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 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 3 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 4 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 5 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 6 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 7 2669 39 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 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 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 10 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 11 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 12 1889 28 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 13 6076 41 THE DYNAMICS OF NUCLEAR RECEPTORS AND NUCLEAR RECEPTOR COREGULATORS IN THE PATHOGENESIS OF ENDOMETRIOSIS. BACKGROUND: ENDOMETRIOSIS IS DEFINED AS THE COLONIZATION AND GROWTH OF ENDOMETRIAL TISSUE AT ANATOMIC SITES OUTSIDE THE UTERINE CAVITY. UP TO 15% OF REPRODUCTIVE-AGED WOMEN IN THE USA SUFFER FROM PAINFUL SYMPTOMS OF ENDOMETRIOSIS, SUCH AS INFERTILITY, PELVIC PAIN, MENSTRUAL CYCLE ABNORMALITIES AND INCREASED RISK OF CERTAIN CANCERS. HOWEVER, MANY OF THE CURRENT CLINICAL TREATMENTS FOR ENDOMETRIOSIS ARE NOT SUFFICIENTLY EFFECTIVE AND YIELD UNACCEPTABLE SIDE EFFECTS. THERE IS CLEARLY AN URGENT NEED TO IDENTIFY NEW MOLECULAR MECHANISMS THAT CRITICALLY UNDERPIN THE INITIATION AND PROGRESSION OF ENDOMETRIOSIS IN ORDER TO DEVELOP MORE SPECIFIC AND EFFECTIVE THERAPEUTICS WHICH LACK THE SIDE EFFECTS OF CURRENT THERAPIES. THE AIM OF THIS REVIEW IS TO DISCUSS HOW NUCLEAR RECEPTORS (NRS) AND THEIR COREGULATORS PROMOTE THE PROGRESSION OF ENDOMETRIOSIS. UNDERSTANDING THE PATHOGENIC MOLECULAR MECHANISMS FOR THE GENESIS AND MAINTENANCE OF ENDOMETRIOSIS AS MODULATED BY NRS AND COREGULATORS CAN REVEAL NEW THERAPEUTIC TARGETS FOR ALTERNATIVE ENDOMETRIOSIS TREATMENTS. METHODS: THIS REVIEW WAS PREPARED USING PUBLISHED GENE EXPRESSION MICROARRAY DATA SETS OBTAINED FROM PATIENTS WITH ENDOMETRIOSIS AND PUBLISHED LITERATURE ON NRS AND THEIR COREGULATORS THAT DEAL WITH ENDOMETRIOSIS PROGRESSION. USING THE ABOVE OBSERVATIONS, OUR CURRENT UNDERSTANDING OF HOW NRS AND NR COREGULATORS ARE INVOLVED IN THE PROGRESSION OF ENDOMETRIOSIS IS SUMMARIZED. RESULTS: ABERRANT LEVELS OF NRS AND NR COREGULATORS IN ECTOPIC ENDOMETRIOSIS LESIONS ARE ASSOCIATED WITH THE PROGRESSION OF ENDOMETRIOSIS. AS AN EXAMPLE, ENDOMETRIOTIC CELL-SPECIFIC ALTERATIONS IN GENE EXPRESSION ARE CORRELATED WITH A DIFFERENTIAL METHYLATION STATUS OF THE GENOME COMPARED WITH THE NORMAL ENDOMETRIUM. THESE DIFFERENTIAL EPIGENETIC REGULATIONS CAN GENERATE FAVORABLE CELL-SPECIFIC NR AND COREGULATOR MILIEUS FOR ENDOMETRIOSIS PROGRESSION. GENETIC ALTERATIONS, SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS AND INSERTION/DELETION POLYMORPHISMS OF NR AND COREGULATOR GENES, ARE FREQUENTLY DETECTED IN ECTOPIC LESIONS COMPARED WITH THE NORMAL ENDOMETRIUM. THESE GENETIC VARIATIONS IMPART NEW MOLECULAR PROPERTIES TO NRS AND COREGULATORS TO INCREASE THEIR CAPACITY TO STIMULATE PROGRESSION OF ENDOMETRIOSIS. FINALLY, POST-TRANSLATIONAL MODIFICATIONS OF NR COREGULATORS, SUCH AS PROTEOLYTIC PROCESSING, GENERATE ENDOMETRIOSIS-SPECIFIC ISOFORMS. COMPARED WITH THE UNMODIFIED COREGULATORS, THESE COREGULATOR ISOFORMS HAVE UNIQUE FUNCTIONS THAT ENHANCE THE PATHOGENESIS OF ENDOMETRIOSIS. CONCLUSIONS: EPIGENETIC/GENETIC VARIATIONS AND POSTTRANSLATIONAL MODIFICATIONS OF NRS AND COREGULATORS ALTER THEIR ORIGINAL FUNCTION SO THAT THEY BECOME POTENT 'DRIVERS' OF ENDOMETRIOSIS PROGRESSION. 2014 14 4688 25 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 28 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 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 17 5242 36 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 18 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 19 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 20 5241 30 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