1 5107 127 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 2 3750 29 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 4403 37 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 4 420 39 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 5 4892 32 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 6 5104 20 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 7 4723 19 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 8 4068 30 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 9 5106 24 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 10 5105 33 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 11 5725 27 SKIN MANIFESTATIONS OF INSULIN RESISTANCE: FROM A BIOCHEMICAL STANCE TO A CLINICAL DIAGNOSIS AND MANAGEMENT. WORLDWIDE, MORE THAN 1.9 BILLION ADULTS ARE OVERWEIGHT, AND AROUND 600 MILLION PEOPLE SUFFER FROM OBESITY. SIMILARLY, ~382 MILLION INDIVIDUALS LIVE WITH DIABETES, AND 40-50% OF THE GLOBAL POPULATION IS LABELED AT "HIGH RISK" (I.E., PREDIABETES). THE IMPACT OF THESE TWO CHRONIC CONDITIONS RELIES NOT ONLY ON THE BURDEN OF ILLNESSES PER SE (I.E., ASSOCIATED INCREASED MORBIDITY AND MORTALITY), BUT ALSO ON THEIR INCREASED COST, BURDEN OF TREATMENT, AND DECREASED HEALTH-RELATED QUALITY OF LIFE. FOR THIS REVIEW A COMPREHENSIVE SEARCH IN SEVERAL DATABASES INCLUDING PUBMED (MEDLINE), OVID EMBASE, WEB OF SCIENCE, AND SCOPUS WAS CONDUCTED. IN BOTH DIABETES AND OBESITY, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS OVERLAP AND ARE INCLUSIVE RATHER THAN EXCLUSIVE. DE FACTO, 70-80% OF THE PATIENTS WITH OBESITY AND VIRTUALLY EVERY PATIENT WITH TYPE 2 DIABETES HAVE INSULIN RESISTANCE. INSULIN RESISTANCE IS A WELL-KNOWN PATHOPHYSIOLOGIC FACTOR IN THE DEVELOPMENT OF TYPE 2 DIABETES, CHARACTERISTICALLY APPEARING YEARS BEFORE ITS DIAGNOSIS. THE GOLD STANDARD FOR INSULIN RESISTANCE DIAGNOSIS (THE EUGLYCEMIC INSULIN CLAMP) IS A COMPLEX, INVASIVE, COSTLY, AND HENCE UNFEASIBLE TEST TO IMPLEMENT IN CLINICAL PRACTICE. LIKEWISE, LABORATORY MEASURES AND DERIVED INDEXES [E.G., HOMEOSTASIS MODEL ASSESSMENT OF INSULIN RESISTANCE (HOMA-IR-)] ARE INDIRECT, IMPRECISE, AND NOT HIGHLY ACCURATE AND REPRODUCIBLE TESTS. HOWEVER, SKIN MANIFESTATIONS OF INSULIN RESISTANCE (E.G., ACROCHORDONS, ACANTHOSIS NIGRICANS, ANDROGENETIC ALOPECIA, ACNE, HIRSUTISM) OFFER A RELIABLE, STRAIGHTFORWARD, AND REAL-TIME WAY TO DETECT INSULIN RESISTANCE. THE OBJECTIVE OF THIS REVIEW IS TO AID CLINICIANS IN RECOGNIZING SKIN MANIFESTATIONS OF INSULIN RESISTANCE. DIAGNOSING THESE SKIN MANIFESTATIONS ACCURATELY MAY CASCADE POSITIVELY IN THE PATIENT'S HEALTH BY TRIGGERING AN ADEQUATE METABOLIC EVALUATION, A TIMELY TREATMENT OR REFERRAL WITH THE ULTIMATE OBJECTIVE OF DECREASING DIABETES AND OBESITY BURDEN, AND IMPROVING THE HEALTH AND THE QUALITY OF CARE FOR THESE PATIENTS. 2017 12 1106 31 COMBINED TOXICITY OF ENDOCRINE-DISRUPTING CHEMICALS: A REVIEW. THE COMBINED TOXICOLOGICAL ASSESSMENT PROVIDES A REALISTIC APPROACH FOR HAZARD EVALUATION OF CHEMICAL COCKTAILS THAT CO-EXISTED IN THE ENVIRONMENT. THIS REVIEW PROVIDES A HOLISTIC INSIGHT INTO THE STUDIES HIGHLIGHTING THE MIXTURE TOXICITY OF THE ENDOCRINE-DISRUPTING CHEMICALS (EDCS), ESPECIALLY FOCUSING ON THE SCREENING OF BIOCHEMICAL PATHWAYS AND OTHER TOXICOGENETIC ENDPOINTS. REVIEWED LITERATURE SHOWED THAT NUMEROUS MULTIPLEXED TOXICOGENOMIC TECHNIQUES WERE APPLIED TO DETERMINE REPRODUCTIVE EFFECTS IN VERTEBRATES, BUT LIMITED STUDIES WERE FOUND IN NON-MAMMALIAN SPECIES AFTER MIXTURE CHEMICAL EXPOSURE. FURTHER, WE FOUND THAT THE EXPERIMENTAL DESIGN AND CONCENTRATION SELECTION ARE THE TWO IMPORTANT PARAMETERS IN MIXTURE TOXICITY STUDIES THAT SHOULD BE TIME- AND COST-EFFECTIVE, HIGHLY PRECISE, AND ENVIRONMENTALLY RELEVANT. A SUMMARY OF EDC MIXTURES AFFECTING THE THYROID AXIS, ESTROGEN AXIS, ANDROGEN AXIS, GROWTH STRESS, AND IMMUNE SYSTEM VIA IN VIVO BIOASSAYS WAS ALSO PRESENTED. IT IS INTERESTING TO MENTION THAT MAJORITY OF ESTROGENIC EFFECTS OF THE MIXTURES WERE SEX-DEPENDENT, PARTICULARLY OBSERVED IN MALE FISH AS COMPARED TO FEMALE FISH. FURTHER, THE ANDROGEN AXIS WAS PERTURBED WITH SERIOUS MALFORMATIONS IN MALE RAT TESTIS (EPIDIDYMAL OR GUBERNACULAR LESIONS, AND DECIDUOUS SPERMATIDS). ALSO, TRANSGENERATIONAL EPIGENETIC EFFECTS WERE PROMOTED IN THE F(3) AND F(4) GENERATIONS IN THE FORM OF DNA METHYLATION EPIMUTATIONS IN SPERM, INCREASING POLYCYSTIC OVARIES AND REDUCING THE OFFSPRING. SIMILARLY, INCREASED OXIDATIVE STRESS, HIGH ANTIOXIDANT ENZYMATIC ACTIVITIES, DISTURBED ESTROUS CYCLE, AND DECREASED STEROIDOGENESIS WERE THE COMMONLY FOUND EFFECTS AFTER ACUTE OR CHRONIC EXPOSURE TO EDC MIXTURES. IMPORTANTLY, THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) MODELS BECAME MORE PREVALENT AND SUITABLE PREDICTIVE MODELS TO UNVEIL THE PROMINENCE OF SYNERGISTIC ESTROGENIC AND ANTI-ANDROGENIC EFFECTS OF CHEMICAL MIXTURES. MORE IMPORTANTLY, THIS REVIEW ENCOMPASSES THE RESEARCH CHALLENGES AND GAPS IN THE EXISTING KNOWLEDGE AND SPECIFIC FUTURE RESEARCH PERSPECTIVES ON COMBINED TOXICITY. 2021 13 4973 39 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 14 4075 33 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES. 2019 15 4806 29 OBESITY AND METABOLIC SYNDROME ASSOCIATED WITH SYSTEMIC INFLAMMATION AND THE IMPACT ON THE MALE REPRODUCTIVE SYSTEM. OBESITY AND METABOLIC SYNDROME (METS) ARE GLOBAL EPIDEMICS, DRIVEN BY AN OBESOGENIC ENVIRONMENT. THIS IS MEDIATED BY COMPLEX UNDERLYING PATHOPHYSIOLOGY, IN WHICH CHRONIC INFLAMMATION IS AN IMPORTANT AETIOLOGICAL AND MECHANISTIC PHENOMENON. A SHIFT TOWARDS A SUBCLINICAL T(H) 1-LYMPHOCYTE MEDIATED INNATE AND CHRONIC INFLAMMATORY RESPONSE IS WELL DEFINED IN OBESITY AND METS, DEMONSTRATED IN MULTIPLE SYSTEMS INCLUDING VISCERAL ADIPOSITY, BRAIN (HYPOTHALAMUS), MUSCLES, VASCULATURE, LIVER, PANCREAS, TESTES, EPIDIDYMIS, PROSTATE AND SEMINAL FLUID. INFLAMMATORY CYTOKINES DISRUPT THE HYPOTHALAMIC-PITUITARY-TESTES AXIS AND STEROIDOGENESIS CASCADES (HYPOGONADOTROPIC HYPOGONADISM), SPERMATOGENESIS (POOR SEMEN PARAMETERS, INCLUDING DNA FRAGMENTATION AND DETRIMENTAL EPIGENETIC MODIFICATION) AND RESULTS IN SUBCLINICAL PROSTATITIS AND PROSTATE HYPERPLASIA. THIS REVIEW AIMS TO HIGHLIGHT THE ROLE OF CHRONIC INFLAMMATION IN OBESITY AND METS, CYTOKINES IN MALE REPRODUCTIVE PHYSIOLOGY AND PATHOPHYSIOLOGY, THE IMPACT ON STEROIDOGENESIS AND SPERMATOGENESIS, PROSTATE PATHOLOGY AND ERECTILE DYSFUNCTION. CURRENTLY, IT IS RECOMMENDED THAT CLINICAL ASSESSMENT OF MALE INFERTILITY AND REPRODUCTIVE DYSFUNCTION IN OBESE AND METS PATIENTS INCLUDES INFLAMMATION ASSESSMENT (HIGHLY SENSITIVE C-REACTIVE PROTEIN), AND APPROPRIATE ADVICE AND THERAPEUTIC OPTIONS ARE INCORPORATED IN THE MANAGEMENT OPTIONS. HOWEVER, THE MECHANISMS AND THERAPEUTIC OPTIONS REMAIN POORLY UNDERSTOOD AND REQUIRE SIGNIFICANT INTERDISCIPLINARY RESEARCH TO IDENTIFY POTENTIAL NOVEL THERAPEUTIC STRATEGIES. 2019 16 3463 42 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 17 1101 21 COMBINATION THERAPY USING LHRH AND SOMATOSTATIN ANALOGUES PLUS DEXAMETHASONE IN ANDROGEN ABLATION REFRACTORY PROSTATE CANCER PATIENTS WITH BONE INVOLVEMENT: A BENCH TO BEDSIDE APPROACH. THE DEVELOPMENT OF RESISTANCE TO ANTICANCER THERAPIES IS A MAJOR HURDLE IN PREVENTING LONG-LASTING CLINICAL RESPONSES TO CONVENTIONAL THERAPIES IN HORMONE-REFRACTORY PROSTATE CANCER. HEREIN, THE MOLECULAR EVIDENCE DOCUMENTING THAT BONE METASTASIS MICROENVIRONMENT SURVIVAL FACTORS (MAINLY THE PARACRINE GROWTH HORMONE-INDEPENDENT, UROKINASE-TYPE PLASMINOGEN ACTIVATOR-MEDIATED INCREASE OF IGF-1 AND THE ENDOCRINE PRODUCTION OF GROWTH HORMONE-DEPENDENT IGF-1, MAINLY LIVER-DERIVED IGF-1 PRODUCTION) PRODUCE AN EPIGENETIC FORM OF PROSTATE CANCER CELLS THAT ARE RESISTANT TO PROAPOPTOTIC THERAPIES IS REVIEWED. CONSEQUENTLY, THE AUTHORS PRESENT THE CONCEPTUAL FRAMEWORK OF A NOVEL ANTIBONE MICROENVIRONMENT SURVIVAL FACTOR, MAINLY AN ANTI-IGF-1 HORMONAL MANIPULATION FOR ANDROGEN ABLATION REFRACTORY PROSTATE CANCER (A COMBINATION OF CONVENTIONAL ANDROGEN ABLATION THERAPY [LUTEINISING HORMONE-RELEASING HORMONE AGONIST-A OR ORCHIECTOMY]) WITH DEXAMETHASONE PLUS SOMATOSTATIN ANALOGUE, WHICH YIELDED DURABLE OBJECTIVE RESPONSES AND MAJOR IMPROVEMENT OF BONE PAIN AND PERFORMANCE STATUS IN STAGE D3 PROSTATE CANCER PATIENTS. 2006 18 4804 24 OBESITY AND MALE INFERTILITY: MECHANISMS AND MANAGEMENT. OBESITY IS CONSIDERED A GLOBAL HEALTH PROBLEM AFFECTING MORE THAN A THIRD OF THE POPULATION. COMPLICATIONS OF OBESITY INCLUDE CARDIOVASCULAR DISEASES, TYPE 2 DIABETES MELLITUS, MALIGNANCY (INCLUDING PROSTATIC CANCER), NEURODEGENERATION AND ACCELERATED AGEING. IN MALES, THESE FURTHER INCLUDE ERECTILE DYSFUNCTION, POOR SEMEN QUALITY AND SUBCLINICAL PROSTATITIS. ALTHOUGH POORLY UNDERSTOOD, IMPORTANT MEDIATORS OF OBESITY THAT MAY INFLUENCE THE MALE REPRODUCTIVE SYSTEM INCLUDE HYPERINSULINEMIA, HYPERLEPTINEMIA, CHRONIC INFLAMMATION AND OXIDATIVE STRESS. OBESITY IS KNOWN TO DISRUPT MALE FERTILITY AND THE REPRODUCTION POTENTIAL, PARTICULARLY THROUGH ALTERATION IN THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS, DISRUPTION OF TESTICULAR STEROIDOGENESIS AND METABOLIC DYSREGULATION, INCLUDING INSULIN, CYTOKINES AND ADIPOKINES. IMPORTANTLY, OBESITY AND ITS UNDERLYING MEDIATORS RESULT IN A NEGATIVE IMPACT ON SEMEN PARAMETERS, INCLUDING SPERM CONCENTRATION, MOTILITY, VIABILITY AND NORMAL MORPHOLOGY. MOREOVER, OBESITY INHIBITS CHROMATIN CONDENSATION, DNA FRAGMENTATION, INCREASES APOPTOSIS AND EPIGENETIC CHANGES THAT CAN BE TRANSFERRED TO THE OFFSPRING. THIS REVIEW DISCUSSES THE IMPACT OF OBESITY ON THE MALE REPRODUCTIVE SYSTEM AND FERTILITY, INCLUDING ASSOCIATED MECHANISMS. FURTHERMORE, WEIGHT MANAGEMENT STRATEGIES, LIFESTYLE CHANGES, PRESCRIPTION MEDICATION, AND COMPLEMENTARY AND ALTERNATIVE MEDICINE IN THE MANAGEMENT OF OBESITY-INDUCED SUBFERTILITY IS DISCUSSED. 2021 19 419 28 ANDROGEN AXIS IN PROSTATE CANCER. ENDOCRINE THERAPY FOR ADVANCED PROSTATE CANCER IS BASED ON ANDROGEN ABLATION OR BLOCKADE OF THE ANDROGEN RECEPTOR (AR). AR ACTION IN PROSTATE CANCER HAS BEEN INVESTIGATED IN A NUMBER OF CELL LINES, THEIR DERIVATIVES, AND TRANSGENIC ANIMALS. AR EXPRESSION IS HETEROGENOUS IN PROSTATE CANCER IN VIVO; IT COULD BE DETECTED IN MOST PRIMARY TUMORS AND THEIR METASTASES. HOWEVER, SOME CELLS LACK THE AR BECAUSE OF EPIGENETIC CHANGES IN THE GENE PROMOTER. AR EXPRESSION INCREASES AFTER CHRONIC ANDROGEN ABLATION IN VITRO. IN SEVERAL XENOGRAFTS, AR UPREGULATION IS THE MOST CONSISTENT CHANGE IDENTIFIED DURING PROGRESSION TOWARDS THERAPY RESISTANCE. IN CONTRAST, THE AR PATHWAY MAY BE BY-PASSED DURING CHRONIC TREATMENT WITH A NONSTEROIDAL ANTI-ANDROGEN. AR SENSITIVITY IN PROSTATE CANCER INCREASES AS A RESULT OF ACTIVATION OF THE RAS/MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY. ONE OF THE MAJOR DIFFICULTIES IN ENDOCRINE THERAPY FOR PROSTATE CANCER IS ACQUISITION OF AGONISTIC PROPERTIES OF AR ANTAGONISTS OBSERVED IN THE PRESENCE OF MUTATED AR. ENHANCEMENT OF AR FUNCTION BY ASSOCIATED COACTIVATOR PROTEINS HAS BEEN EXTENSIVELY INVESTIGATED. COFACTORS SRC-1, RAC3, P300/CBP, TIF-2, AND TIP60 ARE UPREGULATED IN ADVANCED PROSTATE CANCER. MOST STUDIES ON LIGAND-INDEPENDENT ACTIVATION OF THE AR ARE FOCUSED ON HER-2/NEU AND INTERLEUKIN-6 (IL-6). ON THE BASIS OF STUDIES THAT SHOWED OVEREXPRESSION AND ACTIVATION OF THE AR IN ADVANCED PROSTATE CANCER, IT WAS SUGGESTED THAT NOVEL THERAPIES THAT REDUCE AR EXPRESSION WILL PROVIDE A BENEFIT TO PATIENTS. THERE IS EXPERIMENTAL EVIDENCE SHOWING THAT PROSTATE TUMOR GROWTH IN VITRO AND IN VIVO IS INHIBITED FOLLOWING ADMINISTRATION OF CHEMOPREVENTIVE DRUGS OR ANTISENSE OLIGONUCLEOTIDES THAT DOWNREGULATE AR MRNA AND PROTEIN EXPRESSION. 2006 20 6068 32 THE DIET AS A CAUSE OF HUMAN PROSTATE CANCER. ASYMPTOMATIC PROSTATE INFLAMMATION AND PROSTATE CANCER HAVE REACHED EPIDEMIC PROPORTIONS AMONG MEN IN THE DEVELOPED WORLD. ANIMAL MODEL STUDIES IMPLICATE DIETARY CARCINOGENS, SUCH AS THE HETEROCYCLIC AMINES FROM OVER-COOKED MEATS AND SEX STEROID HORMONES, PARTICULARLY ESTROGENS, AS CANDIDATE ETIOLOGIES FOR PROSTATE CANCER. EACH ACTS BY CAUSING EPITHELIAL CELL DAMAGE, TRIGGERING AN INFLAMMATORY RESPONSE THAT CAN EVOLVE INTO A CHRONIC OR RECURRENT CONDITION. THIS MILIEU APPEARS TO SPAWN PROLIFERATIVE INFLAMMATORY ATROPHY (PIA) LESIONS, A TYPE OF FOCAL ATROPHY THAT REPRESENTS THE EARLIEST OF PROSTATE CANCER PRECURSOR LESIONS. RARE PIA LESIONS CONTAIN CELLS WHICH EXHIBIT HIGH C-MYC EXPRESSION, SHORTENED TELOMERE SEGMENTS, AND EPIGENETIC SILENCING OF GENES SUCH AS GSTP1, ENCODING THE PI-CLASS GLUTATHIONE S-TRANSFERASE, ALL CHARACTERISTIC OF PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) AND PROSTATE CANCER. SUBSEQUENT GENETIC CHANGES, SUCH AS THE GENE TRANSLOCATIONS/DELETIONS THAT GENERATE FUSION TRANSCRIPTS BETWEEN ANDROGEN-REGULATED GENES (SUCH AS TMPRSS2) AND GENES ENCODING ETS FAMILY TRANSCRIPTION FACTORS (SUCH AS ERG1), ARISE IN PIN LESIONS AND MAY PROMOTE INVASIVENESS CHARACTERISTIC OF PROSTATIC ADENOCARCINOMA CELLS. LETHAL PROSTATE CANCERS CONTAIN MARKEDLY CORRUPTED GENOMES AND EPIGENOMES. EPIGENETIC SILENCING, WHICH SEEMS TO ARISE IN RESPONSE TO THE INFLAMED MICROENVIRONMENT GENERATED BY DIETARY CARCINOGENS AND/OR ESTROGENS AS PART OF AN EPIGENETIC "CATASTROPHE" AFFECTING HUNDREDS OF GENES, PERSISTS TO DRIVE CLONAL EVOLUTION THROUGH METASTATIC DISSEMINATION. THE CAUSE OF THE INITIAL EPIGENETIC "CATASTROPHE" HAS NOT BEEN DETERMINED BUT LIKELY INVOLVES DEFECTIVE CHROMATIN STRUCTURE MAINTENANCE BY OVER-EXUBERANT DNA METHYLATION OR HISTONE MODIFICATION. WITH DIETARY CARCINOGENS AND ESTROGENS DRIVING PRO-CARCINOGENIC INFLAMMATION IN THE DEVELOPED WORLD, IT IS TEMPTING TO SPECULATE THAT DIETARY COMPONENTS ASSOCIATED WITH DECREASED PROSTATE CANCER RISK, SUCH AS INTAKE OF FRUITS AND VEGETABLES, ESPECIALLY TOMATOES AND CRUCIFERS, MIGHT ACT TO ATTENUATE THE RAVAGES OF THE CHRONIC OR RECURRENT INFLAMMATORY PROCESSES. SPECIFICALLY, NUTRITIONAL AGENTS MIGHT PREVENT PIA LESIONS OR REDUCE THE PROPENSITY OF PIA LESIONS TO SUFFER "CATASTROPHIC" EPIGENOME CORRUPTION. 2014