1 3509 115 IDENTIFYING MECHANISMS OF ENDOMETRIOSIS-ASSOCIATED REDUCED FECUNDITY IN A RAT MODEL: NOVEL INSIGHTS TOWARD UNDERSTANDING HUMAN INFERTILITY. THE EXISTENCE OF ENDOMETRIOSIS HAS BEEN KNOWN SINCE AT LEAST THE NINETEENTH CENTURY, YET THE LACK OF UNDERSTANDING OF CAUSES OF INFERTILITY AND THEREFORE INADEQUATE TREATMENT APPROACHES IN ENDOMETRIOSIS CREATES A SIGNIFICANT CHALLENGE IN REPRODUCTIVE MEDICINE. WOMEN WORLDWIDE SUFFER NOT ONLY PAIN AND INFERTILITY BUT ALSO ECONOMICAL, SOCIETAL, AND PHYSIOLOGICAL BURDENS. STUDIES OF REPRODUCTIVE EVENTS IN WOMEN ARE DIFFICULT TO CONDUCT DUE TO A HOST OF CONFOUNDING PERSONAL AND ENVIRONMENTAL FACTORS AND ETHICALLY LIMITED DUE TO THE VERY NATURE OF WORKING WITH REPRODUCTIVE TISSUES AND CELLS, ESPECIALLY EMBRYOS. ANIMAL MODELS ARE A VIABLE ADJUNCT TO STUDY MECHANISMS CAUSING HUMAN REPRODUCTIVE ANOMALIES AND INFERTILITY IN ENDOMETRIOSIS. THIS CHAPTER DISCUSSES REPRODUCTIVE ANOMALIES CAUSING INFERTILITY IN ENDOMETRIOSIS AND WELL-ESTABLISHED ANIMAL MODELS WHICH HELP DECIPHER THE PROBLEMS AND LEAD TO HERETOFORE UNKNOWN NONSURGICAL, NONHORMONAL METHODS TO MANAGE ENDOMETRIOSIS IN WOMEN. IN ADDITION, STUDIES OF EFFECTS OF DEVELOPMENTAL EXPOSURE TO ENDOMETRIOSIS ARE REVEALING FOR THE FIRST TIME, IN BOTH FEMALE AND MALE OFFSPRING, TRANSGENERATIONAL SUBFERTILITY IN A RAT MODEL PROVIDING INSIGHTS INTO THE FAMILIAL NATURE OF ENDOMETRIOSIS AND POSSIBLE EPIGENETIC INVOLVEMENT. 2020 2 3820 32 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 3 5378 19 RECENT INSIGHTS ON THE GENETICS AND EPIGENETICS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A GYNECOLOGIC DISEASE AFFECTING UP TO 10% OF THE WOMEN AND A MAJOR CAUSE OF PAIN AND INFERTILITY. IT IS CHARACTERIZED BY THE IMPLANTATION OF FUNCTIONAL ENDOMETRIAL TISSUE AT ECTOPIC POSITIONS GENERALLY WITHIN THE PERITONEUM. THIS COMPLEX DISEASE HAS AN IMPORTANT GENETIC COMPONENT WITH A HERITABILITY ESTIMATED AT AROUND 50%. THIS REVIEW AIMS AT PROVIDING RECENT INSIGHTS INTO THE GENETIC BASES OF ENDOMETRIOSIS, AND PRESENTS A DETAILED OVERVIEW OF EVIDENCE OF EPIGENETIC ALTERATIONS SPECIFIC TO THIS DISEASE. IN THE FUTURE, THESE ALTERATIONS MAY CONSTITUTE THERAPEUTIC TARGETS FOR PHARMACOLOGICAL COMPOUNDS ABLE TO MODIFY THE EPIGENETIC CODE. 2017 4 4957 26 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 5 1892 26 ENDOMETRIOSIS: EPIDEMIOLOGY, CLASSIFICATION, PATHOGENESIS, TREATMENT AND GENETICS (REVIEW OF LITERATURE). ENDOMETRIOSIS IS A "MYSTERIOUS" DISEASE AND ITS EXACT CAUSE HAS NOT YET BEEN ESTABLISHED. AMONG THE ETIOLOGICAL FACTORS, CONGENITAL, ENVIRONMENTAL, EPIGENETIC, AUTOIMMUNE AND ALLERGIC FACTORS ARE LISTED. IT IS BELIEVED THAT THE PRIMARY MECHANISM OF THE FORMATION OF ENDOMETRIOSIS FOCI IS RETROGRADE MENSTRUATION, I.E., THE PASSAGE OF MENSTRUAL BLOOD THROUGH THE FALLOPIAN TUBES INTO THE PERITONEAL CAVITY AND IMPLANTATION OF EXFOLIATED ENDOMETRIAL CELLS. HOWEVER, SINCE THIS MECHANISM IS ALSO OBSERVED IN HEALTHY WOMEN, OTHER FACTORS MUST ALSO BE INVOLVED IN THE FORMATION OF ENDOMETRIOSIS FOCI. ENDOMETRIOSIS IS IN MANY WOMEN THE CAUSE OF INFERTILITY, CHRONIC PAIN AND THE DETERIORATION OF THE QUALITY OF LIFE. IT ALSO REPRESENTS A SIGNIFICANT FINANCIAL BURDEN ON HEALTH SYSTEMS. THE ARTICLE PRESENTS A REVIEW OF THE LITERATURE ON ENDOMETRIOSIS-A DISEASE AFFECTING WOMEN THROUGHOUT THE WORLD. 2021 6 6833 24 [HYPOTHETICAL LINK BETWEEN ENDOMETRIOSIS AND XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD]. ENDOMETRIOSIS IS AN OESTROGEN-DEPENDENT INFLAMMATORY DISEASE AFFECTING 10 % OF REPRODUCTIVE-AGED WOMEN. OFTEN ACCOMPANIED BY CHRONIC PELVIC PAIN AND INFERTILITY, ENDOMETRIOSIS RIGOROUSLY INTERFERES WITH WOMEN'S QUALITY OF LIFE. ALTHOUGH THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS REMAINS UNCLEAR, A GROWING BODY OF EVIDENCE POINTS TO THE IMPLICATION OF ENVIRONMENTAL TOXICANTS. OVER THE LAST DECADE, AN INCREASE IN THE INCIDENCE OF ENDOMETRIOSIS HAS BEEN REPORTED AND COINCIDES WITH THE INTRODUCTION OF GENETICALLY MODIFIED FOODS IN OUR DIET. EVEN THOUGH ASSESSMENTS OF GENETICALLY MODIFIED FOOD RISK HAVE NOT INDICATED ANY HAZARD ON HUMAN HEALTH, XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS PESTICIDES RESIDUES AND XENOPROTEINS, COULD BE HARMFUL IN THE LONG-TERM. THE "LOW-DOSE HYPOTHESIS", ACCUMULATION AND BIOTRANSFORMATION OF PESTICIDES-ASSOCIATED GENETICALLY MODIFIED FOOD AND THE MULTIPLIED TOXICITY OF PESTICIDES-FORMULATION ADJUVANTS SUPPORT THIS HYPOTHESIS. THIS REVIEW SUMMARIZES TOXIC EFFECTS (IN VITRO AND ON ANIMAL MODELS) OF SOME XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS GLYPHOSATE AND CRY1AB PROTEIN, AND EXTRAPOLATES ON THEIR POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. THEIR ROLES AS IMMUNE TOXICANTS, PRO-OXIDANTS, ENDOCRINE DISRUPTORS AND EPIGENETIC MODULATORS ARE DISCUSSED. 2010 7 5892 27 SYSTEMS GENETICS VIEW OF ENDOMETRIOSIS: A COMMON COMPLEX DISORDER. ENDOMETRIOSIS IS A CONDITION IN WHICH CELLS DERIVED FROM THE ENDOMETRIUM GROW OUTSIDE THE UTERUS, E.G. IN THE PERITONEUM (EXTERNAL GENITAL ENDOMETRIOSIS). AS THESE CELLS ARE UNDER THE INFLUENCE OF FEMALE HORMONES, MAJOR SYMPTOMS OF ENDOMETRIOSIS ARE PAIN, ESPECIALLY DURING THE CYCLE, AND INFERTILITY. NUMEROUS HYPOTHESES FOR THE FORMATION OF ENDOMETRIOSIS CAN BE FOUND IN THE LITERATURE, BUT THERE IS GROWING EVIDENCE OF SERIOUS GENETIC CONTRIBUTIONS TO ENDOMETRIOSIS SUSCEPTIBILITY. THE INVOLVEMENT OF GENES, STEROID HORMONE METABOLISM, IMMUNOLOGICAL REACTIONS, RECEPTOR FORMATION, INFLAMMATION, PROLIFERATION, APOPTOSIS, INTERCELLULAR ADHESION, CELL INVASION AND ANGIOGENESIS AS WELL AS GENES REGULATING THE ACTIVITY OF AFOREMENTIONED ENZYMES HAVE BEEN SUGGESTED. SOME MORE RECENTLY SUGGESTED CANDIDATE GENES PICKED UP IN GENOME-WIDE ASSOCIATION STUDIES ARE INVOLVED IN ONCOGENESIS, METAPLASIA OF ENDOMETRIUM CELLS AND PATHWAYS OF EMBRYONIC DEVELOPMENT OF THE FEMALE REPRODUCTIVE SYSTEM. HOWEVER, GENE MUTATIONS PROVEN TO BE CAUSATIVE FOR ENDOMETRIOSIS HAVE NOT BEEN IDENTIFIED SO FAR, EVEN THOUGH THE ABNORMAL EXPRESSION OF CANDIDATE GENES FOR ENDOMETRIOSIS COULD BE PROVOKED BY DIFFERENT EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HETEROCHROMATIZATION OR INTRODUCTION OF REGULATORY MIRNA. WE HYPOTHESIZE THAT ENDOMETRIOSIS IS INDUCED BY A COMBINATION OF ABNORMAL GENETIC AND/OR EPIGENETIC MUTATIONS: THE LATTER PAVE THE WAY FOR PATHOLOGICAL CHANGES WHICH BECOME IRREVERSIBLE, AND ACCORDING TO THE "EPIGENETIC LANDSCAPE" THEORY, THIS PROCEEDS TO THE TYPICAL CLINICAL MANIFESTATIONS. TWO STAGES IN THE ENDOMETRIOSIS PATHWAY ARE SUGGESTED: (1) INDUCTION OF PRIMARY ENDOMETRIAL CELLS TOWARD ENDOMETRIOSIS, AND (2) IMPLANTATION AND PROGRESSION OF THESE CELLS INTO ENDOMETRIOSIS LESIONS. THE MODEL FAVORS ENDOMETRIOSIS AS AN OUTGROWTH OF PRIMARY CELLS DIFFERENT IN THEIR ORIGIN, CANALIZATION OF PATHOLOGICAL PROCESSES, MANIFESTATION DIVERSITY PROVOKED BY UNIQUE GENETIC BACKGROUND AND EPIGENETIC INFLUENCES, WHICH RESULT IN MANY DIFFERENT CLINICAL FORMS OF THE DISEASE. 2015 8 4956 25 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 9 1403 19 DIETARY APPROACHES TO WOMEN'S SEXUAL AND REPRODUCTIVE HEALTH. OVER THE COURSE OF THE REPRODUCTIVE LIFE SPAN, IT IS COMMON FOR WOMEN TO EXPERIENCE ONE OR MORE OF THE MOST COMMON GYNECOLOGIC CONDITIONS, INCLUDING SEXUAL DYSFUNCTION, POLYCYSTIC OVARY SYNDROME, FIBROIDS, ENDOMETRIOSIS, AND INFERTILITY. ALTHOUGH CURRENT MANAGEMENT GUIDELINES OFTEN TURN TO THE ESTABLISHED PHARMACEUTICAL APPROACHES FOR EACH OF THESE DIAGNOSES, THE SCIENTIFIC LITERATURE ALSO SUPPORTS AN EVIDENCE-BASED APPROACH ROOTED IN THE PARADIGM OF FOOD AS MEDICINE. ACHIEVING HEALTHY DIETARY PATTERNS IS A CORE GOAL OF LIFESTYLE MEDICINE, AND A PLANT-FORWARD APPROACH AKIN TO THE MEDITERRANEAN DIET HOLDS GREAT PROMISE FOR IMPROVING MANY CHRONIC GYNECOLOGIC DISEASES. FURTHERMORE, CREATING AN OPTIMAL PRECONCEPTION ENVIRONMENT FROM A NUTRITIONAL STANDPOINT MAY FACILITATE EPIGENETIC SIGNALING, THUS IMPROVING THE HEALTH OF FUTURE GENERATIONS. THIS STATE-OF-THE-ART REVIEW EXPLORES THE LITERATURE CONNECTING DIET WITH SEXUAL AND REPRODUCTIVE HEALTH IN PREMENOPAUSAL WOMEN. 2021 10 1888 22 ENDOMETRIOSIS AND IN VITRO FERTILISATION. THE AIM OF THE PRESENT REVIEW WAS TO DISCUSS A MATTER OF CONCERN IN THE CLINICAL FIELD OF OBSTETRICS/GYNECOLOGY, NAMELY THE POTENCY OF IN VITRO FERTILIZATION (IVF) IN THE MANAGEMENT OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY. ENDOMETRIOSIS IS A MEDICAL CONDITION AFFECTING ONE TENTH OF WOMEN IN THEIR FERTILE YEARS, AND ACCOUNTS FOR UP TO 50% OF INFERTILE WOMEN. THUS, SUCH HIGH PREVALENCE HAS ESTABLISHED THE NECESSITY FOR INVESTIGATING THE EFFECTIVENESS OF AVAILABLE TECHNIQUES IN ERADICATING THE DISEASE AND CONSTRAINING INFERTILITY AS WELL AS THE ACCOMPANYING PAIN SYMPTOMS OF ENDOMETRIOSIS. THE UNDERLYING MECHANISMS CONNECTING ENDOMETRIOSIS WITH LOW FECUNDITY HAVE BEEN EXTENSIVELY STUDIED, BOTH IN TERMS OF GENETIC ALTERATIONS AND EPIGENETIC EVENTS THAT CONTRIBUTE TO THE MANIFESTATION OF AN INFERTILITY PHENOTYPE IN WOMEN WITH THE DISEASE. SEVERAL STUDIES HAVE DEALT WITH THE IMPACT OF IVF IN PREGNANCY RATES (PRS) ON PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY REGARDING WOMEN WHO WISH TO CONCEIVE. RESULTS RETRIEVED FROM STUDIES AND META-ANALYSES DEPICT A DIVERSE PATTERN OF IVF SUCCESS, UNDERLINING THE INVOLVEMENT OF INDIVIDUAL PARAMETERS IN THE CONFIGURATION OF THE FINAL OUTCOME. THE ULTIMATE DECISION ON UNDERGOING IVF TREATMENT SHOULD BE BASED ON OBJECTIVE CRITERIA AND CLINICIANS' EXPERIENCE, CUSTOMIZED ACCORDING TO PATIENTS' INDIVIDUAL NEEDS. 2018 11 6237 26 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 12 2086 29 EPIGENETIC DYSREGULATION IN ENDOMETRIOSIS: IMPLICATIONS FOR PATHOPHYSIOLOGY AND THERAPEUTICS. ENDOMETRIOSIS IS A PREVALENT GYNECOLOGICAL CONDITION ASSOCIATED WITH PELVIC PAIN AND INFERTILITY. DESPITE MORE THAN A CENTURY OF RESEARCH, THE ETIOLOGY OF ENDOMETRIOSIS STILL ELUDES SCIENTIFIC CONSENSUS. THIS LACK OF CLARITY HAS RESULTED IN SUBOPTIMAL PREVENTION, DIAGNOSIS, AND TREATMENT OPTIONS. EVIDENCE OF GENETIC CONTRIBUTORS TO ENDOMETRIOSIS IS INTERESTING BUT LIMITED; HOWEVER, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS IN IDENTIFYING EPIGENETIC ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS THROUGH CLINICAL STUDIES, IN VITRO CELL CULTURE EXPERIMENTS, AND IN VIVO ANIMAL MODELS. THE PREDOMINANT FINDINGS INCLUDE ENDOMETRIOSIS-RELATED DIFFERENTIAL EXPRESSION OF DNA METHYLTRANSFERASES AND DEMETHYLASES, HISTONE DEACETYLASES, METHYLTRANSFERASES, AND DEMETHYLASES, AND REGULATORS OF CHROMATIN ARCHITECTURE. THERE IS ALSO AN EMERGING ROLE FOR MIRNAS IN THE CONTROL OF EPIGENETIC REGULATORS IN THE ENDOMETRIUM AND ENDOMETRIOSIS. CHANGES IN THESE EPIGENETIC REGULATORS RESULT IN DIFFERENTIAL CHROMATIN ORGANIZATION AND DNA METHYLATION WITH CONSEQUENCES FOR GENE EXPRESSION INDEPENDENT OF A GENETIC SEQUENCE. EPIGENETICALLY ALTERED EXPRESSION OF GENES RELATED TO STEROID HORMONE PRODUCTION AND SIGNALING, IMMUNE REGULATION, AND ENDOMETRIAL CELL IDENTITY AND FUNCTION HAVE ALL BEEN IDENTIFIED AND APPEAR TO PLAY INTO THE PATHOPHYSIOLOGICAL MECHANISMS OF ENDOMETRIOSIS AS WELL AS RESULTING INFERTILITY. THIS REVIEW SUMMARIZES AND CRITICALLY DISCUSSES EARLY SEMINAL FINDINGS, THE EVER-GROWING RECENT EVIDENCE OF EPIGENETIC CONTRIBUTIONS TO THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS, AND IMPLICATIONS FOR PROPOSED EPIGENETICALLY TARGETED THERAPEUTICS. 2023 13 3743 32 INSIGHTS FROM GENOMIC STUDIES ON THE ROLE OF SEX STEROIDS IN THE AETIOLOGY OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC NEURO-INFLAMMATORY DISORDER THE DEFINING FEATURE OF WHICH IS THE GROWTH OF TISSUE (LESIONS) THAT RESEMBLES THE ENDOMETRIUM OUTSIDE THE UTERUS. ESTIMATES OF PREVALENCE QUOTE RATES OF ~10% OF WOMEN OF REPRODUCTIVE AGE, EQUATING TO AT LEAST 190 MILLION WOMEN WORLD-WIDE. GENETIC, HORMONAL AND IMMUNOLOGICAL FACTORS HAVE ALL BEEN PROPOSED AS CONTRIBUTING TO RISK FACTORS ASSOCIATED WITH THE DEVELOPMENT OF LESIONS. TWIN STUDIES REPORT THE HERITABLE COMPONENT OF ENDOMETRIOSIS AS ~50%. GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) THAT APPEAR OVER-REPRESENTED IN PATIENTS WITH ENDOMETRIOSIS, PARTICULARLY THOSE WITH MORE EXTENSIVE DISEASE (STAGE III/IV). IN DIFFERENT SAMPLE POPULATIONS, THERE HAS BEEN REPLICATION OF SNPS NEAR GENES INVOLVED IN OESTROGEN AND OTHER STEROID REGULATED PATHWAYS INCLUDING ESR1 (OESTROGEN RECEPTOR ALPHA), GREB1, HOXA10, WNT4 AND MAPK KINASE SIGNALLING. COMPARISONS WITH GWAS CONDUCTED ON OTHER PATIENT COHORTS HAVE FOUND LINKS WITH REPRODUCTIVE TRAITS (AGE AT MENARCHE) AND DISORDERS (FIBROIDS, ENDOMETRIAL AND OVARIAN CANCER) AND COMMON CO-MORBIDITIES (MIGRAINE, DEPRESSION, ASTHMA). IN SUMMARY, GENETIC ANALYSES HAVE PROVIDED NEW INSIGHTS INTO THE HORMONE-REGULATED PATHWAYS THAT MAY CONTRIBUTE TO INCREASED RISK OF DEVELOPING ENDOMETRIOSIS SOME OF WHICH MAY ACT IN EARLY LIFE. NEW STUDIES ARE NEEDED TO CLARIFY THE RELATIONSHIP BETWEEN THE MANY SNPS IDENTIFIED, THE GENES THAT THEY REGULATE AND THEIR CONTRIBUTION(S) TO DEVELOPMENT OF DIFFERENT FORMS OF ENDOMETRIOSIS. WE HOPE THAT MORE ADVANCED METHODS ALLOWING INTEGRATION BETWEEN GWAS, EPIGENETIC AND TISSUE EXPRESSION DATA WILL IMPROVE RISK ANALYSIS AND REDUCE DIAGNOSITIC DELAY. LAY SUMMARY: ENDOMETRIOSIS IS A DEBILITATING REPRODUCTIVE DISORDER AFFECTING ~10% OF REPRODUCTIVE-AGE WOMEN, AND THOSE ASSIGNED FEMALE AT BIRTH, WHICH CAUSES A RANGE OF SYMPTOMS INCLUDING CHRONIC PAIN AND INFERTILITY. THE REASON WHY SOME, BUT NOT ALL THESE INDIVIDUALS, DEVELOP THE LESIONS THAT CHARACTERISE THE DISEASE ARE POORLY UNDERSTOOD, BUT RECENTLY ATTENTION HAS FOCUSED ON GENETIC RISK FACTORS TO EXPLAIN WHY THE INCIDENCE IS HIGHER IN SOME FAMILIES. STUDIES ON LARGE COHORTS OF PATIENTS WITH COMPARISON OF THEIR DNA TO WOMEN WITHOUT ENDOMETRIOSIS OR WITH OTHER DISORDERS HAVE DOCUMENTED CHANGES IN GENES ASSOCIATED WITH STEROID HORMONE PRODUCTION OR ACTION. THE RESULTS PROVIDE FURTHER EVIDENCE THAT ENDOMETRIOSIS SHARES GENETIC RISK FACTORS WITH OTHER DISORDERS OF THE REPRODUCTIVE SYSTEM AND A PLATFORM FOR NEW IDEAS RELATED TO RISK, BIOMARKERS AND THERAPIES. 2022 14 4803 23 OBESITY AND MALE INFERTILITY. THE WORLDWIDE PREVALENCE OF OBESITY IS INCREASING AMONG BOTH SEXES, WITH ASSOCIATED IMPACTS ON CHRONIC HEALTH AND MEDICAL COMORBIDITIES. SIMILARLY, THE EFFECTS OF OBESITY ON REPRODUCTIVE HEALTH ARE INCREASINGLY BEING RECOGNIZED. ADIPOSITY IS ASSOCIATED WITH REDUCED FERTILITY IN MEN, WITH A COMPLEX AND MULTIFACTORIAL ETIOLOGY. THE REPORTED EFFECTS OF OBESITY ON SEMEN PARAMETERS AND IMPAIRED FERTILITY ARE CONTRASTING, WITH SOME STUDIES SHOWING A CLEAR REDUCTION IN REPRODUCTIVE OUTCOMES ASSOCIATED WITH INCREASED BODY MASS INDEX, WHILE OTHERS DO NOT SHOW SUCH IMPACTS. THESE CONTROVERSIES MAY BE DUE TO THE COMPLEX PATHOPHYSIOLOGY AND INTERPLAY BETWEEN GONADOTROPINS AND END ORGANS, AS WELL AS GENETIC AND EPIGENETIC CHANGES AND OXIDATIVE STRESS ON MALE FERTILITY AND FUNCTION. THESE DIFFERENT ASPECTS HAVE LED TO HETEROGENEOUS PARTICIPANTS IN STUDIES AND VARYING IMPLICATIONS FOR ASSISTED REPRODUCTIVE OUTCOMES AS WELL AS OFFSPRING HEALTH. TREATMENT MODALITIES TO MANAGE OBESITY INCLUDE LIFESTYLE, MEDICAL, AND SURGICAL OPTIONS, WITH EMERGING AND EFFECTIVE MEDICAL TREATMENTS SHOWING PROMISE IN REPRODUCTIVE OUTCOMES. 2023 15 1248 23 CURRENT EVIDENCE FOR BIOLOGICAL BIOMARKERS AND MECHANISMS UNDERLYING ACUTE TO CHRONIC PAIN TRANSITION ACROSS THE PEDIATRIC AGE SPECTRUM. CHRONIC PAIN IS HIGHLY PREVALENT IN THE PEDIATRIC POPULATION. MANY FACTORS ARE INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN. CURRENTLY, THERE ARE CONCEPTUAL MODELS PROPOSED, BUT THEY LACK A MECHANISTICALLY SOUND INTEGRATED THEORY CONSIDERING THE STAGES OF CHILD DEVELOPMENT. OBJECTIVE BIOMARKERS ARE CRITICALLY NEEDED FOR THE DIAGNOSIS, RISK STRATIFICATION, AND PROGNOSIS OF THE PATHOLOGICAL STAGES OF PAIN CHRONIFICATION. IN THIS ARTICLE, WE SUMMARIZE THE CURRENT EVIDENCE ON MECHANISMS AND BIOMARKERS OF ACUTE TO CHRONIC PAIN TRANSITIONS IN INFANTS AND CHILDREN THROUGH THE DEVELOPMENTAL LENS. THE GOAL IS TO IDENTIFY GAPS AND OUTLINE FUTURE DIRECTIONS FOR BASIC AND CLINICAL RESEARCH TOWARD A DEVELOPMENTALLY INFORMED THEORY OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. AT THE OUTSET, THE IMPORTANCE OF OBJECTIVE BIOMARKERS FOR CHRONIFICATION OF PAIN IN CHILDREN IS OUTLINED, FOLLOWED BY A SUMMARY OF THE CURRENT EVIDENCE ON THE MECHANISMS OF ACUTE TO CHRONIC PAIN TRANSITION IN ADULTS, IN ORDER TO CONTRAST WITH THE DEVELOPMENTAL MECHANISMS OF PAIN CHRONIFICATION IN THE PEDIATRIC POPULATION. EVIDENCE IS PRESENTED TO SHOW THAT CHRONIC PAIN MAY HAVE ITS ORIGIN FROM INSULTS EARLY IN LIFE, WHICH PRIME THE CHILD FOR THE DEVELOPMENT OF CHRONIC PAIN IN LATER LIFE. FURTHERMORE, AVAILABLE GENETIC, EPIGENETIC, PSYCHOPHYSICAL, ELECTROPHYSIOLOGICAL, NEUROIMAGING, NEUROIMMUNE, AND SEX MECHANISMS ARE DESCRIBED IN INFANTS AND OLDER CHILDREN. IN CONCLUSION, FUTURE DIRECTIONS ARE DISCUSSED WITH A FOCUS ON RESEARCH GAPS, TRANSLATIONAL AND CLINICAL IMPLICATIONS. UTILIZATION OF DEVELOPMENTAL MECHANISMS FRAMEWORK TO INFORM CLINICAL DECISION-MAKING AND STRATEGIES FOR PREVENTION AND MANAGEMENT OF ACUTE TO CHRONIC PAIN TRANSITIONS IN CHILDREN, IS HIGHLIGHTED. 2023 16 4435 28 MOLECULAR DYSREGULATIONS UNDERLYING THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A CRIPPLING DISEASE CHARACTERIZED BY THE PRESENCE OF ENDOMETRIUM-LIKE TISSUE OR SCAR OUTSIDE THE UTERINE CAVITY, COMMONLY CONFINED TO THE PERITONEAL AND SEROSAL SURFACES OF THE PELVIC ORGANS. 10-15% OF WOMEN IN REPRODUCTIVE AGE ARE ESTIMATED TO BE AFFECTED BY ENDOMETRIOSIS. MOST OF THESE PATIENTS PRESENT WITH INFERTILITY AND SUFFER FROM PELVIC PAIN. THE BENIGN DISEASE RARELY PROGRESSES TO MALIGNANCY. REGARDLESS OF ITS HIGH PREVALENCE, THE PATHOGENESIS OF THE DISEASE IS NOT FULLY UNDERSTOOD. TREATMENT OPTIONS FOR ENDOMETRIOSIS ARE LIMITED AND ARE OFTEN BASED ON A SYMPTOMATIC APPROACH. THE UNAVAILABILITY OF PROPER DIAGNOSTIC APPROACHES, FEWER THERAPEUTIC OPTIONS, AND SPARSE UNDERSTANDING OF MOLECULAR ALTERATIONS ARE RESPONSIBLE FOR THE CONTINUED DISEASE BURDEN. EXPLORING THE MOLECULAR ELEMENTS CAUSING THE PATHOGENESIS OF ENDOMETRIOSIS MAY LEAD TO A NUMBER OF BREAKTHROUGHS IN THE TREATMENT OF THE ILLNESS, SUCH AS THE DISCOVERY OF NEW BIOMARKERS FOR DIAGNOSIS AND THERAPEUTIC TARGETS THAT CAN BE A GUIDE TO BETTER PROGNOSIS AND REDUCED RECURRENCE. THE GOAL OF THIS REVIEW IS TO PROVIDE THE READER A CRITICAL UNDERSTANDING OF THE DISEASE BY SUMMARIZING THE GENETIC, IMMUNOLOGICAL, HORMONAL, AND EPIGENETIC DEREGULATIONS THAT SUPPORT THE MOLECULAR BASIS FOR DEVELOPMENT OF ENDOMETRIOTIC CYST, WITH A SPECIAL FOCUS ON THE STUDY MODELS NEEDED TO ANALYZE THESE CHANGES IN THE ENDOMETRIOTIC MICROENVIRONMENT. 2021 17 3821 19 INTRODUCTION: FROM PATHOGENESIS TO THERAPY, DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. DEEP ENDOMETRIOSIS REMAINS A SOURCE OF CONTROVERSY. A NUMBER OF THEORIES MAY EXPLAIN ITS PATHOGENESIS AND MANY ARGUMENTS SUPPORT THE HYPOTHESIS THAT GENETIC OR EPIGENETIC CHANGES ARE A PREREQUISITE FOR DEVELOPMENT OF LESIONS INTO DEEP ENDOMETRIOSIS. DEEP ENDOMETRIOSIS IS FREQUENTLY RESPONSIBLE FOR PELVIC PAIN, DYSMENORRHEA, AND/OR DEEP DYSPAREUNIA, BUT CAN ALSO CAUSE OBSTETRICAL COMPLICATIONS. DIAGNOSIS MAY BE IMPROVED BY HIGH-QUALITY IMAGING. THERAPEUTIC APPROACHES ARE A SOURCE OF CONTENTION AS WELL. IN THIS ISSUE'S VIEWS AND REVIEWS, MEDICAL AND SURGICAL STRATEGIES ARE DISCUSSED, AND IT IS EMPHASIZED THAT TREATMENT SHOULD BE DESIGNED ACCORDING TO A PATIENT'S SYMPTOMS AND INDIVIDUAL NEEDS. IT IS ALSO VITAL THAT REFERRAL CENTERS HAVE THE KNOWLEDGE AND EXPERIENCE TO TREAT DEEP ENDOMETRIOSIS MEDICALLY AND/OR SURGICALLY. THE DEBATE MUST CONTINUE BECAUSE EMERGING TRENDS IN THERAPY NEED TO BE FOLLOWED AND INVESTIGATED FOR OPTIMAL MANAGEMENT. 2017 18 5650 25 SEX DIFFERENCES IN THE DEVELOPMENT OF PHYSICAL AGGRESSION: AN INTERGENERATIONAL PERSPECTIVE AND IMPLICATIONS FOR PREVENTIVE INTERVENTIONS. THIS ARTICLE REVIEWS THE STATE OF KNOWLEDGE ON THE DEVELOPMENT OF CHRONIC PHYSICAL AGGRESSION (CPA), WITH THE AIM OF IDENTIFYING THE MOST EFFECTIVE PREVENTION STRATEGIES. WE SPECIFICALLY FOCUS ON THE EARLY DEVELOPMENT OF PHYSICAL AGGRESSION, ON SEX DIFFERENCES IN THE USE OF PHYSICAL AGGRESSION, AND ON THE TRANSMISSION OF BEHAVIOR PROBLEMS FROM ONE GENERATION TO THE OTHER. THE BODY OF RESEARCH ON THE DEVELOPMENT OF CPA FROM THE PAST THREE DECADES THAT WE REVIEW SHOWS INCREASING EVIDENCE THAT ITS PREVENTION REQUIRES A LONG-TERM BIOPSYCHOSOCIAL DEVELOPMENTAL APPROACH WHICH ALSO MUST INCLUDE AN INTERGENERATIONAL PERSPECTIVE. RECENT GENETIC AND EPIGENETIC RESEARCH HAS INDICATED THAT THERE ARE BOTH IMPORTANT GENETIC AND ENVIRONMENTAL EFFECTS ON GENE EXPRESSION WHICH START AT CONCEPTION. WE CONCLUDE THAT ONE OF THE MOST EFFECTIVE STRATEGIES TO BREAK THE INTERGENERATIONAL TRANSMISSION OF CPA INVOLVES GIVING LONG-TERM SUPPORT TO PREGNANT WOMEN WITH A HISTORY OF BEHAVIOR PROBLEMS, THEIR SPOUSE, AND THEIR OFFSPRING. 2019 19 3003 33 GENETIC, EPIGENETIC AND STEM CELL ALTERATIONS IN ENDOMETRIOSIS: NEW INSIGHTS AND POTENTIAL THERAPEUTIC PERSPECTIVES. HUMAN ENDOMETRIUM IS A HIGHLY DYNAMIC TISSUE, UNDERGOING PERIODIC GROWTH AND REGRESSION AT EACH MENSTRUAL CYCLE. ENDOMETRIOSIS IS A FREQUENT CHRONIC PATHOLOGICAL STATUS CHARACTERIZED BY ENDOMETRIAL TISSUE WITH AN ECTOPIC LOCALIZATION, CAUSING PELVIC PAIN AND INFERTILITY AND A VARIABLE CLINICAL PRESENTATION. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION IN APPROXIMATELY 1.0% OF AFFECTED WOMEN, WITH THE INVOLVEMENT OF MULTIPLE PATHWAYS OF DEVELOPMENT. INCREASING EVIDENCE SUPPORTS A KEY CONTRIBUTION OF DIFFERENT STEM/PROGENITOR CELL POPULATIONS NOT ONLY IN THE CYCLIC REGENERATION OF EUTOPIC ENDOMETRIUM, BUT ALSO IN THE PATHOGENESIS OF AT LEAST SOME TYPES OF ENDOMETRIOSIS. EVIDENCE HAS ARISEN FROM EXPERIMENTS IN ANIMAL MODELS OF DISEASE THROUGH DIFFERENT KINDS OF ASSAYS (INCLUDING CLONOGENICITY, THE LABEL-RETAINING CELL APPROACH, THE ANALYSIS OF UNDIFFERENTIATION MARKERS), AS WELL AS FROM DESCRIPTIVE STUDIES ON ECTOPIC AND EUTOPIC TISSUE SAMPLES HARVESTED FROM AFFECTED WOMEN. CHANGES IN STEM CELL POPULATIONS IN ENDOMETRIOTIC LESIONS ARE ASSOCIATED WITH GENETIC AND EPIGENETIC ALTERATIONS, INCLUDING IMBALANCE OF MIRNA EXPRESSION, HISTONE AND DNA MODIFICATIONS AND CHROMOSOMAL ABERRATIONS. THE PRESENT SHORT REVIEW MAINLY SUMMARIZES THE LATEST OBSERVATIONS CONTRIBUTING TO THE CURRENT KNOWLEDGE REGARDING THE PRESENCE AND THE POTENTIAL CONTRIBUTION OF STEM/PROGENITOR CELLS IN EUTOPIC ENDOMETRIUM AND THE AETIOLOGY OF ENDOMETRIOSIS, TOGETHER WITH A REPORT OF THE MOST RECENTLY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS IN ENDOMETRIOSIS. WE ALSO DESCRIBE THE POTENTIAL ADVANTAGES OF SINGLE CELL MOLECULAR PROFILING IN ENDOMETRIUM AND IN ENDOMETRIOTIC LESIONS. ALL THESE DATA CAN HAVE CLINICAL IMPLICATIONS AND PROVIDE A BASIS FOR NEW POTENTIAL THERAPEUTIC APPLICATIONS. 2014 20 6892 17 [SIGNIFICANCE OF PREVENTING DEVELOPMENTAL ORIGINS OF DISEASES IN IMPROVING POPULATION QUALITY]. MORE STUDIES SHOW THAT VARIOUS DISEASES, ESPECIALLY CHRONIC NON-INFECTIOUS DISEASES, HAVE DEVELOPMENTAL ORIGIN. DEVELOPMENTAL ORIGINS OF DISEASES ARE MAINLY DUE TO GAMETES AND EARLY LIFE DEVELOPMENT STAGE BEING EXPOSED TO ADVERSE ENVIRONMENT, RESULTING IN ABNORMAL MODIFICATION OF EPIGENETIC AND STABLE INHERITANCE TO THE ADULT STAGE, WHICH COULD MAKE THE RISK OF VARIOUS LONG-TERM DISEASES OF INDIVIDUALS HIGH. THE THEORY OF DEVELOPMENTAL ORIGIN PROVIDES A NEW PERSPECTIVE FOR THE OCCURRENCE AND DEVELOPMENT OF DISEASES, AND ALSO PROVIDES A THEORETICAL BASIS FOR DISEASE PREVENTION. ATTACHING IMPORTANCE TO MATERNAL AND CHILD HEALTH CARE AND LIFE-CYCLE MANAGEMENT IS CONDUCIVE TO THE PREVENTION OF DEVELOPMENTAL DISEASES AND IS OF GREAT SIGNIFICANCE TO THE IMPROVEMENT OF POPULATION QUALITY. 2023