1 3665 146 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 2 6711 39 VIRTUES AND WEAKNESSES OF DNA METHYLATION AS A TEST FOR CERVICAL CANCER PREVENTION. EPIGENETICS IS THE STUDY OF HERITABLE AND NON-HERITABLE GENETIC CODING THAT IS ADDITIVE TO INFORMATION CONTAINED WITHIN CLASSICAL DNA BASE PAIR SEQUENCES. DIFFERENTIAL METHYLATION HAS A FUNDAMENTAL ROLE IN THE DEVELOPMENT AND OUTCOME OF MALIGNANCIES, CHRONIC AND DEGENERATIVE DISEASES AND AGING. DNA METHYLATION CAN BE MEASURED ACCURATELY AND EASILY VIA VARIOUS MOLECULAR METHODS AND HAS BECOME A KEY TECHNOLOGY FOR RESEARCH AND HEALTHCARE DELIVERY, WITH IMMEDIATE ROLES IN THE ELUCIDATION OF DISEASE NATURAL HISTORY, DIAGNOSTICS AND DRUG DISCOVERY. THIS REVIEW FOCUSES ON CANCERS OF THE LOWER GENITAL TRACT, FOR WHICH THE MOST EPIGENETIC INFORMATION EXISTS. DNA METHYLATION HAS BEEN PROPOSED AS A TRIAGE FOR WOMEN INFECTED WITH HUMAN PAPILLOMAVIRUS (HPV) AND MAY EVENTUALLY DIRECTLY COMPLEMENT OR REPLACE HPV SCREENING AS A ONE-STEP MOLECULAR DIAGNOSTIC AND PROGNOSTIC TEST. METHYLATION OF HUMAN GENES IS STRONGLY ASSOCIATED WITH CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN) AND CANCER. OF THE MORE THAN 100 HUMAN METHYLATION BIOMARKER GENES TESTED SO FAR IN CERVICAL TISSUE, CLOSE TO 20 HAVE BEEN REPORTED IN DIFFERENT STUDIES, AND APPROXIMATELY 10 HAVE BEEN REPEATEDLY SHOWN TO HAVE ELEVATED METHYLATION IN CERVICAL CANCERS AND HIGH-GRADE CIN (CIN2 AND CIN3), MOST PROMINENTLY CADM1, EPB41L3, FAM19A4, MAL, MIR-124, PAX1 AND SOX1. OBTAINING CONSISTENT PERFORMANCE DATA FROM THE LITERATURE IS QUITE DIFFICULT BECAUSE MOST METHYLATION STUDIES USED A VARIETY OF DIFFERENT ASSAY METHODOLOGIES AND HAD INCOMPLETE AND/OR BIASED CLINICAL SPECIMEN SETS, VARYING ASSAY THRESHOLDS AND DISPARATE TARGET GENE REGIONS. THERE HAVE BEEN RELATIVELY FEW VALIDATION STUDIES OF DNA METHYLATION BIOMARKERS IN LARGE POPULATION-BASED SCREENING STUDIES, BUT AN ENCOURAGING DEVELOPMENT MORE RECENTLY IS THE EXECUTION OF WELL-DESIGNED STUDIES TO TEST THE TRUE PERFORMANCE OF THE MARKERS IN REAL-WORLD SETTINGS. METHYLATION OF HPV GENES, ESPECIALLY HPV16, HPV18, HPV31, HPV33 AND HPV45, IN DISEASE PROGRESSION HAS BEEN A MAJOR FOCUS OF RESEARCH. ELEVATED METHYLATION OF THE HPV16 L1 AND L2 OPEN READING FRAMES, IN PARTICULAR, IS ASSOCIATED WITH CIN2, CIN3 AND INVASIVE CANCER. ESSENTIALLY ALL CANCERS HAVE HIGH LEVELS OF METHYLATION FOR HUMAN GENES AND FOR DRIVER HPV TYPES, WHICH SUGGESTS THAT QUANTITATIVE METHYLATION TESTS MAY HAVE UTILITY IN PREDICTING CIN2 AND CIN3 THAT ARE LIKELY TO PROGRESS. IT IS STILL EARLY IN THE PROCESS OF DEVELOPMENT OF METHYLATION BIOMARKERS, BUT ALREADY THEY ARE SHOWING STRONG PROMISE AS A UNIVERSAL AND SYSTEMATIC APPROACH TO MOLECULAR TRIAGE, APPLICABLE TO ALL CANCERS, NOT JUST CANCER OF THE CERVIX. DNA METHYLATION TESTING IS BETTER THAN HPV GENOTYPING TRIAGE AND IS COMPETITIVE WITH OR COMPLEMENTARY TO OTHER APPROACHES SUCH AS CYTOLOGY AND P16 STAINING. GENOME-WIDE STUDIES ARE UNDERWAY TO SYSTEMATICALLY EXPAND METHYLATION CLASSIFIER PANELS AND FIND THE BEST COMBINATIONS OF BIOMARKERS. METHYLATION TESTING IS LIKELY TO SHOW BIG IMPROVEMENTS IN PERFORMANCE IN THE NEXT 5 YEARS. 2016 3 2692 27 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 4 6313 38 THE RELATIONSHIP BETWEEN MERCURY EXPOSURE AND EPIGENETIC ALTERATIONS REGARDING HUMAN HEALTH, RISK ASSESSMENT AND DIAGNOSTIC STRATEGIES. BACKGROUND: EXPOSURE TO THE ENVIRONMENTAL TOXICANTS POSES A SERIOUS THREAT TO HUMAN HEALTH. THE EXTENT OF EXPOSURE AND THE DEVELOPMENT OF DISEASES ARE INTERRELATED WITH EACH OTHER. CHRONIC EXPOSURE TO MERCURY (HG) INCREASES THE RISK OF DEVELOPING SERIOUS HUMAN DISORDERS FROM EMBRYO TO ADULTHOOD. OBJECTIVES: THE PURPOSE OF THIS REVIEW IS TO HIGHLIGHT THE MOST COMMON HUMAN DISORDERS INDUCED BY HG EXPOSURE ON THE BASIS OF EPIGENETIC MECHANISMS. A GROWING BODY OF EVIDENCE SHOWS THAT HG EXPOSURE LEADS TO ALTERATIONS IN THE EPIGENETIC MARKERS. METHODS: WE PERFORMED AN ORGANIZED SEARCH OF THE AVAILABLE LITERATURE USING PUBMED, GOOGLE SCHOLAR, MEDLINE, REAXYS, EMBASE AND SCOPUS DATABASES. ALL THE RELEVANT CITATIONS, INCLUDING RESEARCH AND REVIEW ARTICLES IN ENGLISH WERE EVALUATED. THE SEARCH TERMS INCLUDED MERCURY, HG, EPIGENETICS, EPIGENETIC ALTERATIONS, DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS (MIRNAS), AND RISK ASSESSMENT. RESULTS: DATA ON HUMAN TOXICITY DUE TO HG EXPOSURE SHOWS BROAD VARIATIONS IN TERMS OF CHEMICAL NATURE, DOSES, AND THE RATE OF EXPOSURE. HG CONSUMPTION EITHER VIA FOODS OR ENVIRONMENTAL SOURCES MAY CREATE DELETERIOUS HEALTH EFFECTS ON VARIOUS PHYSIOLOGICAL SYSTEMS AT LEAST PARTIALLY THROUGH AN EPIGENETIC MECHANISM. CONCLUSION: HG EXPOSURE COULD TRIGGER EPIGENETIC ALTERATIONS, HENCE LEADING TO VARIOUS HUMAN DISORDERS INCLUDING REDUCED NEWBORN CEREBELLUM SIZE, ADVERSE BEHAVIORAL OUTCOMES, ATHEROSCLEROSIS AND MYOCARDIAL INFARCTION. SIMILARLY, IN ADULTS, OCCUPATIONAL HG EXPOSURE HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF AUTOIMMUNITY. IT HAS BEEN REVEALED THAT MIRNAS IN THE WOMAN'S CERVIX ARE A NOVEL RESPONDER TO MATERNAL HG EXPOSURE DURING PREGNANCY. HG-INDUCED EPIGENETIC ALTERATIONS ANALYSIS OF KIDNEY TISSUES SHOWED A SIGNIFICANT INTERRUPTION IN RENAL FUNCTION. DNA METHYLATION AND HISTONE POST-TRANSLATION MODIFICATIONS ARE PREDOMINANT TYPES OF HG EPIGENETIC ALTERATIONS. 2019 5 5697 48 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 6 1249 32 CURRENT KNOWLEDGE ON ENDOMETRIOSIS ETIOLOGY: A SYSTEMATIC REVIEW OF LITERATURE. OBJECTIVE: TO REVIEW THE MECHANISMS OF ENDOMETRIOSIS DEVELOPMENT, INCLUDING THOSE RELATED TO EPIGENETIC MUTATIONS, CELLULAR DYSREGULATION, INFLAMMATORY PROCESSES, AND OXIDATIVE STRESS. METHODS: A SYSTEMATIC LITERATURE REVIEW REGARDING CURRENT ASPECTS OF ENDOMETRIOSIS ETIOLOGY, GENESIS AND DEVELOPMENT WAS PERFORMED USING THE PUBMED, GOOGLE SCHOLAR, AND ELIBRARY DATABASES. KEYWORDS INCLUDED ENDOMETRIOSIS, ETIOLOGY, DEVELOPMENT, GENESIS, ASSOCIATIONS AND MECHANISMS. A MULTILINGUAL SEARCH WAS PERFORMED. RESULTS: SEVERAL MECHANISMS UNDERLINE THE PATHOPHYSIOLOGICAL PATHWAYS FOR ENDOMETRIOSIS DEVELOPMENT. EPIGENETIC MUTATIONS, EXTERNAL AND INTERNAL INFLUENCES, AND CHRONIC CONDITIONS HAVE A SIGNIFICANT IMPACT ON ENDOMETRIOSIS DEVELOPMENT, SURVIVAL AND REGULATION. SEVERAL HISTORICALLY VALID THEORIES ON ENDOMETRIOSIS DEVELOPMENT WERE DISCUSSED, AS WELL AS UPDATED FINDINGS. CONCLUSION: DESPITE RECENT ADVANCES, FUNDAMENTAL PROBLEMS IN UNDERSTANDING ENDOMETRIOSIS REMAIN UNRESOLVED. THE IDENTIFICATION OF UNKNOWN CIRCULATING EPITHELIAL PROGENITORS OR STEM CELLS THAT ARE RESPONSIBLE FOR EPITHELIAL GROWTH IN BOTH THE ENDOMETRIUM AND ENDOMETRIOTIC FOCI SEEMS TO BE THE NEXT STEP IN SOLVING THESE QUESTIONS. 2021 7 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 8 1929 30 ENVIRONMENTAL EXPOSURE, DNA METHYLATION, AND GENE REGULATION: LESSONS FROM DIETHYLSTILBESTEROL-INDUCED CANCERS. DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT REGULATES CHROMOSOMAL STABILITY AND GENE EXPRESSION. ABNORMAL DNA METHYLATION PATTERNS HAVE BEEN OBSERVED IN MANY TYPES OF HUMAN TUMORS, INCLUDING THOSE OF THE BREAST, PROSTATE, COLON, THYROID, STOMACH, UTERUS, AND CERVIX. WE AND OTHERS HAVE SHOWN THAT EXPOSURE TO A WIDE VARIETY OF XENOBIOTICS DURING CRITICAL PERIODS OF MAMMALIAN DEVELOPMENT CAN PERSISTENTLY ALTER THE PATTERN OF DNA METHYLATION, RESULTING IN POTENTIALLY ADVERSE BIOLOGICAL EFFECTS SUCH AS ABERRANT GENE EXPRESSION. THUS, THIS EPIGENETIC MECHANISM MAY UNDERLIE THE OBSERVED INCREASED RISK IN ADULTHOOD OF SEVERAL CHRONIC DISEASES, INCLUDING CANCER, IN RESPONSE TO XENOBIOTIC EXPOSURES EARLY IN LIFE. WE PRESENT HERE THE LESSONS LEARNED FROM STUDIES ON THE EFFECTS OF PERINATAL DIETHYLSTILBESTEROL (DES) EXPOSURE ON THE METHYLATION PATTERN OF THE PROMOTERS OF SEVERAL ESTROGEN-RESPONSIVE GENES ASSOCIATED WITH THE DEVELOPMENT OF REPRODUCTIVE ORGANS. PERINATAL DES EXPOSURE, WHICH INDUCES EPITHELIAL TUMORS OF THE UTERUS IN MICE AND IS ASSOCIATED WITH SEVERAL REPRODUCTIVE TRACT ABNORMALITIES AND INCREASED VAGINAL AND CERVICAL CANCER RISK IN WOMEN, PROVIDES A CLEAR EXAMPLE OF HOW ESTROGENIC XENOBIOTIC EXPOSURE DURING A CRITICAL PERIOD OF DEVELOPMENT CAN ABNORMALLY DEMETHYLATE DNA SEQUENCES DURING ORGAN DEVELOPMENT AND POSSIBLY INCREASE CANCER RISK LATER IN LIFE. IN ADDITION, NUTRITIONAL FACTORS AND STRESS MAY ALSO ALTER DNA METHYLATION DURING EARLY LIFE AND MODULATE THE RISK OF CANCER AND OTHER CHRONIC DISEASES IN ADULTHOOD. WE SUGGEST THAT DNA METHYLATION STATUS MAY BE INFLUENCED BY ENVIRONMENTAL EXPOSURES IN EARLY LIFE, LEADING TO INCREASED RISK OF CANCER IN ADULTHOOD. 2003 9 6682 38 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 10 2876 25 FUNCTIONAL ROLES OF LONG NONCODING RNA MALAT1 IN GYNECOLOGIC CANCERS. GYNECOLOGIC CANCERS ARE REPRODUCTIVE DISORDERS CHARACTERIZED BY PELVIC PAIN AND INFERTILITY. THE IDENTIFICATION OF NEW PREDICTIVE MARKERS AND THERAPEUTIC TARGETS FOR THE TREATMENT OF GYNECOLOGIC CANCERS IS URGENTLY NECESSARY. ONE OF THE RECENT SUCCESSES IN GYNECOLOGIC CANCERS RESEARCH IS IDENTIFYING THE ROLE OF SIGNALING PATHWAYS IN THE PATHOGENESIS OF THE DISEASE. RECENT EXPERIMENTS SHOWED LONG NONCODING RNAS (LNCRNA) CAN BE NOVEL THERAPEUTIC APPROACHES FOR THE DIAGNOSIS AND TREATMENT OF GYNECOLOGIC CANCERS. LNCRNA ARE TRANSCRIBED RNA MOLECULES THAT PLAY PIVOTAL ROLES IN MULTIPLE BIOLOGICAL PROCESSES BY REGULATING THE DIFFERENT STEPS OF GENE EXPRESSION. METASTASIS-ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT-1 (MALAT1) IS A WELL-KNOWN LNCRNA THAT PLAYS FUNCTIONAL ROLES IN GENE EXPRESSION, RNA PROCESSING, AND EPIGENETIC REGULATION. HIGH EXPRESSION OF MALAT1 IS CLOSELY RELATED TO NUMEROUS HUMAN DISEASES. IT IS GENERALLY BELIEVED THAT MALAT1 EXPRESSION IS ASSOCIATED WITH CANCER CELL GROWTH, AUTOPHAGY, INVASION, AND METASTASIS. MALAT1 BY TARGETING MULTIPLE SIGNALING PATHWAYS AND MICRORNAS (MIRNAS) COULD CONTRIBUTE TO THE PATHOGENESIS OF GYNECOLOGIC CANCERS. IN THIS REVIEW, WE WILL SUMMARIZE FUNCTIONAL ROLES OF MALAT1 IN THE MOST COMMON GYNECOLOGIC CANCERS, INCLUDING ENDOMETRIUM, BREAST, OVARY, AND CERVIX. 2023 11 5522 34 RISK OF OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON AND ARSENIC ON PULMONARY DISORDERS: UNDERSTANDING THE GENETIC-EPIGENETIC INTERPLAY AND FUTURE PROSPECTS. BACKGROUND: EPIDEMIOLOGICAL STUDIES SUGGEST STRONG ASSOCIATION OF LUNG DISORDERS WITH OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON AND ARSENIC. THE CHRONIC OCCUPATIONAL EXPOSURE PRIMARILY THROUGH INHALATION RESULTS IN ADVERSE OUTCOME ON THE RESPIRATORY TRACT WHICH MAY ALSO BE FATAL. ALTHOUGH SEVERAL MECHANISMS HAVE ATTRIBUTED TOWARDS THESE DISEASES; THE MOLECULAR PATHOGENESIS IS STILL UNKNOWN. OBJECTIVE: IN THIS REVIEW, WE INVESTIGATED THE PLAUSIBLE MOLECULAR MECHANISM BASED ON CURRENT RESEARCH THAT MAY IDENTIFY THE GENETIC AND EPIGENETIC SUSCEPTIBILITY OF RESPIRATORY DISORDERS UPON SUCH OCCUPATIONAL EXPOSURES IN HUMANS. METHODS: WE CONSIDERED GENETIC VARIANTS AND EPIGENETIC ALTERATIONS ASSOCIATED WITH PULMONARY EXPOSURE HAZARDS LEADING TO ASBESTOSIS, SILICOSIS AND ARSENICOSIS. OUR REVIEW IS STRINGENTLY BASED ON THE LITERATURES AVAILABLE THROUGH PEER-REVIEWED ARTICLES MOSTLY PUBLISHED IN THE LAST 10 YEARS. RELEVANT SEARCH WERE CONDUCTED USING KEYWORDS LIKE "OCCUPATIONAL LUNG DISORDERS" ALONG WITH "ASBESTOS", "SILICON" AND "ARSENIC". RESULTS: TILL SEPTEMBER 2015, PUBMED SEARCH YIELDED APPROXIMATELY 780 ARTICLES RELATING TO ASBESTOS EXPOSURE; 240 ARTICLES FOR SILICON EXPOSURE AND 60 ARTICLES FOR ARSENIC EXPOSURE. EXTENSIVE SCREENING FOR GENETIC AND EPIGENETIC FACTORS IDENTIFIED CERTAIN GENES AND RELATED PATHWAYS THAT ARE IMPORTANT TO DETERMINE THE SUSCEPTIBILITY OF AN INDIVIDUAL TOWARDS SUCH OCCUPATIONAL EXPOSURE. CONCLUSION: THE LINK BETWEEN GENOTYPE AND PHENOTYPE AND ITS ASSOCIATION WITH DISEASE SUSCEPTIBILITY IS VERY COMPLEX IN NATURE DUE TO SEVERAL FACTORS LIKE PERSON'S ENVIRONMENT, LIFESTYLE AND NUTRITIONAL STATUS. THE EPIGENOME IS DYNAMIC AS WELL AS REVERSIBLE AND CAN BE RESHAPED FURTHER BY CERTAIN DIETARY COMPONENTS THROUGHOUT ITS LIFE. IN THE PRESENT REVIEW, WE HAVE ADDRESSED THE ROLE OF MOLECULAR PATHOGENESIS OF OCCUPATIONAL LUNG DISEASES BASED ON THE GENETIC VARIABILITY AND EPIGENETIC ALTERATIONS AND ALSO ATTEMPTED TO HIGHLIGHT THE PROMISING ASPECT OF DIETARY INTERVENTIONS TO COUNTER TOXIC OUTCOMES UPON OCCUPATIONAL EXPOSURE TO ASBESTOS, SILICON OR ARSENIC. 2016 12 4957 30 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 13 6237 24 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 3773 23 INTERACTION OF CERVICAL MICROBIOME WITH EPIGENOME OF EPITHELIAL CELLS: SIGNIFICANCE OF INFLAMMATION TO PRIMARY HEALTHCARE. ONE PILLAR OF THE PREDICTIVE, PREVENTIVE, AND PERSONALIZED MEDICINE FRAMEWORK STRATEGIES IS THE FEMALE HEALTH. THE EVALUATION OF WOMEN'S LIFESTYLE AND DIETARY HABITS IN CONTEXT WITH GENETIC AND MODIFIABLE RISK FACTORS MAY REFLECT THE PREVENTION OF CERVICAL CANCER BEFORE THE OCCURRENCE OF CLINICAL SYMPTOMS AND PREDICTION OF CERVICAL LESION BEHAVIOR. THE MAIN AIM OF THIS REVIEW IS TO ANALYZE PUBLICATIONS IN THE FIELD OF PRECISION MEDICINE THAT ALLOW THE USE OF RESEARCH KNOWLEDGE OF CERVICAL MICROBIOME, EPIGENETIC MODIFICATIONS, AND INFLAMMATION IN POTENTIAL APPLICATION IN CLINICAL PRACTICE. PERSONALIZED APPROACH IN EVALUATING PATIENT'S RISK OF FUTURE DEVELOPMENT OF CERVICAL ABNORMALITY SHOULD CONSIDER THE BIOMARKERS OF THE LOCAL MICROENVIRONMENT CHARACTERIZED BY THE MICROBIAL COMPOSITION, EPIGENETIC PATTERN OF CERVICAL EPITHELIUM, AND PRESENCE OF CHRONIC INFLAMMATION. NOVEL SEQUENCING TECHNIQUES ENABLE A MORE DETAILED CHARACTERIZATION OF ACTUAL STATE IN CERVICAL EPITHELIUM. BETTER UNDERSTANDING OF ALL CHANGES IN MULTIOMICS LEVEL ENABLES A BETTER ASSESSMENT OF DISEASE PROGNOSIS AND SELECTS THE ELIGIBLE TARGETED THERAPY IN PERSONALIZED MEDICINE. RESTORING OF HEALTHY VAGINAL MICROFLORA AND REVERSING THE OUTBREAK OF CERVICAL ABNORMALITY CAN BE ALSO ACHIEVED BY DIETARY HABITS AS WELL AS UPTAKE OF PREBIOTICS, PROBIOTICS, SYNBIOTICS, MICROBIAL TRANSPLANTATION, AND OTHERS. 2022 15 6338 28 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 16 6381 32 THE ROLE OF ONCOGENIC DNA VIRUSES IN PENILE CANCER DEVELOPMENT. PENILE CANCER IS A RELATIVELY RARE NEOPLASIA IN DEVELOPED COUNTRIES, WITH SIGNIFICANT MORBIDITY AND MORTALITY IN DEVELOPING COUNTRIES. PENILE CANCER CAN BE SUBDIVIDED INTO HUMAN PAPILLOMAVIRUS (HPV)-POSITIVE AND HPV-NEGATIVE CASES. WORLDWIDE, THE HPV PREVALENCE IN PENILE CANCER SAMPLES IS AROUND 50%, AND HPV16 IS THE MOST PREVALENT GENOTYPE. ALTHOUGH HPV IS AN IMPORTANT FACTOR FOR CANCER DEVELOPMENT, OTHER ONCOGENIC FACTORS MAY BE ASSOCIATED WITH CARCINOGENESIS. SOME OF THESE FACTORS CAN BE INFECTIOUS, SUCH AS THE EPSTEIN-BARR VIRUS (EBV), AS WELL AS THE MERKEL CELL POLYOMAVIRUS (MCPYV). THE PREVALENCE RATES OF NEARLY 50% FOR BOTH HPV AND EBV INFECTIONS INDICATE AN IMPORTANT ROLE OF THESE VIRUSES IN PENILE TISSUE MALIGNANCY, REINFORCING THE IDEA OF A MULTIFACTORIAL ETIOLOGY OF THE DISEASE. ALTHOUGH THE HPV ROLE IS BETTER UNDERSTOOD, EBV IS THOUGHT TO FACILITATE PERSISTENCE, INTEGRATION, AND MUTATIONS. RECENT STUDIES ON THE MERKEL CELL POLYOMAVIRUS HAVE NOT SHOWN A RELEVANT PREVALENCE IN PENILE CANCER SAMPLES, BUT ITS PRESENCE INDICATES THE OPPORTUNISTIC INFECTIOUS POTENTIAL OF THIS VIRUS. REGARDING HPV-NEGATIVE CASES, THE LITERATURE SUGGESTS A LINK WITH YOUNGER AGE AND EPIGENETIC ALTERATIONS, MAINLY THROUGH THE P16INK4A PATHWAY. RECENTLY, SEVERAL BIOMARKERS THAT MIGHT ACT AS PROGNOSTIC TOOLS (E.G., KI-67, SQUAMOUS CELL CARCINOMA ANTIGEN, AMONG OTHERS) HAVE BEEN PROPOSED, BUT THE RESULTS REMAIN CONTROVERSIAL. IN ADDITION, OTHER RISK FACTORS HAVE ALSO BEEN ASSOCIATED WITH PENILE CARCINOGENESIS, SUCH AS THE PRESENCE OF PHIMOSIS, NONCIRCUMCISION, CHRONIC INFLAMMATION, AND NUMBER OF SEXUAL PARTNERS. FURTHER STUDIES ARE NEEDED TO DEVELOP TOOLS FOR EARLY DETECTION AND EPIDEMIOLOGICAL SURVEILLANCE OF PENILE CANCER. 2019 17 236 28 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 18 4950 26 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 19 1887 35 ENDOMETRIAL RECEPTIVITY IN WOMEN OF ADVANCED AGE: AN UNDERRATED FACTOR IN INFERTILITY. BACKGROUND: MODERN LIFESTYLE HAS LED TO AN INCREASE IN THE AGE AT CONCEPTION. ADVANCED AGE IS ONE OF THE CRITICAL RISK FACTORS FOR FEMALE-RELATED INFERTILITY. IT IS WELL KNOWN THAT MATERNAL AGE POSITIVELY CORRELATES WITH THE DETERIORATION OF OOCYTE QUALITY AND CHROMOSOMAL ABNORMALITIES IN OOCYTES AND EMBRYOS. THE EFFECT OF AGE ON ENDOMETRIAL FUNCTION MAY BE AN EQUALLY IMPORTANT FACTOR INFLUENCING IMPLANTATION RATE, PREGNANCY RATE, AND OVERALL FEMALE FERTILITY. HOWEVER, THERE ARE ONLY A FEW PUBLISHED STUDIES ON THIS TOPIC, SUGGESTING THAT THIS AREA HAS BEEN UNDER-EXPLORED. IMPROVING OUR KNOWLEDGE OF ENDOMETRIAL AGING FROM THE BIOLOGICAL (CELLULAR, MOLECULAR, HISTOLOGICAL) AND CLINICAL PERSPECTIVES WOULD BROADEN OUR UNDERSTANDING OF THE RISKS OF AGE-RELATED FEMALE INFERTILITY. OBJECTIVE AND RATIONALE: THE OBJECTIVE OF THIS NARRATIVE REVIEW IS TO CRITICALLY EVALUATE THE EXISTING LITERATURE ON ENDOMETRIAL AGING WITH A FOCUS ON SYNTHESIZING THE EVIDENCE FOR THE IMPACT OF ENDOMETRIAL AGING ON CONCEPTION AND PREGNANCY SUCCESS. THIS WOULD PROVIDE INSIGHTS INTO EXISTING GAPS IN THE CLINICAL APPLICATION OF RESEARCH FINDINGS AND PROMOTE THE DEVELOPMENT OF TREATMENT OPTIONS IN THIS FIELD. SEARCH METHODS: THE REVIEW WAS PREPARED USING PUBMED (MEDLINE) UNTIL FEBRUARY 2023 WITH THE KEYWORDS SUCH AS 'ENDOMETRIAL AGING', 'RECEPTIVITY', 'DECIDUALIZATION', 'HORMONE', 'SENESCENCE', 'CELLULAR', 'MOLECULAR', 'METHYLATION', 'BIOLOGICAL AGE', 'EPIGENETIC', 'OOCYTE RECIPIENT', 'OOCYTE DONATION', 'EMBRYO TRANSFER', AND 'PREGNANCY RATE'. ARTICLES IN A LANGUAGE OTHER THAN ENGLISH WERE EXCLUDED. OUTCOMES: IN THE AGING ENDOMETRIUM, ALTERATIONS OCCUR AT THE MOLECULAR, CELLULAR, AND HISTOLOGICAL LEVELS SUGGESTING THAT AGING HAS A NEGATIVE EFFECT ON ENDOMETRIAL BIOLOGY AND MAY IMPAIR ENDOMETRIAL RECEPTIVITY. ADDITIONALLY, ADVANCED AGE INFLUENCES CELLULAR SENESCENCE, WHICH PLAYS AN IMPORTANT ROLE DURING THE INITIAL PHASE OF IMPLANTATION AND IS A MAJOR OBSTACLE IN THE DEVELOPMENT OF SUITABLE SENOLYTIC AGENTS FOR ENDOMETRIAL AGING. AGING IS ALSO ACCOUNTABLE FOR CHRONIC CONDITIONS ASSOCIATED WITH INFLAMMAGING, WHICH EVENTUALLY CAN LEAD TO INCREASED PRO-INFLAMMATION AND TISSUE FIBROSIS. FURTHERMORE, ADVANCED AGE INFLUENCES EPIGENETIC REGULATION IN THE ENDOMETRIUM, THUS ALTERING THE RELATION BETWEEN ITS EPIGENETIC AND CHRONOLOGICAL AGE. THE STUDIES IN OOCYTE DONATION CYCLES TO DETERMINE THE EFFECT OF AGE ON ENDOMETRIAL RECEPTIVITY WITH RESPECT TO THE RATES OF IMPLANTATION, CLINICAL PREGNANCY, MISCARRIAGE, AND LIVE BIRTH HAVE REVEALED CONTRADICTORY INFERENCES INDICATING THE NEED FOR FUTURE RESEARCH ON THE MECHANISMS AND CORRESPONDING CAUSAL EFFECTS OF WOMEN'S AGE ON ENDOMETRIAL RECEPTIVITY. WIDER IMPLICATIONS: INCREASING AGE CAN BE ACCOUNTABLE FOR FEMALE INFERTILITY AND IVF FAILURES. BASED ON THE COMPLIED OBSERVATIONS AND SYNTHESIZED CONCLUSIONS IN THIS REVIEW, ADVANCED AGE HAS BEEN SHOWN TO HAVE A NEGATIVE IMPACT ON ENDOMETRIAL FUNCTIONING. THIS INFORMATION CAN PROVIDE RECOMMENDATIONS FOR FUTURE RESEARCH FOCUSING ON MOLECULAR MECHANISMS OF AGE-RELATED CELLULAR SENESCENCE, CELLULAR COMPOSITION, AND TRANSCRIPTOMIC CHANGES IN RELATION TO ENDOMETRIAL AGING. ADDITIONALLY, FURTHER PROSPECTIVE RESEARCH IS NEEDED TO EXPLORE NEWLY EMERGING THERAPEUTIC OPTIONS, SUCH AS THE SENOLYTIC AGENTS THAT CAN TARGET ENDOMETRIAL AGING WITHOUT AFFECTING DECIDUALIZATION. MOREOVER, CLINICAL TRIAL PROTOCOLS, FOCUSING ON OOCYTE DONATION CYCLES, WOULD BE BENEFICIAL IN UNDERSTANDING THE DIRECT CLINICAL IMPLICATIONS OF ENDOMETRIAL AGING ON PREGNANCY OUTCOMES. 2023 20 4956 21 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