEMONSTRATED THAT THE EUTOPIC ENDOMETRIAL CELLS IN INDIVIDUALS WITH ENDOMETRIOSIS REMAIN MUCH MORE RESISTANT TO THE IMMUNOLOGICAL ANNIHILATION PROCESS CAUSED BY CERTAIN ELEMENTS OF THE IMMUNE SYSTEM. NEVERTHELESS, EUTOPIC ENDOMETRIAL CELLS HAVE THE POTENTIAL TO SIMILARLY ESCALATE THE EXPRESSION OF AROMATASE RECEPTORS ON THE SURFACE OF THE PATHOLOGICAL CELLS, WHICH IN THE FINAL CASCADE CAUSE AN INCREASE IN THE CONCENTRATION OF ESTROGEN, AS WELL AS OTHER INFLAMMATORY PROTEINS THAT CONTRIBUTE TO PATHOLOGICAL OUTGROWTH. DATA REVEAL OCCURRENCE AMONG FIRST-DEGREE RELATIVES, SUGGESTING THAT THE SPECIFIC CASCADE COULD BE RELATED TO INHERITED AS WELL AS EPIGENETIC (ACQUIRED) MECHANISMS. IN WOMEN WITH THE DISEASE, CONFIRMED BY LAPAROSCOPIC PROCEDURES, DIAGNOSIS OF ENDOMETRIOSIS CAN BE ESTABLISHED ALSO VIA DETECTION BY GENE POLYMORPHISM IN THE GENES WHICH ARE RESPONSIBLE FOR RESPONSIBLE FOR THE DETOXIFICATION PHASE OF ESTROGEN RECEPTORS AND OTHER IMMUNOMODULATOR COMPONENTS. A RECENT PUBLICATION AIMS TO REVEAL A NEW PROSPECT FOR THE NON-INVASIVE DIAGNOSIS, DETECTION, AND ESTIMATION OF CERTAIN BIOMARKERS FOR MUCH MORE SPECIFIC INVESTIGATION OF THE DISEASE'S PROGRESSION. 2021 8 6272 29 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 9 4310 32 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 10 5892 44 SYSTEMS GENETICS VIEW OF ENDOMETRIOSIS: A COMMON COMPLEX DISORDER. ENDOMETRIOSIS IS A CONDITION IN WHICH CELLS DERIVED FROM THE ENDOMETRIUM GROW OUTSIDE THE UTERUS, E.G. IN THE PERITONEUM (EXTERNAL GENITAL ENDOMETRIOSIS). AS THESE CELLS ARE UNDER THE INFLUENCE OF FEMALE HORMONES, MAJOR SYMPTOMS OF ENDOMETRIOSIS ARE PAIN, ESPECIALLY DURING THE CYCLE, AND INFERTILITY. NUMEROUS HYPOTHESES FOR THE FORMATION OF ENDOMETRIOSIS CAN BE FOUND IN THE LITERATURE, BUT THERE IS GROWING EVIDENCE OF SERIOUS GENETIC CONTRIBUTIONS TO ENDOMETRIOSIS SUSCEPTIBILITY. THE INVOLVEMENT OF GENES, STEROID HORMONE METABOLISM, IMMUNOLOGICAL REACTIONS, RECEPTOR FORMATION, INFLAMMATION, PROLIFERATION, APOPTOSIS, INTERCELLULAR ADHESION, CELL INVASION AND ANGIOGENESIS AS WELL AS GENES REGULATING THE ACTIVITY OF AFOREMENTIONED ENZYMES HAVE BEEN SUGGESTED. SOME MORE RECENTLY SUGGESTED CANDIDATE GENES PICKED UP IN GENOME-WIDE ASSOCIATION STUDIES ARE INVOLVED IN ONCOGENESIS, METAPLASIA OF ENDOMETRIUM CELLS AND PATHWAYS OF EMBRYONIC DEVELOPMENT OF THE FEMALE REPRODUCTIVE SYSTEM. HOWEVER, GENE MUTATIONS PROVEN TO BE CAUSATIVE FOR ENDOMETRIOSIS HAVE NOT BEEN IDENTIFIED SO FAR, EVEN THOUGH THE ABNORMAL EXPRESSION OF CANDIDATE GENES FOR ENDOMETRIOSIS COULD BE PROVOKED BY DIFFERENT EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HETEROCHROMATIZATION OR INTRODUCTION OF REGULATORY MIRNA. WE HYPOTHESIZE THAT ENDOMETRIOSIS IS INDUCED BY A COMBINATION OF ABNORMAL GENETIC AND/OR EPIGENETIC MUTATIONS: THE LATTER PAVE THE WAY FOR PATHOLOGICAL CHANGES WHICH BECOME IRREVERSIBLE, AND ACCORDING TO THE "EPIGENETIC LANDSCAPE" THEORY, THIS PROCEEDS TO THE TYPICAL CLINICAL MANIFESTATIONS. TWO STAGES IN THE ENDOMETRIOSIS PATHWAY ARE SUGGESTED: (1) INDUCTION OF PRIMARY ENDOMETRIAL CELLS TOWARD ENDOMETRIOSIS, AND (2) IMPLANTATION AND PROGRESSION OF THESE CELLS INTO ENDOMETRIOSIS LESIONS. THE MODEL FAVORS ENDOMETRIOSIS AS AN OUTGROWTH OF PRIMARY CELLS DIFFERENT IN THEIR ORIGIN, CANALIZATION OF PATHOLOGICAL PROCESSES, MANIFESTATION DIVERSITY PROVOKED BY UNIQUE GENETIC BACKGROUND AND EPIGENETIC INFLUENCES, WHICH RESULT IN MANY DIFFERENT CLINICAL FORMS OF THE DISEASE. 2015 11 2275 38 EPIGENETIC REGULATION AND T-CELL RESPONSES IN ENDOMETRIOSIS - SOMETHING OTHER THAN AUTOIMMUNITY. ENDOMETRIOSIS IS DEFINED AS THE PRESENCE OF ENDOMETRIAL-LIKE GLANDS AND STROMA LOCATED OUTSIDE THE UTERINE CAVITY. THIS COMMON, ESTROGEN DEPENDENT, INFLAMMATORY CONDITION AFFECTS UP TO 15% OF REPRODUCTIVE-AGED WOMEN AND IS A WELL-RECOGNIZED CAUSE OF CHRONIC PELVIC PAIN AND INFERTILITY. DESPITE THE STILL UNKNOWN ETIOLOGY OF ENDOMETRIOSIS, MUCH EVIDENCE SUGGESTS THE PARTICIPATION OF EPIGENETIC MECHANISMS IN THE DISEASE ETIOPATHOGENESIS. THE MAIN RATIONALE IS BASED ON THE FACT THAT HERITABLE PHENOTYPE CHANGES THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE ARE COMMON TRIGGERS FOR HORMONAL, IMMUNOLOGICAL, AND INFLAMMATORY DISORDERS, WHICH PLAY A KEY ROLE IN THE FORMATION OF ENDOMETRIOTIC FOCI. EPIGENETIC MECHANISMS REGULATING T-CELL RESPONSES, INCLUDING DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS, DESERVE ATTENTION BECAUSE TISSUE-RESIDENT T LYMPHOCYTES WORK IN CONCERT WITH ORGAN STRUCTURAL CELLS TO GENERATE APPROPRIATE IMMUNE RESPONSES AND ARE FUNCTIONALLY SHAPED BY ORGAN-SPECIFIC ENVIRONMENTAL CONDITIONS. THUS, A FAILURE TO PRECISELY REGULATE IMMUNE CELL TRANSCRIPTION MAY RESULT IN COMPROMISED IMMUNOLOGICAL INTEGRITY OF THE ORGAN WITH AN INCREASED RISK OF INFLAMMATORY DISORDERS. THE COEXISTENCE OF ENDOMETRIOSIS AND AUTOIMMUNITY IS A WELL-KNOWN OCCURRENCE. RECENT RESEARCH RESULTS INDICATE REGULATORY T-CELL (TREG) ALTERATIONS IN ENDOMETRIOSIS, AND AN INCREASED NUMBER OF HIGHLY ACTIVE TREGS AND MACROPHAGES HAVE BEEN FOUND IN PERITONEAL FLUID FROM WOMEN WITH ENDOMETRIOSIS. ELIMINATION OF THE REGULATORY FUNCTION OF T CELLS AND AN IMBALANCE BETWEEN T HELPER CELLS OF THE TH1 AND TH2 TYPES HAVE BEEN REPORTED IN THE ENDOMETRIA OF WOMEN WITH ENDOMETRIOSIS-ASSOCIATED INFERTILITY. THIS REVIEW AIMS TO PRESENT THE STATE OF THE ART IN RECOGNITION EPIGENETIC REPROGRAMMING OF T CELLS AS THE KEY FACTOR IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS IN THE CONTEXT OF T-CELL-RELATED AUTOIMMUNITY. THE NEW POTENTIAL THERAPEUTIC APPROACHES BASED ON EPIGENETIC MODULATION AND/OR ADOPTIVE TRANSFER OF T CELLS WILL ALSO BE OUTLINED. 2022 12 1114 32 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 13 4966 41 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 14 4688 47 NEW UNDERSTANDING OF DIAGNOSIS, TREATMENT AND PREVENTION OF ENDOMETRIOSIS. FOR 100 YEARS, PELVIC ENDOMETRIOSIS HAS BEEN CONSIDERED TO ORIGINATE FROM THE IMPLANTATION OF ENDOMETRIAL CELLS FOLLOWING RETROGRADE MENSTRUATION OR METAPLASIA. SINCE SOME OBSERVATIONS, SUCH AS THE CLONAL ASPECT, THE BIOCHEMICAL VARIABILITY OF LESIONS AND ENDOMETRIOSIS IN WOMEN WITHOUT ENDOMETRIUM, THE GENETIC-EPIGENETIC (G-E) THEORY DESCRIBES THAT ENDOMETRIOSIS ONLY BEGINS AFTER A SERIES OF CUMULATIVE G-E CELLULAR CHANGES. THIS EXPLAINS THAT THE ENDOMETRIOTIC MAY ORIGINATE FROM ANY PLURIPOTENT CELL APART FROM THE ENDOMETRIUM, THAT 'ENDOMETRIUM-LIKE CELLS' CAN HARBOUR IMPORTANT G-E DIFFERENCES, AND THAT THE RISK IS HIGHER IN PREDISPOSED WOMEN WITH MORE INHERITED INCIDENTS. A CONSEQUENCE IS A HIGH RISK AFTER PUBERTY WHICH DECREASES PROGRESSIVELY THEREAFTER. CONSIDERING A 10-YEAR DELAY BETWEEN INITIATION AND PERFORMING A LAPAROSCOPY, THIS WAS OBSERVED IN THE UNITED ARAB EMIRATES, BELGIUM, FRANCE AND USA. THE SUBSEQUENT GROWTH VARIES WITH THE G-E CHANGES AND THE ENVIRONMENT BUT IS SELF-LIMITING PROBABLY BECAUSE OF THE IMMUNOLOGIC REACTION AND FIBROSIS. THAT EACH LESION HAS A DIFFERENT SET OF G-E INCIDENTS EXPLAINS THE VARIABILITY OF PAIN AND THE RESPONSE TO HORMONAL TREATMENT. NEW LESIONS MAY DEVELOP, BUT RECURRENCES AFTER SURGICAL EXCISION ARE RARE. THE FIBROSIS AROUND ENDOMETRIOSIS BELONGS TO THE BODY AND DOES NOT NEED TO BE REMOVED. THIS SUGGESTS CONSERVATIVE EXCISION OR MINIMAL BOWEL WITHOUT SAFETY MARGINS AND SUPERFICIAL TREATMENT OF OVARIAN ENDOMETRIOSIS. THIS G-E CONCEPT ALSO SUGGESTS PREVENTION BY DECREASING OXIDATIVE STRESS FROM RETROGRADE MENSTRUATION OR THE PERITONEAL MICROBIOME. THIS SUGGESTS THE PREVENTION OF VAGINAL INFECTIONS AND CHANGES IN THE GASTROINTESTINAL MICROBIOTA THROUGH FOOD INTAKE AND EXERCISE. IN CONCLUSION, A HIGHER RISK OF INITIATING ENDOMETRIOSIS DURING ADOLESCENCE WAS OBSERVED IN UAE, FRANCE, BELGIUM AND USA. THIS NEW UNDERSTANDING AND THE LIMITED GROWTH OPENS PERSPECTIVES FOR EARLIER DIAGNOSIS AND BETTER TREATMENT. 2022 15 3665 30 INFECTION AS A POTENTIAL COFACTOR IN THE GENETIC-EPIGENETIC PATHOPHYSIOLOGY OF ENDOMETRIOSIS: A SYSTEMATIC REVIEW. BACKGROUND: THE GENETIC-EPIGENETIC THEORY POSTULATES THAT ENDOMETRIOSIS IS TRIGGERED BY A CUMULATIVE SET OF GENETIC-EPIGENETIC (GE) INCIDENTS. PELVIC AND UPPER GENITAL TRACT INFECTION MIGHT INDUCE GE INCIDENTS AND THUS PLAY A ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS. THUS, THIS ARTICLE AIMS TO REVIEW THE ASSOCIATION OF ENDOMETRIOSIS WITH UPPER GENITAL TRACT AND PELVIC INFECTIONS. METHODS: PUBMED, SCOPUS AND GOOGLE SCHOLAR WERE SEARCHED FOR 'ENDOMETRIOSIS AND (INFECTION OR PID OR BACTERIA OR VIRUSES OR MICROBIOME OR MICROBIOTA)', FOR 'REPRODUCTIVE MICROBIOME' AND FOR 'REPRODUCTIVE MICROBIOME AND ENDOMETRIOSIS', RESPECTIVELY. ALL 384 ARTICLES, THE FIRST 120 'BEST MATCH' ARTICLES IN PUBMED FOR 'REPRODUCTIVE MICROBIOME' AND THE FIRST 160 HITS IN GOOGLE SCHOLAR FOR 'REPRODUCTIVE MICROBIOME AND ENDOMYTRIOSIS' WERE HAND SEARCHED FOR DATA DESCRIBING AN ASSOCIATION BETWEEN ENDOMETRIOSIS AND BACTERIAL, VIRAL OR OTHER INFECTIONS. ALL 31 ARTICLES FOUND WERE INCLUDED IN THIS MANUSCRIPT. RESULTS: WOMEN WITH ENDOMETRIOSIS HAVE A SIGNIFICANTLY INCREASED RISK OF LOWER GENITAL TRACT INFECTION, CHRONIC ENDOMETRITIS, SEVERE PID AND SURGICAL SITE INFECTIONS AFTER HYSTERECTOMY. THEY HAVE MORE COLONY FORMING UNITS OF GARDNERELLA, STREPTOCOCCUS, ENTEROCOCCI AND ESCHERICHIA COLI IN THE ENDOMETRIUM. IN THE CERVIX ATOPOBIUM IS ABSENT, BUT GARDNERELLA, STREPTOCOCCUS, ESCHERICHIA, SHIGELLA, AND UREOPLASMA ARE INCREASED. THEY HAVE HIGHER CONCENTRATIONS OF ESCHERICHIA COLI AND HIGHER CONCENTRATIONS OF BACTERIAL ENDOTOXINS IN MENSTRUAL BLOOD. A SHIGELLA/ESCHERICHIA DOMINANT STOOL MICROBIOME IS MORE FREQUENT. THE PERITONEAL FLUID OF WOMEN WITH ENDOMETRIOSIS CONTAINS HIGHER CONCENTRATIONS OF BACTERIAL ENDOTOXINS AND AN INCREASED INCIDENCE OF MOLLICUTES AND OF HPV VIRUSES. ENDOMETRIOSIS LESIONS HAVE A SPECIFIC BACTERIAL COLONISATION WITH MORE FREQUENTLY MOLLICUTES (54%) AND BOTH HIGH AND MEDIUM-RISK HPV INFECTIONS (11%). THEY CONTAIN DNA WITH 96% HOMOLOGY WITH SHIGELLA. IN MICE TRANSPLANTED ENDOMETRIUM CHANGES THE GUT MICROBIOME WHILE THE GUT MICROBIOME INFLUENCES THE GROWTH OF THESE ENDOMETRIOSIS LESIONS. CONCLUSIONS: ENDOMETRIOSIS IS ASSOCIATED WITH MORE UPPER GENITAL TRACT AND PERITONEAL INFECTIONS. THESE INFECTIONS MIGHT BE CO-FACTORS CAUSING GE INCIDENTS AND INFLUENCING ENDOMETRIOSIS GROWTH. 2019 16 6237 37 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 17 4435 33 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 18 4956 29 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 19 1889 25 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 20 3820 27 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