1 5104 60 POLYCYSTIC OVARIAN SYNDROME. WOMEN WITH PCOS PRESENT WITH SIGNS OF CHRONIC ANOVULATION, HYPERANDROGENISM, AND METABOLIC ABNORMALITIES. THE NIH RECENTLY EMBRACED THE ROTTERDAM CRITERIA TO BROADLY IDENTIFY ALL THE PHENOTYPES OF PCOS. WOMEN WITH PCOS ARE OFTEN OBESE WITH INSULIN RESISTANCE AND HENCE HAVE AN INCREASED SUSCEPTIBILITY TO GLUCOSE INTOLERANCE AND TYPE 2 DIABETES. FUTURE RESEARCH SHOULD FOCUS ON THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS OF PCOS TO DEVELOP NEW THERAPIES TO ADDRESS THE PREVENTION OF THIS DISORDER AND ITS LONG-TERM COMPLICATIONS. 2015 2 3750 22 INSULIN RESISTANCE IN POLYCYSTIC OVARY SYNDROME ACROSS VARIOUS TISSUES: AN UPDATED REVIEW OF PATHOGENESIS, EVALUATION, AND TREATMENT. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON ENDOCRINE DISORDER CHARACTERIZED BY CHRONIC OVULATION DYSFUNCTION AND OVERABUNDANCE OF ANDROGENS; IT AFFECTS 6-20% OF WOMEN OF REPRODUCTIVE AGE. PCOS INVOLVES VARIOUS PATHOPHYSIOLOGICAL FACTORS, AND AFFECTED WOMEN USUALLY HAVE SIGNIFICANT INSULIN RESISTANCE (IR), WHICH IS A MAJOR CAUSE OF PCOS. IR AND COMPENSATORY HYPERINSULINAEMIA HAVE DIFFERING PATHOGENESES IN VARIOUS TISSUES, AND IR VARIES AMONG DIFFERENT PCOS PHENOTYPES. GENETIC AND EPIGENETIC CHANGES, HYPERANDROGENAEMIA, AND OBESITY AGGRAVATE IR. INSULIN SENSITIZATION DRUGS ARE A NEW TREATMENT MODALITY FOR PCOS. WE SEARCHED PUBMED, GOOGLE SCHOLAR, ELSEVIER, AND UPTODATE DATABASES IN THIS REVIEW, AND FOCUSED ON THE PATHOGENESIS OF IR IN WOMEN WITH PCOS AND THE PATHOPHYSIOLOGY OF IR IN VARIOUS TISSUES. IN ADDITION, THE REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE CURRENT PROGRESS IN THE EFFICACY OF INSULIN SENSITIZATION THERAPY IN THE MANAGEMENT OF PCOS, PROVIDING THE LATEST EVIDENCE FOR THE CLINICAL TREATMENT OF WOMEN WITH PCOS AND IR. 2023 3 4892 24 OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: OXIDATIVE STRESS IN POLYCYSTIC OVARY SYNDROME. IN BRIEF: A GENETIC, EPIGENETIC, AND ENVIRONMENTAL ASSOCIATION EXISTS BETWEEN OXIDATIVE STRESS (OS) AND POLYCYSTIC OVARY SYNDROME (PCOS), EXPRESSED IN A MULTIFACETED CLINICAL PROFILE. THIS REVIEW SUMMARIZES AND DISCUSSES THE ROLE OF OS IN THE PATHOGENESIS OF PCOS SYNDROME, FOCUSING ON METABOLIC, REPRODUCTIVE, AND CANCER COMPLICATIONS. ABSTRACT: OXIDATIVE STRESS (OS), AN IMBALANCE BETWEEN OXIDANTS AND ANTIOXIDANTS IN CELLS, IS ONE OF MANY FACTORS PLAYING ESSENTIAL ROLES IN THE PATHOGENESIS OF POLYCYSTIC OVARY SYNDROME (PCOS). PCOS IS DESCRIBED MAINLY AS A DISPROPORTION OF REPRODUCTIVE HORMONES, LEADING TO CHRONIC ANOVULATION AND INFERTILITY IN WOMEN. INTERESTINGLY, OS IN PCOS MAY BE ASSOCIATED WITH MANY DISORDERS AND DISEASES. THIS REVIEW FOCUSES ON CHARACTERISTIC MARKERS OF OS IN PCOS AND THE RELATIONSHIP BETWEEN OS AND PCOS RELATED TO INSULIN RESISTANCE (IR), HYPERANDROGENEMIA, OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND CANCER. INTERESTINGLY, IN PATIENTS WITH PCOS, AN INCREASE IN OXIDATIVE STATUS AND INSUFFICIENT COMPENSATION OF THE INCREASE IN ANTIOXIDANT STATUS BEFORE ANY CARDIOVASCULAR COMPLICATIONS ARE OBSERVED. MOREOVER, FREE RADICALS PROMOTE CARCINOGENESIS IN PCOS PATIENTS. HOWEVER, DESPITE THESE DATA, IT HAS NOT BEEN ESTABLISHED WHETHER OXYGEN STRESS INFLUENCES PCOS DEVELOPMENT OR A SECONDARY DISORDER RESULTING FROM HYPERGLYCEMIA, IR, AND CARDIOVASCULAR AND CANCER COMPLICATIONS IN WOMEN. 2022 4 5107 20 POLYCYSTIC OVARY SYNDROME: A BRAIN DISORDER CHARACTERIZED BY EATING PROBLEMS ORIGINATING DURING PUBERTY AND ADOLESCENCE. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE CONDITION ASSOCIATED WITH REPRODUCTIVE AND PSYCHIATRIC DISORDERS, AND WITH OBESITY. EATING DISORDERS, SUCH AS BULIMIA AND RECURRENT DIETING, ARE ALSO LINKED TO PCOS. THEY CAN LEAD TO THE EPIGENETIC DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS, THEREBY IMPACTING ON OVARIAN FOLLICULOGENESIS. WE POSTULATE THAT PCOS IS INDUCED BY PSYCHOLOGICAL DISTRESS AND EPISODES OF OVEREATING AND/OR DIETING DURING PUBERTY AND ADOLESCENCE, WHEN BODY DISSATISFACTION AND EMOTIONAL DISTRESS ARE OFTEN PRESENT. WE PROPOSE THAT UPREGULATED ACTIVATION OF THE CENTRAL HPG AXIS DURING THIS PERIOD CAN BE EPIGENETICALLY ALTERED BY PSYCHOLOGICAL STRESSORS AND BY BULIMIA/RECURRENT DIETING, WHICH ARE COMMON DURING ADOLESCENCE AND WHICH CAN LEAD TO PCOS. THIS HYPOTHESIS IS BASED ON EVENTS THAT OCCUR DURING A LARGELY NEGLECTED STAGE OF FEMALE REPRODUCTIVE DEVELOPMENT. TO DATE, MOST RESEARCH INTO THE ORIGINS OF PCOS HAS FOCUSED ON THE PRENATAL INDUCTION OF THIS DISORDER, PARTICULARLY IN UTERO ANDROGENIZATION AND THE ROLE OF ANTI-MULLERIAN HORMONE. ESTABLISHING CAUSALITY IN OUR PERIPUBERTAL MODEL REQUIRES PROSPECTIVE COHORT STUDIES FROM INFANCY. MECHANISTIC STUDIES SHOULD CONSIDER THE ROLE OF THE GUT MICROBIOTA IN ADDITION TO THE EPIGENETIC REGULATION OF (NEURO) HORMONES. FINALLY, CLINICIANS SHOULD CONSIDER THE IMPORTANCE OF UNDERLYING CHRONIC PSYCHOLOGICAL DISTRESS AND EATING DISORDERS IN PCOS. 2020 5 4723 18 NONHUMAN PRIMATE MODELS OF POLYCYSTIC OVARY SYNDROME. WITH CLOSE GENOMIC AND PHENOTYPIC SIMILARITY TO HUMANS, NONHUMAN PRIMATE MODELS PROVIDE COMPREHENSIVE EPIGENETIC MIMICS OF POLYCYSTIC OVARY SYNDROME (PCOS), SUGGESTING EARLY LIFE TARGETING FOR PREVENTION. FETAL EXPOSURE TO TESTOSTERONE (T), OF ALL NONHUMAN PRIMATE EMULATIONS, PROVIDES THE CLOSEST PCOS-LIKE PHENOTYPES, WITH EARLY-TO-MID GESTATION T-EXPOSED FEMALE RHESUS MONKEYS EXHIBITING ADULT REPRODUCTIVE, ENDOCRINOLOGICAL AND METABOLIC DYSFUNCTIONAL TRAITS THAT ARE CO-PATHOLOGIES OF PCOS. LATE GESTATIONAL T EXPOSURE, WHILE INDUCING ADULT OVARIAN HYPERANDROGENISM AND MENSTRUAL ABNORMALITIES, HAS LESS DYSFUNCTIONAL METABOLIC ACCOMPANIMENT. FETAL EXPOSURES TO DIHYDROTESTOSTERONE (DHT) OR DIETHYLSTILBESTROL (DES) SUGGEST ANDROGENIC AND ESTROGENIC ASPECTS OF FETAL PROGRAMMING. NEONATAL EXPOSURE TO T PRODUCES NO PCOS-LIKE OUTCOME, WHILE CONTINUOUS T TREATMENT OF JUVENILE FEMALES CAUSES PRECOCIOUS WEIGHT GAIN AND EARLY MENARCHE (HIGH T), OR HIGH LH AND WEIGHT GAIN (MODERATE T). ACUTE T EXPOSURE OF ADULT FEMALES GENERATES POLYFOLLICULAR OVARIES, WHILE CHRONIC T EXPOSURE INDUCES SUBTLE MENSTRUAL IRREGULARITIES WITHOUT METABOLIC DYSFUNCTION. 2013 6 4403 21 MODULATION OF THE INFLAMMATORY RESPONSE IN POLYCYSTIC OVARY SYNDROME (PCOS)-SEARCHING FOR EPIGENETIC FACTORS. POLYCYSTIC OVARY SYNDROME (PCOS) IS THE MOST COMMON ENDOCRINE DISORDER IN WOMEN OF REPRODUCTIVE AGE. DESPITE ITS INCIDENCE, THE SYNDROME IS POORLY UNDERSTOOD AND REMAINS UNDERDIAGNOSED, AND FEMALE PATIENTS ARE DIAGNOSED WITH A DELAY. THE HETEROGENOUS NATURE OF THIS COMPLEX DISORDER RESULTS FROM THE COMBINED OCCURRENCE OF GENETIC, ENVIRONMENTAL, ENDOCRINE, AND BEHAVIORAL FACTORS. PRIMARY CLINICAL MANIFESTATIONS OF PCOS ARE DERIVED FROM THE EXCESS OF ANDROGENS (ANOVULATION, POLYCYSTIC OVARY MORPHOLOGY, LACK OF OR SCANTY, IRREGULAR MENSTRUAL PERIODS, ACNE AND HIRSUTISM), WHEREAS THE SECONDARY MANIFESTATIONS INCLUDE MULTIPLE METABOLIC, CARDIOVASCULAR, AND PSYCHOLOGICAL DISORDERS. DIETARY AND LIFESTYLE FACTORS PLAY IMPORTANT ROLES IN THE DEVELOPMENT AND COURSE OF PCOS, WHICH SUGGESTS STRONG EPIGENETIC AND ENVIRONMENTAL INFLUENCES. MANY STUDIES HAVE SHOWN A STRONG ASSOCIATION BETWEEN PCOS AND CHRONIC, LOW-GRADE INFLAMMATION BOTH IN THE OVARIAN TISSUE AND THROUGHOUT THE BODY. IN THE VAST MAJORITY OF PCOS PATIENTS, ELEVATED VALUES OF INFLAMMATORY MARKERS OR THEIR GENE MARKERS HAVE BEEN REPORTED. DEVELOPMENT OF THE VICIOUS CYCLE OF THE CHRONIC INFLAMMATORY STATE IN PCOS IS ADDITIONALLY STIMULATED BY HYPERINSULINEMIA AND OBESITY. CHANGES IN DNA METHYLATION, HISTONE ACETYLATION AND NONCODING RNA LEVELS ARE PRESENTED IN THIS REVIEW IN THE CONTEXT OF OXIDATIVE STRESS, REACTIVE OXYGEN SPECIES, AND INFLAMMATORY SIGNALING IN PCOS. EPIGENETIC MODULATION OF ANDROGENIC ACTIVITY IN RESPONSE TO INFLAMMATORY SIGNALING IS ALSO DISCUSSED. 2022 7 5105 29 POLYCYSTIC OVARIAN SYNDROME: A COMPLEX DISEASE WITH A GENETICS APPROACH. POLYCYSTIC OVARIAN SYNDROME (PCOS) IS A COMPLEX ENDOCRINE DISORDER AFFECTING FEMALES IN THEIR REPRODUCTIVE AGE. THE EARLY DIAGNOSIS OF PCOS IS COMPLICATED AND COMPLEX DUE TO OVERLAPPING SYMPTOMS OF THIS DISEASE. THE MOST ACCEPTED DIAGNOSTIC APPROACH TODAY IS THE ROTTERDAM CONSENSUS (2003), WHICH SUPPORTS THE POSITIVE DIAGNOSIS OF PCOS WHEN PATIENTS PRESENT TWO OUT OF THE FOLLOWING THREE SYMPTOMS: BIOCHEMICAL AND CLINICAL SIGNS OF HYPERANDROGENISM, OLIGO, AND ANOVULATION, ALSO POLYCYSTIC OVARIAN MORPHOLOGY ON SONOGRAPHY. GENETIC VARIANCE, EPIGENETIC CHANGES, AND DISTURBED LIFESTYLE LEAD TO THE DEVELOPMENT OF PATHOPHYSIOLOGICAL DISTURBANCES, WHICH INCLUDE HYPERANDROGENISM, INSULIN RESISTANCE, AND CHRONIC INFLAMMATION IN PCOS FEMALES. AT THE MOLECULAR LEVEL, DIFFERENT PROTEINS AND MOLECULAR AND SIGNALING PATHWAYS ARE INVOLVED IN DISEASE PROGRESSION, WHICH LEADS TO THE FAILURE OF A SINGLE GENETIC DIAGNOSTIC APPROACH. THE GENETIC APPROACH TO ELUCIDATE THE MECHANISM OF PATHOGENESIS OF PCOS WAS RECENTLY DEVELOPED, WHEREBY FOUR PHENOTYPIC VARIANCES OF PCOS CATEGORIZE PCOS PATIENTS INTO CLASSIC, OVULATORY, AND NON-HYPERANDROGENIC TYPES. GENETIC STUDIES HELP TO IDENTIFY THE ROOT CAUSE FOR THE DEVELOPMENT OF THIS PCOS. PCOS GENETIC INHERITANCE IS AUTOSOMAL DOMINANT BUT THE LATEST INVESTIGATIONS REVEALED IT AS A MULTIGENE ORIGIN DISEASE. DIFFERENT GENETIC LOCI AND SPECIFIC GENES HAVE BEEN IDENTIFIED SO FAR AS BEING ASSOCIATED WITH THIS DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND RELATED GENETIC STUDIES HAVE CHANGED THE SCENARIO FOR THE DIAGNOSIS AND TREATMENT OF THIS REPRODUCTIVE AND METABOLIC CONDITION KNOWN AS PCOS. THIS REVIEW ARTICLE BRIEFLY DISCUSSES DIFFERENT GENES ASSOCIATED DIRECTLY OR INDIRECTLY WITH DISEASE DEVELOPMENT AND PROGRESSION. 2022 8 4973 26 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 9 1834 23 EFFECTS OF MINDFULNESS-BASED THERAPY ON CLINICAL SYMPTOMS AND DNA METHYLATION IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME AND HIGH METABOLIC RISK. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE AND METABOLIC DISORDER AFFECTING WOMEN OF REPRODUCTIVE AGE. RESEARCH HAS SHOWN THAT EPIGENETIC ALTERATIONS SUCH AS DNA METHYLATION MAY PLAY A ROLE IN THE DEVELOPMENT AND PROGRESSION OF ABNORMAL OVARIAN FUNCTION AND METABOLIC DISORDERS IN PCOS. STUDIES HAVE IDENTIFIED SPECIFIC GENES (RELATED WITH INSULIN SIGNALING AND STEROID HORMONE METABOLISM) THAT ARE METHYLATED IN WOMEN WITH PCOS. DNA METHYLATION APPEARS TO RESPOND TO VARIOUS INTERVENTIONS AIMED AT ALTERING HEALTH AND LIFESTYLE FACTORS. WE TESTED THE EFFICACY OF A MINDFULNESS-BASED STRESS REDUCTION PROGRAM (MBSR) IN PCOS PATIENTS. WE EXAMINED ITS EFFECTS ON ANTHROPOMETRIC MEASUREMENTS, MENTAL HEALTH AND WELLBEING, AND ALTERATIONS IN DNA METHYLATION IN PERIPHERAL BLOOD. MBSR WAS ASSOCIATED WITH A REDUCTION IN BODY MASS INDEX, WAIST CIRCUMFERENCE AND BLOOD GLUCOSE LEVEL, AN IMPROVEMENT IN SUBJECTIVELY PERCEIVED GENERAL HEALTH, EMOTIONAL ROLE LIMITATION, AND LEVELS OF PAIN, AS WELL AS MINDFULNESS-LIKE TRAITS. MBSR REDUCED THE EXPRESSION OF ANXIOUS SYMPTOMATOLOGY AND SUBJECTIVELY PERCEIVED STRESS. METHYLATION CHANGES WERE OBSERVED IN FOUR GENES: COMT, FST, FKBP51, AND MAOA. WE CONCLUDE THAT MBSR MAY BE A USEFUL SUPPLEMENTARY THERAPY TO MITIGATE THE DELETERIOUS EFFECTS OF PCOS ON MENTAL HEALTH. 2023 10 3916 17 LINE1 CPG-DNA HYPOMETHYLATION IN GRANULOSA CELLS AND BLOOD LEUKOCYTES IS ASSOCIATED WITH PCOS AND RELATED TRAITS. CONTEXT: ALTERED GLOBAL DNA METHYLATION IS INDICATIVE OF EPIGENOMIC INSTABILITY CONCERNING CHRONIC DISEASES. INVESTIGATING ITS INCIDENCE AND ASSOCIATION WITH POLYCYSTIC OVARY SYNDROME (PCOS) IS ESSENTIAL TO UNDERSTAND THE ETIOPATHOGENESIS OF THIS DISORDER. OBJECTIVES: WE ASSESSED GLOBAL DNA METHYLATION DIFFERENCES IN PERIPHERAL BLOOD LEUKOCYTES (PBLS) AND CUMULUS GRANULOSA CELLS (CGCS) OF CONTROLS AND WOMEN WITH PCOS; AND THEIR ASSOCIATION WITH PCOS AND ITS TRAITS. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURE: THIS STUDY INCLUDED A TOTAL OF 102 CONTROLS AND WOMEN WITH PCOS. FORTY-ONE WOMEN UNDERGOING CONTROLLED OVARIAN HYPERSTIMULATION (COH) AND 61 WOMEN NOT UNDERGOING COH WERE RECRUITED FROM IN VITRO FERTILIZATION (IVF) AND INFERTILITY CLINICS. DNA METHYLATION WAS MEASURED BY ELISA FOR 5'-METHYL-CYTOSINE CONTENT AND BISULFITE SEQUENCING OF 5'-UNTRANSLATED REGION (5'-UTR) OF LONG INTERSPERSED NUCLEOTIDE ELEMENT-1 (LINE1/L1). RESULTS: TOTAL 5'-METHYL-CYTOSINE AND L1 METHYLATION LEVELS IN PBLS AND CGCS WERE SIMILAR BETWEEN CONTROLS AND WOMEN WITH PCOS. METHYLATION ASSESSED AT CPG SITES OF L1 5'-UTR REVEALED A SINGLE CPG-SITE (CPG-4) TO BE CONSISTENTLY HYPOMETHYLATED IN PBLS OF BOTH PCOS GROUPS AND CGCS OF STIMULATED PCOS GROUP. IN UNSTIMULATED WOMEN, HYPOMETHYLATION AT CPG-4 WAS STRONGLY ASSOCIATED WITH PCOS SUSCEPTIBILITY, WHEREAS IN STIMULATED GROUP IT SHOWED STRONG ASSOCIATIONS WITH PCOS AND ITS HORMONAL TRAITS. FURTHERMORE, CGCS DEMONSTRATED CONSISTENT GLOBAL AND CPG-DNA HYPOMETHYLATION RELATIVE TO PBLS, IRRESPECTIVE OF NORMAL OR DISEASE STATES. CONCLUSION: OUR STUDY REVEALED STRONG ASSOCIATION OF SINGLE HYPOMETHYLATED CPG-SITE WITH PCOS. IDENTIFICATION AND CHARACTERIZATION OF MORE SUCH METHYL-CPG SIGNATURES IN REPETITIVE ELEMENTS IN LARGER STUDY POPULATIONS WOULD PROVIDE VALUABLE EPIGENETIC INSIGHTS INTO PCOS. 2017 11 2205 21 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES. 2006 12 4068 18 MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. MATERNAL POLYCYSTIC OVARY SYNDROME (PCOS), A CONDITION ASSOCIATED WITH HYPERANDROGENISM, IS SUGGESTED TO INCREASE ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. BECAUSE PCOS IS CLOSELY LINKED TO OBESITY, WE INVESTIGATED THE IMPACT OF AN ADVERSE HORMONAL OR METABOLIC MATERNAL ENVIRONMENT AND OFFSPRING OBESITY ON ANXIETY IN THE OFFSPRING. THE OBESE PCOS PHENOTYPE WAS INDUCED BY CHRONIC HIGH-FAT-HIGH-SUCROSE (HFHS) CONSUMPTION TOGETHER WITH PRENATAL DIHYDROTESTOSTERONE EXPOSURE IN MOUSE DAMS. ANXIETY-LIKE BEHAVIOR WAS ASSESSED IN ADULT OFFSPRING WITH THE ELEVATED-PLUS MAZE AND OPEN-FIELD TESTS. THE INFLUENCE OF MATERNAL ANDROGENS AND MATERNAL AND OFFSPRING DIET ON GENES IMPLICATED IN ANXIETY WERE ANALYZED IN THE AMYGDALA AND HYPOTHALAMUS WITH REAL-TIME PCR ( N = 47). INDEPENDENT OF DIET, FEMALE OFFSPRING EXPOSED TO MATERNAL ANDROGENS WERE MORE ANXIOUS AND DISPLAYED UP-REGULATION OF ADRENOCEPTOR ALPHA 1B IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE ( CRH). BY CONTRAST, MALE OFFSPRING EXPOSED TO A HFHS MATERNAL DIET HAD INCREASED ANXIETY-LIKE BEHAVIOR AND SHOWED UP-REGULATION OF EPIGENETIC MARKERS IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CRH. OVERALL, THERE WERE SUBSTANTIAL SEX DIFFERENCES IN GENE EXPRESSION IN THE BRAIN. THESE FINDINGS PROVIDE NOVEL INSIGHT INTO HOW MATERNAL ANDROGENS AND OBESITY EXERT SEX-SPECIFIC EFFECTS ON BEHAVIOR AND GENE EXPRESSION IN THE OFFSPRING OF A PCOS MOUSE MODEL.-MANTI, M., FORNES, R., QI, X., FOLMERZ, E., LINDEN HIRSCHBERG, A., DE CASTRO BARBOSA, T., MALIQUEO, M., BENRICK, A., STENER-VICTORIN, E. MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. 2018 13 3085 14 GENOME-WIDE SCREEN OF OVARY-SPECIFIC DNA METHYLATION IN POLYCYSTIC OVARY SYNDROME. OBJECTIVE: TO COMPARE GENOME-WIDE DNA METHYLATION PROFILES IN OVARY TISSUE FROM WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS) AND HEALTHY CONTROLS. DESIGN: CASE-CONTROL STUDY MATCHED FOR AGE AND BODY MASS INDEX. SETTING: UNIVERSITY-AFFILIATED HOSPITAL. PATIENT(S): TEN WOMEN WITH PCOS WHO UNDERWENT OVARIAN DRILLING TO INDUCE OVULATION AND 10 HEALTHY WOMEN WHO WERE UNDERGOING LAPAROSCOPIC STERILIZATION, HYSTERECTOMY FOR BENIGN CONDITIONS, DIAGNOSTIC LAPAROSCOPY FOR PELVIC PAIN, OR OOPHORECTOMY FOR NONOVARIAN INDICATIONS. INTERVENTION(S): NONE. MAIN OUTCOME MEASURE(S): GENOME-WIDE DNA METHYLATION PATTERNS DETERMINED BY IMMUNOPRECIPITATION AND MICROARRAY (MEDIP-CHIP) ANALYSIS. RESULT(S): THE METHYLATION LEVELS WERE STATISTICALLY SIGNIFICANTLY HIGHER IN CPG ISLAND SHORES (CGI SHORES), WHICH LIE OUTSIDE OF CORE PROMOTER REGIONS, AND LOWER WITHIN GENE BODIES IN WOMEN WITH PCOS RELATIVE TO THE CONTROLS. IN ADDITION, HIGH CPG CONTENT PROMOTERS WERE THE MOST FREQUENTLY HYPERMETHYLATED PROMOTERS IN PCOS OVARIES BUT WERE MORE OFTEN HYPOMETHYLATED IN CONTROLS. SECOND, 872 CGIS, SPECIFICALLY METHYLATED IN PCOS, REPRESENTED 342 GENES THAT COULD BE ASSOCIATED WITH VARIOUS MOLECULAR FUNCTIONS, INCLUDING PROTEIN BINDING, HORMONE ACTIVITY, AND TRANSCRIPTION REGULATOR ACTIVITY. FINALLY, METHYLATION DIFFERENCES WERE VALIDATED IN SEVEN GENES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THESE GENES CORRELATED TO SEVERAL FUNCTIONAL FAMILIES RELATED TO THE PATHOGENESIS OF PCOS AND MAY BE POTENTIAL BIOMARKERS FOR THIS DISEASE. CONCLUSION(S): OUR RESULTS DEMONSTRATED THAT EPIGENETIC MODIFICATION DIFFERS BETWEEN PCOS AND NORMAL OVARIES, WHICH MAY HELP TO FURTHER UNDERSTAND THE PATHOPHYSIOLOGY OF THIS DISEASE. 2015 14 5106 21 POLYCYSTIC OVARY SYNDROME IN ADULT WOMEN. POLYCYSTIC OVARY SYNDROME IS THE MOST PREVALENT ENDOCRINE-METABOLIC PATHOLOGY IN PRE-MENOPAUSAL WOMEN. ITS ETIOPATHOGENESIS IS COMPLEX, MULTIFACTORIAL AND HETEROGENEOUS, INCLUDING THE INTERACTION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ANDROGENIC EXCESS CONSTITUTES THE DISEASE'S MAIN PHYSIOPATHOLOGICAL MECHANISM AND RESULTS IN REPRODUCTIVE, METABOLIC AND COSMETIC ALTERATIONS WHICH NEGATIVELY IMPACT THESE PATIENTS' QUALITY OF LIFE. THE CRITERIA ESTABLISHED IN THE ROTTERDAM CONSENSUS AND THEIR CORRECT APPLICATION FORM THE NECESSARY BASIS FOR THIS SYNDROME'S PROPER DIAGNOSIS. IN THE ABSENCE OF AN AETIOLOGICAL TREATMENT, THE AIM IS TO IMPROVE THE CLINICAL SIGNS AND SYMPTOMS DERIVED FROM HYPERANDROGENISM, OVARIAN DYSFUNCTION AND EXISTING METABOLIC COMPLICATIONS, AND, THEREFORE, THEY MUST BE CHRONIC AND INDIVIDUALISED. 2019 15 5878 18 SYNERGISTIC EFFECTS OF HYPERANDROGENEMIA AND OBESOGENIC WESTERN-STYLE DIET ON TRANSCRIPTION AND DNA METHYLATION IN VISCERAL ADIPOSE TISSUE OF NONHUMAN PRIMATES. POLYCYSTIC OVARY SYNDROME (PCOS) IS A MAJOR REPRODUCTIVE DISORDER THAT IS RESPONSIBLE FOR 80% OF ANOVULATORY INFERTILITY AND THAT IS ASSOCIATED WITH HYPERANDROGENEMIA, INCREASED RISK OF OBESITY, AND WHITE ADIPOSE TISSUE (WAT) DYSFUNCTION. WE HAVE PREVIOUSLY DEMONSTRATED THAT THE COMBINATION OF CHRONIC TESTOSTERONE (T) TREATMENT AND AN OBESOGENIC WESTERN-STYLE DIET (WSD) EXERTS SYNERGISTIC FUNCTIONAL EFFECTS ON WAT, LEADING TO INCREASED LIPID ACCUMULATION IN VISCERAL ADIPOCYTES BY AN UNKNOWN MECHANISM. IN THIS STUDY, WE EXAMINED THE WHOLE-GENOME TRANSCRIPTIONAL RESPONSE IN VISCERAL WAT TO T AND WSD, ALONE AND IN COMBINATION. WE OBSERVED A SYNERGISTIC EFFECT OF T AND WSD ON GENE EXPRESSION, RESULTING IN UPREGULATION OF LIPID STORAGE GENES CONCOMITANT WITH ADIPOCYTE HYPERTROPHY. BECAUSE DNA METHYLATION IS KNOWN TO BE ASSOCIATED WITH BODY FAT DISTRIBUTION AND THE ETIOLOGY OF PCOS, WE CONDUCTED WHOLE-GENOME DNA METHYLATION ANALYSIS OF VISCERAL WAT. WHILE ONLY A FRACTION OF DIFFERENTIALLY EXPRESSED GENES ALSO EXHIBITED DIFFERENTIAL DNA METHYLATION, IN SILICO ANALYSIS SHOWED THAT DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN TRANSCRIPTION FACTOR BINDING MOTIFS, SUGGESTING A POTENTIAL GENE REGULATORY ROLE FOR THESE REGIONS. IN SUMMARY, THIS STUDY DEMONSTRATES THAT HYPERANDROGENEMIA ALONE DOES NOT INDUCE GLOBAL TRANSCRIPTIONAL AND EPIGENETIC RESPONSE IN YOUNG FEMALE MACAQUES UNLESS COMBINED WITH AN OBESOGENIC DIET. 2019 16 420 22 ANDROGEN-MEDIATED PERTURBATION OF THE HEPATIC CIRCADIAN SYSTEM THROUGH EPIGENETIC MODULATION PROMOTES NAFLD IN PCOS MICE. IN WOMEN, EXCESS ANDROGEN CAUSES POLYCYSTIC OVARY SYNDROME (PCOS), A COMMON FERTILITY DISORDER WITH COMORBID METABOLIC DYSFUNCTIONS INCLUDING DIABETES, OBESITY, AND NONALCOHOLIC FATTY LIVER DISEASE. USING A PCOS MOUSE MODEL, THIS STUDY SHOWS THAT CHRONIC HIGH ANDROGEN LEVELS CAUSE HEPATIC STEATOSIS WHILE HEPATOCYTE-SPECIFIC ANDROGEN RECEPTOR (AR)-KNOCKOUT RESCUES THIS PHENOTYPE. MOREOVER, THROUGH RNA-SEQUENCING AND METABOLOMIC STUDIES, WE HAVE IDENTIFIED KEY METABOLIC GENES AND PATHWAYS AFFECTED BY HYPERANDROGENISM. OUR STUDIES REVEAL THAT A LARGE NUMBER OF METABOLIC GENES ARE DIRECTLY REGULATED BY ANDROGENS THROUGH AR BINDING TO ANDROGEN RESPONSE ELEMENT SEQUENCES ON THE PROMOTER REGION OF THESE GENES. INTERESTINGLY, A NUMBER OF CIRCADIAN GENES ARE ALSO DIFFERENTIALLY REGULATED BY ANDROGENS. IN VIVO AND IN VITRO STUDIES USING A CIRCADIAN REPORTER [PERIOD2::LUCIFERASE (PER2::LUC)] MOUSE MODEL DEMONSTRATE THAT ANDROGENS CAN DIRECTLY DISRUPT THE HEPATIC TIMING SYSTEM, WHICH IS A KEY REGULATOR OF LIVER METABOLISM. CONSEQUENTLY, STUDIES SHOW THAT ANDROGENS DECREASE H3K27ME3, A GENE SILENCING MARK ON THE PROMOTER OF CORE CLOCK GENES, BY INHIBITING THE EXPRESSION OF HISTONE METHYLTRANSFERASE, EZH2, WHILE INDUCING THE EXPRESSION OF THE HISTONE DEMETHYLASE, JMJD3, WHICH IS RESPONSIBLE FOR ADDING AND REMOVING THE H3K27ME3 MARK, RESPECTIVELY. FINALLY, WE REPORT THAT UNDER HYPERANDROGENIC CONDITIONS, SOME OF THE SAME CIRCADIAN/METABOLIC GENES THAT ARE UPREGULATED IN THE MOUSE LIVER ARE ALSO ELEVATED IN NONHUMAN PRIMATE LIVERS. IN SUMMARY, THESE STUDIES NOT ONLY PROVIDE AN OVERALL UNDERSTANDING OF HOW HYPERANDROGENISM ASSOCIATED WITH PCOS AFFECTS LIVER GENE EXPRESSION AND METABOLISM BUT ALSO OFFER INSIGHT INTO THE UNDERLYING MECHANISMS LEADING TO HEPATIC STEATOSIS IN PCOS. 2022 17 259 24 ADVANCES IN PCOS PATHOGENESIS AND PROGRESSION-MITOCHONDRIAL MUTATIONS AND DYSFUNCTION. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON FEMALE ENDOCRINE DISORDER, WHICH STILL REMAINS LARGELY UNSOLVED IN TERMS OF ETIOLOGY AND PATHOGENESIS DESPITE IMPORTANT ADVANCES IN OUR UNDERSTANDING OF ITS GENETIC, EPIGENETIC, OR ENVIRONMENTAL FACTOR IMPLICATIONS. IT IS A HETEROGENEOUS DISEASE, FREQUENTLY ASSOCIATED WITH INSULIN RESISTANCE, CHRONIC INFLAMMATION, AND OXIDATIVE STRESS AND PROBABLY ACCOMPANIED WITH SUBCLINICAL CARDIOVASCULAR DISEASE (CVD) AND SOME MALIGNANT LESIONS AS WELL, SUCH AS ENDOMETRIAL CANCER. DISCREPANCIES IN THE CLINICAL PHENOTYPE AND PROGRESSION OF PCOS EXIST BETWEEN DIFFERENT POPULATION GROUPS, WHICH NUCLEAR GENETIC STUDIES HAVE SO FAR FAILED TO EXPLAIN. OVER THE LAST YEARS, MITOCHONDRIAL DYSFUNCTION HAS BEEN INCREASINGLY RECOGNIZED AS AN IMPORTANT CONTRIBUTOR TO AN ARRAY OF DISEASES. BECAUSE MITOCHONDRIA ARE UNDER THE DUAL GENETIC CONTROL OF BOTH THE MITOCHONDRIAL AND NUCLEAR GENOMES, MUTATIONS WITHIN EITHER DNA MOLECULE MAY RESULT IN DEFICIENCY IN RESPIRATORY CHAIN FUNCTION THAT LEADS TO A REDUCED ABILITY TO PRODUCE CELLULAR ADENOSINE-5'-TRIPHOSPHATE AND TO AN EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES. HOWEVER, THE ASSOCIATION BETWEEN VARIANTS IN MITOCHONDRIAL GENOME, MITOCHONDRIAL DYSFUNCTION, AND PCOS HAS BEEN INVESTIGATED TO A LESSER EXTENT. MAY MUTATIONS IN MITOCHONDRIAL DNA (MTDNA) BECOME AN ADDITIONAL TARGET OF INVESTIGATIONS ON THE MISSING PCOS HERITABILITY? ARE MUTATIONS IN MTDNA IMPLICATED IN THE INITIATION AND PROGRESSION OF PCOS COMPLICATIONS, E.G., CVDS, DIABETES MELLITUS, CANCERS? 2018 18 6116 18 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 19 6825 13 [GENETIC AND EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME]. THE DEVELOPMENT OF POLYCYSTIC OVARY SYNDROME AND ITS EXACT PATHOPHYSIOLOGICAL MECHANISM IS STILL UNCLEAR, BUT ENVIRONMENTAL AND GENETIC FACTORS LIKELY PLAY A ROLE. EXPOSITION TO TERATOGENIC EFFECTS DURING THE PRENATAL DEVELOPMENT CAN LEAD TO CHRONIC DISEASES IN THE POSTNATAL PERIOD. THIS FINDING CONFIRMS THE COMMON FAMILIAL AGGREGATION AS WELL. A LITERATURE SEARCH WAS CONDUCTED UP TO JANUARY 1, 2016 FOR ARTICLES DEALING WITH THE GENETIC OR EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME. THIS REVIEW WILL DISCUSS THE CURRENT UNDERSTANDING OF THE GENETIC BASIS AND CLINICAL PRESENTATION OF THIS DISEASE. ORV. HETIL., 2016, 157(32), 1275-1281. 2016 20 1341 22 DETANGLING THE INTERRELATIONS BETWEEN MAFLD, INSULIN RESISTANCE, AND KEY HORMONES. METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) HAS INCREASINGLY BECOME A SIGNIFICANT AND HIGHLY PREVALENT CAUSE OF CHRONIC LIVER DISEASE, DISPLAYING A WIDE ARRAY OF RISK FACTORS AND PATHOPHYSIOLOGIC MECHANISMS OF WHICH ONLY A FEW HAVE SO FAR BEEN CLEARLY ELUCIDATED. A BIDIRECTIONAL INTERACTION BETWEEN HORMONAL DISCREPANCIES AND METABOLIC-RELATED DISORDERS, INCLUDING OBESITY, TYPE 2 DIABETES MELLITUS (T2DM), AND POLYCYSTIC OVARIAN SYNDROME (PCOS) HAS BEEN DESCRIBED. SINCE THE CHANGE IN NOMENCLATURE FROM NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) TO MAFLD IS BASED ON THE CLEAR IMPACT OF METABOLIC ELEMENTS ON THE DISEASE, THE RECIPROCAL INTERACTIONS OF HORMONES SUCH AS INSULIN, ADIPOKINES (LEPTIN AND ADIPONECTIN), AND ESTROGENS HAVE STRONGLY POINTED TO THE INTRINSIC LINKS THAT LEAD TO THE HETEROGENEOUS EPIDEMIOLOGY, CLINICAL PRESENTATIONS, AND RISK FACTORS INVOLVED IN MAFLD IN DIFFERENT POPULATIONS. THE OBJECTIVE OF THIS WORK IS TWOFOLD. FIRSTLY, THERE IS A BRIEF DISCUSSION REGARDING THE CHANGE IN NOMENCLATURE AS WELL AS EPIDEMIOLOGY, RISK FACTORS, AND PATHOPHYSIOLOGIC MECHANISMS OTHER THAN HORMONAL EFFECTS, WHICH INCLUDE NUTRITION AND THE GUT MICROBIOME, AS WELL AS GENETIC AND EPIGENETIC INFLUENCES. SECONDLY, WE REVIEW THE BASIS OF THE MOST IMPORTANT HORMONAL FACTORS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF MAFLD THAT ACT BOTH INDEPENDENTLY AND IN AN INTERRELATED MANNER. 2022