Resistance and aerobic training increases genome-wide DNA methylation in women with polycystic ovary syndrome.

Physical activity is a first-line treatment for polycystic ovary syndrome (PCOS). Resistance or aerobic exercise improves metabolic complications, reproductive outcomes, and quality of life in PCOS. DNA methylation reprogramming during exercise may be the major modifier behind these changes. We sought to evaluate genome-wide DNA methylation changes after supervised resistance and aerobic exercise in women with PCOS. Exercises were performed in 56 women with PCOS (resistance, n = 30; aerobic, n = 26), for 16 weeks (wks), three times per week, in 50-minute to one-hour sessions. Anthropometric indices and hormonal and metabolic parameters were measured before and after training. Genome-wide leukocyte DNA methylation was analysed by Infinium Human MethylationEPIC 850K BeadChip microarrays (Illumina). Both resistance and aerobic exercise improved anthropometric indices, metabolic dysfunction, and hyperandrogenism in PCOS after the training programme, but no differences were observed between the two exercises. Resistance and aerobic exercise increased genome-wide DNA methylation, although resistance changed every category in the CpG island context (islands, shores, shelve, and open sea), whereas aerobic exercise altered CpG shores and the open sea. Using a stringent FDR (>40), 6 significantly differentially methylated regions (DMRs) were observed in the resistance exercise cohort and 14 DRMs in the aerobic cohort, all of which were hypermethylated. The increase in genome-wide DNA methylation may be related to the metabolic and hormonal changes observed in PCOS after resistance and aerobic exercise. Since the mammalian genome is hypermethylated globally to prevent genomic instability and ageing, resistance and aerobic exercise may promote health and longevity through environmentally induced epigenetic changes.

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection.

Penile squamous cell carcinoma (SCC) is a rare and aggressive tumour mainly related to lifestyle behaviour and human papillomavirus (HPV) infection. Environmentally induced loss of imprinting (LOI) at the H19 differentially methylated region (H19DMR) is associated with many cancers in the early events of tumorigenesis and may be involved in the pathogenesis of penile SCC. We sought to evaluate the DNA methylation pattern at H19DMR and its association with HPV infection in men with penile SCC by bisulfite sequencing (bis-seq). We observed an average methylation of 32.2% ± 11.6% at the H19DMR of penile SCC and did not observe an association between the p16INK4a+ (p = 0.59) and high-risk HPV+ (p = 0.338) markers with methylation level. The average methylation did not change according to HPV positive for p16INK4a+ or hrHPV+ (35.4% ± 10%) and negative for both markers (32.4% ± 10.1%) groups. As the region analysed has a binding site for the CTCF protein, the hypomethylation at the surrounding CpG sites might alter its insulator function. In addition, there was a positive correlation between intense polymorphonuclear cell infiltration and hypomethylation at H19DMR (p = 0.035). Here, we report that hypomethylation at H19DMR in penile SCC might contribute to tumour progression and aggressiveness regardless of HPV infection.

Physical Performance Regarding Handgrip Strength in Women with Polycystic Ovary Syndrome.

OBJECTIVE: The present study aimed to investigate the physical performance of handgrip strength (HGS) in women with polycystic ovary syndrome (PCOS). METHODS: A case-control study that included 70 women with PCOS and 93 age-matched healthy women aged between 18 and 47 years with body mass index (BMI) between 18 Kg/m2-39.9 Kg/m2. The serum levels of total testosterone, androstenedione, insulin, estradiol, thyroid-stimulating hormone (TSH), prolactin, sex hormone-binding globulin (SHBG), and 17-hydroxyprogesterone (17-OHP) were measured. The free androgen index (FAI) and the homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. The body composition regions of interest (ROIs) were assessed by dual-energy X-ray absorptiometry (DXA), and the handgrip strength (HGS) was evaluated for both the dominant and the non-dominant hands with a manual Sammons Preston (Bolingbrook, IL, US) bulb dynamometer. RESULTS: Women with PCOS had high serum levels of total testosterone (p < 0.01), androstenedione (p = 0.03), and insulin (p < 0.01), as well as high FAI (p < 0.01) and HOMA-IR (p = 0.01) scores. Compared with the non-PCOS group, the PCOS group had greater total lean mass in the dominant hand (p < 0.03) and greater HGS in both the dominant and the non-dominant hands (p < 0.01). The HGS was correlated with lean mass (p < 0.01). CONCLUSION: Women with PCOS have greater HGS. This may be associated with age and BMI, and it may be related to lean mass. In addition, the dominance effect on muscle mass may influence the physical performance regarding HGS in women with PCOS.

OBJETIVO: O objetivo deste estudo foi avaliar a força de preensão manual (FPM) em mulheres com síndrome dos ovários policísticos (SOP). MéTODOS: Estudo de caso-controle que incluiu 70 mulheres com SOP e 93 mulheres saudáveis com idade entre 18 e 47 anos e índice de massa corporal (IMC) de 18 Kg/m2 a 39.9 Kg/m2. Foram dosados os níveis séricos de testosterona total, androstenediona, insulina, estradiol, hormônio estimulador da tireoide (HET), prolactina, globulina de ligação ao hormônio sexual (GLHS), e 17-hidroxiprogesterona (17-OHP). Foram calculados o índice de androgênio livre (IAL) e a avaliação do modelo homeostático da resistência à insulina (AMH-RI). As regiões de interesse (RIs) da composição corporal foram avaliadas por absorciometria de raios-x de dupla energia (ARDE), e a força de preensão manual (FPM) das mãos dominante e não dominante foi avaliada com um dinamômetro manual Sammons Preston (Bolingbrook, IL, EUA). RESULTADOS: Mulheres com SOP apresentaram níveis séricos elevados de testosterona total (p < 0.01), androstenediona (p = 0.03), e insulina (P < 0.01), assim como valores altos no IAL (p < 0.01) e no AMH-RI (p = 0.01). Comparado ao grupo controle, o grupo SOP apresentou maior massa magra total na mão dominante (p < 0.03) e maior FPM em ambas as mãos (p < 0.01). A FPM foi correlacionada com a massa muscular magra (p <0.01). CONCLUSãO: Mulheres com SOP têm maior FPM, que pode estar associada à idade, ao IMC, e à massa magra. Além disso, o efeito de dominância na massa muscular pode influenciar o desempenho físico na força de preensão manual em mulheres com SOP.

Effects of continuous and intermittent aerobic physical training on hormonal and metabolic profile, and body composition in women with polycystic ovary syndrome: A randomized controlled trial.

OBJECTIVE: To evaluate the effects of continuous (CA) and intermittent (IA) aerobic training on hormonal and metabolic parameters and body composition of women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, interventional, randomized study. METHODS: Randomized controlled training (RCT) with sample allocation and stratification into three groups: CAT (n = 28) and IAT (n = 29) training and no training [control (CG), n = 30]. Before and after 16 weeks of intervention (CAT or IAT) or observation (CG), hormonal and metabolic parameters, body composition and anthropometric indices were evaluated. Aerobic physical training on a treadmill consisted of 30- to 50-minute sessions with intensities ranging from 60% to 90% of the maximum heart rate. RESULTS: In the CA group, there was reduction in waist circumference (WC) (P = .045), hip circumference (P = .032), cholesterol (P ≤ .001), low-density lipoprotein (P = .030) and testosterone (P ≤ .001). In the IAT group, there was a reduction in WC (P = .014), waist-to-hip ratio (P = .012), testosterone (P = .019) and the free androgen index (FAI) (P = .037). The CG showed increases in WC (P = .049), total body mass (P = .015), body fat percentage (P = .034), total mass of the arms (P ≤ .001), trunk fat percentage (P = .033), leg fat percentage (P = .021) and total gynoid mass (P = .011). CONCLUSION: CAT and IAT training reduced anthropometric indices and hyperandrogenism in PCOS, whereas only IAT training reduced the FAI. Furthermore, only CAT training improved the lipid profile.

MicroRNA expression profiling provides novel insights into immune-related pathways involved in gastric cancer.

Gastric cancer is one of the most common cancers, and an increasing number of studies have found that microRNAs (miRNAs) play essential roles in gastric cancer progression; however, the roles of specific miRNAs involved in the immune response to this disease remain unclear. We compared the miRNA expression in tissues from primary gastric cancer patients and healthy controls to find miRNAs dysregulated in gastric cancer and used bioinformatics tools to determine potential roles of these miRNAs in the immune system. We evaluated 25 primary gastric cancer tissues and five healthy gastric tissues. Quantitative real-time polymerase chain reaction was performed for a set of miRNAs, followed by the prediction of their target genes and functional enrichment analysis of these targets. Analysis of a microarray dataset showed that the miRNA miR-196a-5p was significantly upregulated, while miR-374a-5p and miR-375 were downregulated in gastric cancer patients. In addition, miR-374-5p was significantly downregulated in patients with metastasis compared with its expression levels in non-metastatic patients (p = 0.03). Bioinformatics analysis suggested that the pathways regulated by these differentially expressed miRNAs were related to the immune response, cell adhesion, and cell migration. Most importantly, this study provides a new insight into the potential use of multiple miRNAs to find distinct pathways of immune regulation in gastric cancer.

Epidrugs: targeting epigenetic marks in cancer treatment.

Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic landscape in the cancer epigenome is one of the most promising target therapies in both treatment and reversibility of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for the individual variation in drug response. Thus, this review focuses on the emerging area of pharmaco(epi)genomics, specifically highlighting epigenetic reprogramming during tumorigenesis and how epigenetic markers are targeted as a therapy (epidrugs) and the clinical implications of this for cancer treatment.

Progesterone Receptor B (PGR-B) Is Partially Methylated in Eutopic Endometrium From Infertile Women With Endometriosis.

Endometriosis is frequently related to infertility and little is known about the mechanisms underlying this association. Some studies point to an endometrial factor involved in this condition, which could compromise embryo implantation. Progesterone plays crucial role in endometrial receptivity by acting through progesterone receptor (PGR) isoforms PR-A and PR-B whose expression is epigenetically regulated by DNA methylation, in a specific promoter region for each isoform. Epigenetic changes in PGR-A and PGR-B may be related to progesterone resistance of endometriosis-related infertility. In order to better understand the mechanisms involved in endometrial receptivity, this case-control study aimed to compare the methylation pattern of PGR-A and PGR-B in eutopic endometrium from infertile women with and without endometriosis during the secretory phase. Endometrial biopsies from 19 patients (10 infertile women with endometriosis and 9 infertile controls) with regular cycles were performed during the secretory phase and were dated according to Noyes' criteria. The percentage of DNA methylation at PGR-A and PGR-B was carried out by high-resolution melting assay. The PGR-A gene showed 0% of DNA methylation (unmethylated) in both control and endometriosis groups. However, PGR-B gene showed a partially methylated pattern in majority of the patients (n = 7), with methylation percentage corresponding to 50%, while in the control group the percentage of methylation was 20% (hypomethylated; P = .04). The increased percentage of methylation at PGR-B may be related to reduced gene expression, which could compromise the endometrial receptivity in patients with endometriosis.

A Nonrandomized Trial of Progressive Resistance Training Intervention in Women With Polycystic Ovary Syndrome and Its Implications in Telomere Content.

BACKGROUND: Physical activity is known to relieve the metabolic complications of polycystic ovary syndrome (PCOS), and exercise is also associated with telomere biology. We investigated the changes induced by progressive resistance training (PRT) in telomere content and metabolic disorder in women with PCOS and controls. PARTICIPANTS AND METHODS: Forty-five women with PCOS and 52 healthy women aged 18 to 37 years were submitted to PRT. A linear periodization of PRT was prepared based on a trend of decreasing volume and intensity throughout the training period. The volunteers performed PRT 3 times a week for 4 months. The participants' physical characteristics and hormonal concentrations were measured before and after PRT, as telomere content that was measured using quantitative real-time polymerase chain reaction. RESULTS: Briefly, Progressive resistance training reduced waist circumference, body fat percentage, plasma testosterone and sex hormone-binding globulin concentrations, glycemia, and free androgen index. Fasting insulin and insulin resistance index were greater in women with PCOS. Androstenedione and homocysteine increased after PRT. There were no differences in telomere content between controls (0.96 ± 0.3 before vs 0.85 ± 0.21 after) and women with PCOS (0.94 ± 0.33 before vs 0.88 ± 0.39 after). Adjusted analysis showed telomere shortening after PRT in all women (0.95 ± 0.31 before vs 0.86 ± 0.31 after; P = .03). In women with PCOS, increased homocysteine levels were related to telomere reduction and increased androstenedione was positively correlated with telomere content after PRT. CONCLUSIONS: Progressive resistance training had positive effects on the hormonal and physical characteristics of women with PCOS and controls, but telomere content was reduced and homocysteine level increased in all participants.

Resistance Exercise Impacts Lean Muscle Mass in Women with Polycystic Ovary Syndrome.

PURPOSE: This study investigated the effects of progressive resistance training (PRT) on lean muscle mass (LMM) in women with or without polycystic ovary syndrome (PCOS) and its effects on metabolic factors and concentrations of related steroid hormones. DESIGN: This was a nonrandomized, therapeutic, open, single-arm study. PARTICIPANTS: All in all, 45 sedentary women with PCOS and 52 without (non-PCOS), 18-37 yr of age, with body mass indexes (BMI) of 18-39.9 kg·m(-2) of all races and social status, performed PRT three times a week for 4 months. Before and after PRT, the concentrations of hormones and metabolic factors and waist circumference were measured. LMM and total body fat percentage were determined using dual-energy x-ray absorptiometry. Clinical characteristics, LMM, and fasting glucose were adjusted for confounding covariables and compared using general linear mixed models. Each patient's menstrual history was taken before study enrollment and after PRT. RESULTS: PRT resulted in reduced plasma testosterone and fasting glucose levels. After PRT, the androstenedione concentration increased and the sex hormone-binding globulin concentration decreased in women with PCOS. The waist circumference was reduced (P < 0.01) and the muscle mass index, lean mass (LM)/height2, increased in women with PCOS (P = 0.04). Women with PCOS showed increased muscle mass indexes of appendicular LM/height2 (P = 0.03) and LM/height2 (P < 0.01) compared with the baseline. Total LM and trunk LM were elevated in women with PCOS (P = 0.01) at the baseline and after PRT. CONCLUSION: To our knowledge, this is the first report to show that resistance exercise alone can improve hyperandrogenism, reproductive function, and body composition by decreasing visceral fat and increasing LMM, but it has no metabolic impact on women with PCOS.

Inflammatory biomarkers and telomere length in women with polycystic ovary syndrome.

OBJECTIVE: To analyze whether leukocyte telomere length (LTL) is impaired in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Hospital. PATIENT(S): A total of 274 women, including 150 patients with PCOS and 124 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Body mass index (BMI), waist circumference, systemic arterial pressure, lipid profile, E(2), LH, T, androstenedione, PRL, TSH, sex hormone-binding globulin, C-reactive protein (CRP), homocysteine, free androgen index, and the homeostatic model of insulin sensitivity (HOMA-IR) index were analyzed. The LTL evaluation was measured by quantitative polymerase chain reaction. RESULT(S): The PCOS group had higher values for weight, BMI, waist circumference, systolic arterial pressure, triglycerides, LH, T, insulin, CRP, free androgen index, and HOMA-IR compared with the control group. Sex hormone-binding globulin and E(2) levels were lower in the PCOS group than in the control group. The LTL did not differ between groups. Age, BMI, and HOMA-IR had no significant effect on LTL. The inflammatory biomarkers CRP and homocysteine were negatively correlated with LTL in patients with PCOS. CONCLUSION(S): Our results showed no differences in LTL between patients with PCOS and controls, but CRP and homocysteine biomarkers negatively correlated with LTL in the PCOS group.

Women with polycystic ovary syndrome have greater muscle strength irrespective of body composition.

The aim of this study was to compare metabolic parameters, body composition (BC) and muscle strength of women with and without polycystic ovary syndrome (PCOS). This was a case-control study that evaluated 40 women with PCOS and 40 controls. Androgens and insulin resistance were measured. BC was based on dual-energy X-ray absorptiometry. Isometric handgrip and maximal dynamic muscle strength (1-RM) strength tests were performed. Median total testosterone (p < 0.01), free androgen index (p < 0.01), insulin (p < 0.01) and homeostasis model assessment-insulin resistance (p = 0.02) were higher and sex hormone binding globulin (SBHG) (p = 0.04) was lower in the PCOS group. Normoweight women with PCOS had higher percentages of android body fat. However, the prevalence of android fat distribution was higher in the PCOS than in the control group (p = 0.04). The strength 1-RM in bench press (p < 0.01), muscle strength relative to lean muscle mass in the dominant lower limb (p = 0.04) and isometric handgrip strength tests (p = 0.03) was higher in the PCOS group. PCOS was a determinant of strength in the bench press exercise (p = 0.04). The hyperandrogenism was a predictor of increased strength in biceps curl exercises (p = 0.03) in the dominant lower limb (p = 0.02) and isometric handgrip strength (p = 0.03). In conclusion, women with PCOS have greater muscle strength and a higher prevalence of central obesity, but no difference in BC. Muscle strength may be related to high androgen levels in these women.