1 236 126 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 2 4413 30 MOLECULAR AND CELLULAR INSIGHTS INTO THE DEVELOPMENT OF UTERINE FIBROIDS. UTERINE LEIOMYOMAS REPRESENT THE MOST COMMON BENIGN GYNECOLOGIC TUMOR. THESE HORMONE-DEPENDENT SMOOTH-MUSCLE FORMATIONS OCCUR WITH AN ESTIMATED PREVALENCE OF ~70% AMONG WOMEN OF REPRODUCTIVE AGE AND CAUSE SYMPTOMS INCLUDING PAIN, ABNORMAL UTERINE BLEEDING, INFERTILITY, AND RECURRENT ABORTION. DESPITE THE PREVALENCE AND PUBLIC HEALTH IMPACT OF UTERINE LEIOMYOMAS, AVAILABLE TREATMENTS REMAIN LIMITED. AMONG THE POTENTIAL CAUSES OF LEIOMYOMAS, EARLY HORMONAL EXPOSURE DURING PERIODS OF DEVELOPMENT MAY RESULT IN DEVELOPMENTAL REPROGRAMMING VIA EPIGENETIC CHANGES THAT PERSIST IN ADULTHOOD, LEADING TO DISEASE ONSET OR PROGRESSION. RECENT DEVELOPMENTS IN UNBIASED HIGH-THROUGHPUT SEQUENCING TECHNOLOGY ENABLE POWERFUL APPROACHES TO DETECT DRIVER MUTATIONS, YIELDING NEW INSIGHTS INTO THE GENOMIC INSTABILITY OF LEIOMYOMAS. CURRENT DATA ALSO SUGGEST THAT EACH LEIOMYOMA ORIGINATES FROM THE CLONAL EXPANSION OF A SINGLE TRANSFORMED SOMATIC STEM CELL OF THE MYOMETRIUM. IN THIS REVIEW, WE PROPOSE AN INTEGRATED CELLULAR AND MOLECULAR VIEW OF THE ORIGINS OF LEIOMYOMAS, AS WELL AS PARADIGM-SHIFTING STUDIES THAT WILL LEAD TO BETTER UNDERSTANDING AND THE FUTURE DEVELOPMENT OF NON-SURGICAL TREATMENTS FOR THESE HIGHLY FREQUENT TUMORS. 2021 3 5127 30 POSTMENOPAUSAL UTERINE LEIOMYOMAS AND CHRONIC LYMPHADENOPATHY: EXPLORING EPIGENETIC CHANGES AND PATHOPHYSIOLOGY. UTERINE LEIOMYOMAS (LM) ARE TUMORS ARISING FROM THE NON-NEOPLASTIC PROLIFERATION OF SMOOTH MUSCLE CELLS WITHIN THE MYOMETRIUM. LIKE BENIGN TUMORS, LM ARE NOT GENERALLY SPREAD THROUGH THE LYMPHATIC SYSTEM, AND THEREFORE SHOULD NOT BE ASSOCIATED WITH LYMPHADENOPATHY. HEREIN, WE PRESENT A CASE OF A 60-YEAR-OLD FEMALE WHO PRESENTED TO THE CLINIC WITH POSTMENOPAUSAL BLEEDING IN THE SETTING OF SONOGRAPHICALLY EVIDENT UTERINE LM AND ABDOMINAL LYMPHADENOPATHY. A LYMPH NODE BIOPSY REVEALED PLASMA CELLS AND AN EOSINOPHILIC MATERIAL PRESUMPTIVELY DIAGNOSED AS AMYLOID. SHE THEN UNDERWENT AN ABDOMINAL HYSTERECTOMY FOR DEFINITIVE TREATMENT OF LM. SURGICAL PATHOLOGY CONFIRMED THE CLINICAL DIAGNOSIS OF UTERINE AND CERVICAL LEIOMYOMA. CURRENT LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC ABNORMALITIES CONTRIBUTE TO THE PATHOGENESIS OF LM IN ADDITION TO HORMONAL SIGNALS SUCH AS ESTROGEN AND PROGESTERONE. IT IS UNUSUAL FOR LM TO OCCUR IN POST-MENOPAUSAL WOMEN DUE TO REDUCED HORMONAL INFLUENCE. THEREFORE, THIS CASE EXPLORED AN ALTERNATIVE MECHANISM OF TUMOR PROLIFERATION. THIS CASE HYPOTHESIZES THAT GENETIC MUTATIONS AND EPIGENETIC CHANGES RESULTING FROM CHRONIC INFLAMMATORY OFFENSES CONTRIBUTED TO LM GROWTH AND LYMPHADENOPATHY. 2021 4 6338 26 THE ROLE OF ENDOCRINE-DISRUPTING CHEMICALS IN UTERINE FIBROID PATHOGENESIS. PURPOSE OF REVIEW: UTERINE LEIOMYOMA (FIBROIDS) IS A GYNECOLOGIC DISORDER IMPACTING THE MAJORITY OF WOMEN IN THE UNITED STATES. WHEN SYMPTOMATIC, THESE NONCANCEROUS TUMORS CAN CAUSE SEVERE MORBIDITY INCLUDING PELVIC PAIN, MENORRHAGIA, AND INFERTILITY. ENDOCRINE-DISRUPTING CHEMICALS (EDCS) MAY REPRESENT A MODIFIABLE RISK FACTOR. THE AIM OF THIS REVIEW IS TO SUMMARIZE RECENT HUMAN AND EXPERIMENTAL EVIDENCE ON EDCS EXPOSURES AND FIBROIDS. RECENT FINDINGS: MULTIPLE EDCS ARE ASSOCIATED WITH FIBROID OUTCOMES AND/OR PROCESSES INCLUDING PHTHALATES, PARABENS, ENVIRONMENTAL PHENOLS, ALTERNATE PLASTICIZERS, DIETHYLSTILBESTROL, ORGANOPHOSPHATE ESTERS, AND TRIBUTYLTIN. EPIDEMIOLOGIC STUDIES SUGGEST EXPOSURE TO CERTAIN EDCS, SUCH AS DI-(2-ETHYLHXYL)-PHTHALATE (DEHP), ARE ASSOCIATED WITH INCREASED FIBROID RISK AND SEVERITY. BOTH HUMAN AND EXPERIMENTAL STUDIES INDICATE THAT EPIGENETIC PROCESSES MAY PLAY AN IMPORTANT ROLE IN LINKING EDCS TO FIBROID PATHOGENESIS. IN-VITRO AND IN-VIVO STUDIES SHOW THAT DEHP, BISPHENOL A, AND DIETHYLSTILBESTROL CAN IMPACT BIOLOGICAL PATHWAYS CRITICAL TO FIBROID PATHOGENESIS. SUMMARY: WHILE RESEARCH ON EDCS AND FIBROIDS IS STILL EVOLVING, RECENT EVIDENCE SUGGESTS EDC EXPOSURES MAY CONTRIBUTE TO FIBROID RISK AND PROGRESSION. FURTHER RESEARCH IS NEEDED TO EXAMINE THE IMPACTS OF EDC MIXTURES AND TO IDENTIFY CRITICAL BIOLOGICAL PATHWAYS AND WINDOWS OF EXPOSURE. THESE RESULTS COULD OPEN THE DOOR TO NEW PREVENTION STRATEGIES FOR FIBROIDS. 2020 5 1744 39 EARLY LIFE ADVERSE ENVIRONMENTAL EXPOSURES INCREASE THE RISK OF UTERINE FIBROID DEVELOPMENT: ROLE OF EPIGENETIC REGULATION. UTERINE FIBROIDS [UF(S), AKA: LEIOMYOMA] ARE THE MOST IMPORTANT BENIGN NEOPLASTIC THREAT TO WOMEN'S HEALTH. THEY ARE THE MOST COMMON CAUSE OF HYSTERECTOMY IMPOSING UNTOLD PERSONAL CONSEQUENCES AND 100S OF BILLIONS OF HEALTHCARE DOLLARS, WORLDWIDE. CURRENTLY, THERE IS NO LONG TERM EFFECTIVE FDA-APPROVED MEDICAL TREATMENT AVAILABLE, AND SURGERY IS THE MAINSTAY. THE ETIOLOGY OF UFS IS NOT FULLY UNDERSTOOD. IN THIS REGARD, WE AND OTHERS HAVE RECENTLY REPORTED THAT SOMATIC MUTATIONS IN THE GENE ENCODING THE TRANSCRIPTIONAL MEDIATOR SUBUNIT MED12 ARE FOUND TO OCCUR AT A HIGH FREQUENCY ( APPROXIMATELY 85%) IN UFS. UFS LIKELY ORIGINATE WHEN A MED12 MUTATION OCCURS IN A MYOMETRIAL STEM CELL CONVERTING IT INTO A TUMOR-FORMING STEM CELL LEADING TO A CLONAL FIBROID LESION. ALTHOUGH THE MOLECULAR ATTRIBUTES UNDERLYING THE MECHANISTIC FORMATION OF UFS IS LARGELY UNKNOWN, A GROWING BODY OF LITERATURE IMPLICATES UNFAVORABLE EARLY LIFE ENVIRONMENTAL EXPOSURES AS POTENTIALLY IMPORTANT CONTRIBUTORS. EARLY LIFE EXPOSURE TO EDCS DURING SENSITIVE WINDOWS OF DEVELOPMENT CAN REPROGRAM NORMAL PHYSIOLOGICAL RESPONSES AND ALTER DISEASE SUSCEPTIBILITY LATER IN LIFE. NEONATAL EXPOSURE TO THE EDCS SUCH AS DIETHYLSTILBESTROL (DES) AND GENISTEIN DURING REPRODUCTIVE TRACT DEVELOPMENT HAS BEEN SHOWN TO INCREASE THE INCIDENCE, MULTIPLICITY AND OVERALL SIZE OF UFS IN THE EKER RAT MODEL, CONCOMITANTLY REPROGRAMMING ESTROGEN-RESPONSIVE GENE EXPRESSION. IMPORTANTLY, EDC EXPOSURE REPRESSES ENHANCER OF ZESTE 2 (EZH2) AND REDUCES LEVELS OF HISTONE 3 LYSINE 27 TRIMETHYLATION (H3K27ME3) REPRESSIVE MARK THROUGH ESTROGEN RECEPTOR/PHOSPHATIDYLINOSITIDE 3-KINASES/PROTEIN KINASE B NON-GENOMIC SIGNALING IN THE DEVELOPING UTERUS. CONSIDERING THE FACT THAT DISTINCT MEDIATOR COMPLEX SUBUNIT 12 (MED12) MUTATIONS ARE DETECTED IN DIFFERENT FIBROID LESIONS IN THE SAME UTERUS, THE EMERGENCE OF EACH MED12 MUTATION IS LIKELY AN INDEPENDENT EVENT IN AN ALTERED MYOMETRIAL STEM CELL. IT IS THEREFORE POSSIBLE THAT A CHRONIC REDUCTION IN DNA REPAIR CAPACITY EVENTUALLY CAUSES THE EMERGENCE OF MUTATIONS SUCH AS MED12 IN MYOMETRIAL STEM CELLS CONVERTING THEM INTO FIBROID TUMOR-FORMING STEM CELLS, AND THEREBY LEADS TO THE DEVELOPMENT OF UFS. ADVANCING OUR UNDERSTANDING OF THE MECHANISTIC ROLE EPIGENETIC REGULATION OF STEM CELLS PLAYS IN MEDIATING RISK AND TUMORIGENESIS WILL HELP IN POINTING THE WAY TOWARD THE DEVELOPMENT OF NOVEL THERAPEUTIC OPTIONS. 2016 6 4950 31 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 7 828 41 CHARACTERIZATION OF M (6) A MODIFIERS AND RNA MODIFICATIONS IN UTERINE FIBROIDS. UTERINE LEIOMYOMA OR FIBROIDS ARE THE MOST COMMON PREVALENT NONCANCEROUS TUMORS OF THE UTERINE MUSCLE LAYER. COMMON SYMPTOMS ASSOCIATED WITH FIBROIDS INCLUDE PELVIC PAIN, HEAVY MENSTRUAL BLEEDING, ANEMIA, AND PELVIC PRESSURE. THESE TUMORS ARE A LEADING CAUSE OF GYNECOLOGICAL CARE BUT LACK LONG-TERM THERAPY AS THE ORIGIN AND DEVELOPMENT OF FIBROIDS ARE NOT WELL UNDERSTOOD. SEVERAL NEXT-GENERATION SEQUENCING TECHNOLOGIES HAVE BEEN PERFORMED TO IDENTIFY THE UNDERLYING GENETIC AND EPIGENETIC BASIS OF FIBROIDS. HOWEVER, THERE REMAINS A SYSTEMIC GAP IN OUR UNDERSTANDING OF MOLECULAR AND BIOLOGICAL PROCESS THAT DEFINE UTERINE FIBROIDS. RECENT EPITRANSCRIPTOMICS STUDIES HAVE UNRAVELED RNA MODIFICATIONS THAT ARE ASSOCIATED WITH ALL FORMS OF RNA AND ARE THOUGHT TO INFLUENCE BOTH NORMAL PHYSIOLOGICAL FUNCTIONS AND THE PROGRESSION OF DISEASES. WE QUANTIFIED RNA EXPRESSION PROFILES BY ANALYZING PUBLICLY AVAILABLE RNA-SEQ DATA FOR 15 KNOWN EPIGENETIC MEDIATORS TO IDENTIFY THEIR EXPRESSION PROFILE IN UTERINE FIBROIDS COMPARED TO MYOMETRIUM. TO VALIDATE OUR FINDINGS, WE PERFORMED RT-QPCR ON A SEPARATE COHORT OF UTERINE FIBROIDS TARGETING THESE MODIFIERS CONFIRMING OUR RNA-SEQ DATA. WE THEN EXAMINED PROTEIN PROFILES OF KEY M (6) A MODIFIERS IN FIBROIDS AND THEIR MATCHED MYOMETRIUM. IN CONCORDANCE WITH OUR RNA EXPRESSION PROFILES, NO SIGNIFICANT DIFFERENCES WERE OBSERVED IN THESE PROTEINS IN UTERINE FIBROIDS COMPARED TO MYOMETRIUM. TO DETERMINE ABUNDANCE OF RNA MODIFICATIONS, MRNA AND SMALL RNA FROM FIBROIDS AND MATCHED MYOMETRIUM WERE ANALYZED BY UHPLC MS/MS. IN ADDITION TO THE PREVALENT N6-METHYLADENOSINE (M (6) A), WE IDENTIFIED 11 OTHER KNOWN MODIFIERS BUT DID NOT IDENTIFY ANY ABERRANT EXPRESSION IN FIBROIDS. WE THEN MINED A PREVIOUSLY PUBLISHED DATASET AND IDENTIFIED DIFFERENTIAL EXPRESSION OF M (6) A MODIFIERS THAT WERE SPECIFIC TO FIBROID GENETIC SUB-TYPE. OUR ANALYSIS ALSO IDENTIFIED M (6) A CONSENSUS MOTIFS ON GENES PREVIOUSLY IDENTIFIED TO BE DYSREGULATED IN UTERINE FIBROIDS. OVERALL, USING STATE-OF-THE-ART MASS SPECTROMETRY, RNA EXPRESSION AND PROTEIN PROFILES, WE CHARACTERIZED AND IDENTIFIED DIFFERENTIALLY EXPRESSED M (6) A MODIFIERS IN RELATION TO DRIVER MUTATIONS. DESPITE THE USE OF SEVERAL DIFFERENT APPROACHES, WE IDENTIFIED LIMITED DIFFERENTIAL EXPRESSION OF RNA MODIFIERS AND ASSOCIATED MODIFICATIONS IN UTERINE FIBROIDS. HOWEVER, CONSIDERING THE HIGHLY HETEROGENOUS GENOMIC AND CELLULAR NATURE OF FIBROIDS, AND THE POSSIBLE CONTRIBUTION OF SINGLE MOLECULE M (6) A MODIFICATIONS TO FIBROID PATHOLOGY, THERE IS A NEED FOR GREATER IN-DEPTH CHARACTERIZATION OF M (6) A MARKS AND MODIFIERS IN A LARGER AND VARIED PATIENT COHORT. 2023 8 6682 39 UTERINE LEIOMYOMA: AVAILABLE MEDICAL TREATMENTS AND NEW POSSIBLE THERAPEUTIC OPTIONS. CONTEXT: UTERINE LEIOMYOMAS (FIBROIDS OR MYOMAS) ARE BENIGN TUMORS OF THE UTERUS AND ARE CLINICALLY APPARENT IN UP TO 25% OF REPRODUCTIVE-AGE WOMEN. HEAVY OR ABNORMAL UTERINE BLEEDING, PELVIC PAIN OR PRESSURE, INFERTILITY, AND RECURRENT PREGNANCY LOSS ARE GENERALLY ASSOCIATED WITH LEIOMYOMA. ALTHOUGH SURGICAL AND RADIOLOGICAL THERAPIES ARE FREQUENTLY USED FOR THE MANAGEMENT OF THIS TUMOR, MEDICAL THERAPIES ARE CONSIDERED THE FIRST-LINE TREATMENT OF LEIOMYOMA. EVIDENCE ACQUISITION AND SYNTHESIS: A REVIEW WAS CONDUCTED OF ELECTRONIC AND PRINT DATA COMPRISING BOTH ORIGINAL AND REVIEW ARTICLES ON PATHOPHYSIOLOGY AND MEDICAL TREATMENTS OF UTERINE LEIOMYOMA RETRIEVED FROM THE PUBMED OR GOOGLE SCHOLAR DATABASE UP TO JUNE 2012. THESE RESOURCES WERE INTEGRATED WITH THE AUTHORS' KNOWLEDGE OF THE FIELD. CONCLUSION: TO DATE, SEVERAL PATHOGENETIC FACTORS SUCH AS GENETIC FACTORS, EPIGENETIC FACTORS, ESTROGENS, PROGESTERONE, GROWTH FACTORS, CYTOKINES, CHEMOKINES, AND EXTRACELLULAR MATRIX COMPONENTS HAVE BEEN IMPLICATED IN LEIOMYOMA DEVELOPMENT AND GROWTH. ON THE BASIS OF CURRENT HYPOTHESES, SEVERAL MEDICAL THERAPIES HAVE BEEN INVESTIGATED. GNRH AGONIST HAS BEEN APPROVED BY US FOOD AND DRUG ADMINISTRATION FOR REDUCING FIBROID VOLUME AND RELATED SYMPTOMS. IN ADDITION, THE FDA ALSO APPROVED AN INTRAUTERINE DEVICE, LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM (MIRENA), FOR ADDITIONAL USE TO TREAT HEAVY MENSTRUAL BLEEDING IN INTRAUTERINE DEVICE USERS ONLY. CURRENTLY, MIFEPRISTONE, ASOPRISNIL, ULIPRISTAL ACETATE, AND EPIGALLOCATECHIN GALLATE HAVE BEEN SHOWN TO BE EFFECTIVE FOR FIBROID REGRESSION AND SYMPTOMATIC IMPROVEMENT WHICH ARE ALL IN CLINICAL TRIAL. IN ADDITION, SOME SYNTHETIC AND NATURAL COMPOUNDS AS WELL AS GROWTH FACTOR INHIBITORS ARE NOW UNDER LABORATORY INVESTIGATION, AND THEY COULD SERVE AS FUTURE THERAPEUTIC OPTIONS. 2013 9 2692 26 EVOLUTION OF THE CONCEPTS OF ENDOMETROSIS, POST BREEDING ENDOMETRITIS, AND SUSCEPTIBILITY OF MARES. IN THIS PAPER, THE EVOLUTION OF OUR UNDERSTANDING ABOUT POST BREEDING ENDOMETRITIS (PBE), THE SUSCEPTIBILITY OF MARES, AND EVENTS LEADING TO ENDOMETROSIS ARE REVIEWED. WHEN SPERM ARRIVE IN THE UTERUS, PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES ARE RELEASED. THEY ATTRACT NEUTROPHILS AND INDUCE MODULATORY CYTOKINES WHICH CONTROL INFLAMMATION. IN SUSCEPTIBLE MARES, THIS PHYSIOLOGICAL DEFENSE CAN BE PROLONGED SINCE THE PATTERN OF CYTOKINE RELEASE DIFFERS FROM THAT OF RESISTANT MARES BEING DELAYED AND WEAKER FOR ANTI-INFLAMMATORY CYTOKINES. DELAYED UTERINE CLEARANCE DUE TO CONFORMATIONAL DEFECTS, DEFICIENT MYOMETRIAL CONTRACTIONS, AND FAILURE OF THE CERVIX TO RELAX IS DETECTED BY INTRAUTERINE FLUID ACCUMULATION AND IS AN IMPORTANT REASON FOR SUSCEPTIBILITY TO ENDOMETRITIS. MULTIPAROUS AGED MARES ARE MORE LIKELY TO BE SUSCEPTIBLE. UNTREATED PROLONGED PBE CAN LEAD TO BACTERIAL OR FUNGAL ENDOMETRITIS CALLED PERSISTENT OR CHRONIC ENDOMETRITIS. EXUBERANT OR PROLONGED NEUTROPHILIA AND CYTOKINE RELEASE CAN HAVE DELETERIOUS AND PERMANENT EFFECTS IN INDUCING ENDOMETROSIS. INTERACTIONS OF NEUTROPHILS, CYTOKINES, AND PROSTAGLANDINS IN THE FORMATION OF COLLAGEN AND EXTRACELLULAR MATRIX IN THE PATHOGENESIS OF FIBROSIS ARE DISCUSSED. ENDOMETRITIS AND ENDOMETROSIS ARE INTERCONNECTED, INFLUENCING EACH OTHER. IT IS SUGGESTED THAT THEY REPRESENT EPIGENETIC CHANGES INDUCED BY AGE AND HOSTILE UTERINE ENVIRONMENT. 2022 10 3174 33 H19 LNCRNA IDENTIFIED AS A MASTER REGULATOR OF GENES THAT DRIVE UTERINE LEIOMYOMAS. UTERINE LEIOMYOMAS OR FIBROIDS (UFS) ARE BENIGN TUMORS CHARACTERIZED BY HYPERPLASTIC SMOOTH MUSCLE CELLS AND EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM). AFFLICTING ~80% OF WOMEN, AND SYMPTOMATIC IN 25%, UFS BRING TREMENDOUS SUFFERING AND ARE AN ECONOMIC BURDEN WORLDWIDE; THEY CAUSE SEVERE PAIN AND BLEEDING, AND ARE THE LEADING CAUSE OF HYSTERECTOMY. YET, UFS ARE SEVERELY UNDERSTUDIED WITH FEW EFFECTIVE TREATMENT OPTIONS AVAILABLE; THOSE THAT ARE AVAILABLE FREQUENTLY HAVE SIGNIFICANT SIDE EFFECTS SUCH AS MENOPAUSAL SYMPTOMS. RECENTLY, INTEGRATED GENOME-SCALE STUDIES HAVE REVEALED MUTATIONS AND FIBROID SUBTYPE-SPECIFIC EXPRESSION CHANGES IN KEY DRIVER GENES, WITH MED12 AND HMGA2 TOGETHER CONTRIBUTING TO NEARLY 90% OF ALL UFS, BUT THEIR REGULATION OF EXPRESSION IS POORLY CHARACTERIZED. HERE WE REPORT THAT THE EXPRESSION OF H19 LONG NONCODING RNA (LNCRNA) IS ABERRANTLY INCREASED IN UFS. USING CELL CULTURE AND GENOME-WIDE TRANSCRIPTOME AND METHYLATION PROFILING ANALYSES, WE DEMONSTRATE THAT H19 PROMOTES EXPRESSION OF MED12, HMGA2, AND KEY ECM-REMODELING GENES VIA MULTIPLE MECHANISMS INCLUDING A NEW CLASS OF EPIGENETIC MODIFICATION BY TET3. OUR RESULTS MARK THE FIRST EXAMPLE OF AN EVOLUTIONARILY CONSERVED LNCRNA IN PATHOGENESIS OF UFS AND REGULATION OF TET EXPRESSION. GIVEN THE LINK BETWEEN A H19 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AND INCREASED RISK AND TUMOR SIZE OF UFS, AND THE EXISTENCE OF MULTIPLE FIBROID SUBTYPES DRIVEN BY KEY PATHWAY GENES REGULATED BY H19, WE PROPOSE A UNIFYING MECHANISM FOR PATHOGENESIS OF UTERINE FIBROIDS MEDIATED BY H19 AND IDENTIFY A PATHWAY FOR FUTURE EXPLORATION OF NOVEL TARGET THERAPIES FOR UTERINE LEIOMYOMAS. 2019 11 3870 32 JUNCTIONAL ZONE ENDOMETRIUM ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. PURPOSE OF REVIEW: TO INVESTIGATE THE JZE ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. RECENT FINDINGS: JZE WAS FOUND TO BE SIGNIFICANTLY EXTENDED IN PATIENTS WITH ENDOMETRIOSIS, LEADING TO THE CONCLUSION THAT ENDOMETRIOSIS IS A PRIMARY DISEASE OF THE UTERUS, MUCH LIKE ADENOMYOSIS. STATISTICAL CORRELATION WAS THEN DEMONSTRATED BETWEEN THE SEVERITY OF ENDOMETRIOSIS AND THE DEPTH OF THE ADENOMYOSIS INFILTRATES, HENCE THE THICKENING OF THE JZE. STEM CELLS, PREDOMINANTLY FOUND IN THE JZE WERE ALSO FOUND IN HISTOLOGICAL SECTIONS OF LEIOMYOMA, SUGGESTED TO BE THE ORIGIN OF LEIOMYOMA. THIS RESERVOIR OF JZE STEM CELLS IS INFLUENCED BY DIFFERENT STRESSORS LEADING TO THEIR DIFFERENTIATION INTO LEIOMYOMA, ENDOMETRIOSIS, ADENOMYOSIS OR ENDOMETRIAL CANCER, ACCORDING TO THE STRESSOR. THE VARIABILITY IN PRESENTATION WAS HYPOTHESIZED TO BE CONNECTED TO GENETIC AND EPIGENETIC FACTORS. JZE WAS ALSO SUGGESTED TO ACT AS A BARRIER, STOPPING ENDOMETRIAL CARCINOMA CELLS INVASION AND METASTASIS. IN ADDITION, JZE PLAYS A MAJOR ROLE IN CONCEPTION, PREGNANCY AND POSTPARTUM. SUMMARY: JZE IS AN IMPORTANT ANATOMICAL LANDMARK OF THE UTERUS CONTRIBUTING TO NORMAL UTERINE FUNCTION UNDER THE INFLUENCE OF OVARIAN HORMONES. ALTERATIONS OF THE JZE THICKNESS AND CONTRACTILITY CAN BE USED AS PATHOGNOMONIC CLINICAL MARKERS IN INFERTILITY AND CHRONIC PELVIC PAIN, FOR SUBENDOMETRIAL AND MYOMETRIAL DISORDERS, FOR EXAMPLE, ADENOMYOSIS AND FIBROIDS. PROSPECTIVE RANDOMIZED CONTROL TRIALS WILL CLARIFY THE DIAGNOSTIC STEPS, IMAGING MODALITIES TO FOLLOW AND PROBABLY TRIAGE THE PATIENTS BETWEEN MEDICAL AND SURGICAL TREATMENTS. 2019 12 2295 28 EPIGENETIC REGULATION IN UTERINE FIBROIDS-THE ROLE OF TEN-ELEVEN TRANSLOCATION ENZYMES AND THEIR POTENTIAL THERAPEUTIC APPLICATION. UTERINE FIBROIDS (UFS) ARE MONOCLONAL, BENIGN TUMORS THAT CONTAIN ABNORMAL SMOOTH MUSCLE CELLS AND THE ACCUMULATION OF EXTRACELLULAR MATRIX (ECM). ALTHOUGH BENIGN, UFS ARE A MAJOR SOURCE OF GYNECOLOGIC AND REPRODUCTIVE DYSFUNCTION, RANGING FROM MENORRHAGIA AND PELVIC PAIN TO INFERTILITY, RECURRENT MISCARRIAGE, AND PRETERM LABOR. MANY RISK FACTORS ARE INVOLVED IN THE PATHOGENESIS OF UFS VIA GENETIC AND EPIGENETIC MECHANISMS. THE LATTER INVOLVING DNA METHYLATION AND DEMETHYLATION REACTIONS PROVIDE SPECIFIC DNA METHYLATION PATTERNS THAT REGULATE GENE EXPRESSION. ACTIVE DNA DEMETHYLATION REACTIONS MEDIATED BY TEN-ELEVEN TRANSLOCATION PROTEINS (TETS) AND ELEVATED LEVELS OF 5-HYDROXYMETHYLCYTOSINE HAVE BEEN SUGGESTED TO BE INVOLVED IN UF FORMATION. THIS REVIEW PAPER SUMMARIZES THE MAIN FINDINGS REGARDING THE FUNCTION OF TET ENZYMES AND THEIR ACTIVITY DYSREGULATION THAT MAY TRIGGER THE DEVELOPMENT OF UFS. UNDERSTANDING THE ROLE THAT EPIGENETICS PLAYS IN THE PATHOGENESIS OF UFS MAY POSSIBLY LEAD TO A NEW TYPE OF PHARMACOLOGICAL FERTILITY-SPARING TREATMENT METHOD. 2022 13 6237 31 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 1114 38 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 15 4956 28 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 16 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 17 4957 36 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 18 752 28 CARDIOMETABOLIC RISK FACTORS AND BENIGN GYNECOLOGIC DISORDERS. IMPORTANCE: WHILE IT HAS LONG BEEN KNOWN THAT POLYCYSTIC OVARIAN SYNDROME IS ASSOCIATED WITH CARDIOMETABOLIC RISK FACTORS (CMRFS), THERE IS EMERGING EVIDENCE THAT OTHER BENIGN GYNECOLOGIC CONDITIONS, SUCH AS UTERINE LEIOMYOMAS, ENDOMETRIOSIS, AND EVEN HYSTERECTOMY WITHOUT OOPHORECTOMY, CAN BE ASSOCIATED WITH CMRFS. UNDERSTANDING THE EVIDENCE AND MECHANISMS OF THESE ASSOCIATIONS CAN LEAD TO NOVEL PREVENTIVE AND THERAPEUTIC INTERVENTIONS. OBJECTIVE: THIS ARTICLE DISCUSSES THE EVIDENCE AND THE POTENTIAL MECHANISMS MEDIATING THE ASSOCIATION BETWEEN CMRFS AND BENIGN GYNECOLOGIC DISORDERS. EVIDENCE ACQUISITION: WE REVIEWED PUBMED, EMBASE, SCOPUS, AND GOOGLE SCHOLAR DATABASES TO OBTAIN PLAUSIBLE CLINICAL AND BIOLOGICAL EVIDENCE, INCLUDING HORMONAL, IMMUNOLOGIC, INFLAMMATORY, GROWTH FACTOR-RELATED, GENETIC, EPIGENETIC, ATHEROGENIC, VITAMIN D-RELATED, AND DIETARY FACTORS. RESULTS: CARDIOMETABOLIC RISK FACTORS APPEAR TO CONTRIBUTE TO UTERINE LEIOMYOMA PATHOGENESIS. FOR EXAMPLE, OBESITY CAN MODULATE LEIOMYOMATOUS CELLULAR PROLIFERATION AND EXTRACELLULAR MATRIX DEPOSITION THROUGH HYPERESTROGENIC STATES, CHRONIC INFLAMMATION, INSULIN RESISTANCE, AND ADIPOKINES. ON THE OTHER HAND, ENDOMETRIOSIS HAS BEEN SHOWN TO INDUCE SYSTEMIC INFLAMMATION, THEREBY INCREASING CARDIOMETABOLIC RISKS, FOR EXAMPLE, THROUGH INDUCING ATHEROSCLEROTIC CHANGES. CONCLUSION AND RELEVANCE: CLINICAL IMPLICATIONS OF THESE ASSOCIATIONS ARE 2-FOLD. FIRST, SCREENING AND EARLY MODIFICATION OF CMRFS CAN BE PART OF A PREVENTIVE STRATEGY FOR UTERINE LEIOMYOMAS AND HYSTERECTOMY. SECOND, PATIENTS DIAGNOSED WITH UTERINE LEIOMYOMAS OR ENDOMETRIOSIS CAN BE SCREENED AND CLOSELY FOLLOWED FOR CMRFS AND CARDIOVASCULAR DISEASE. 2019 19 1891 36 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 3820 25 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