Metabolic features of women with polycystic ovary syndrome in Latin America : a systematic review

Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder that commonly affects women of childbearing age and has been associated with metabolic and reproductive abnormalities. Only a few studies have investigated metabolic traits in women with PCOS in Latin America. Therefore, we conducted a systematic review to provide an overview of the available evidence on the metabolic profile of Latin American women with PCOS. Methods: We searched PubMed, Cochrane Central Register of Controlled Trials, and Embase databases for cross-sectional, case-control, or cohort studies focusing on populations of countries in South and Central America and Mexico, published until October 31, 2019. We selected studies that reported the diagnostic criteria for PCOS. In the absence of a control group, we included studies if they reported relevant metabolic data. Results: The initial search yielded 4878 records, of which 41 studies were included in the systematic review. Sample sizes ranged from 10 to 288 in PCOS groups and from 10 to 1500 in control groups. The prevalence of phenotypes A and B (classic PCOS) ranged from 65.8% to 87.5% as reported in studies from Argentina, Brazil, and Chile. Metabolic syndrome ranged from 33.3% to 44.0% for phenotype A, from 15.0% to 58.0% for phenotype B, from 11.9% to 36.0% for phenotype C, and from 14.2% to 66.0% for phenotype D. Women with PCOS had higher body mass index, waist circumference, blood pressure, glucose, and homeostasis model assessment index as well as a more adverse lipid profile than those without PCOS. Conclusions: Evidence from the present systematic review suggests that anthropometric and metabolic profiles are worse in women with PCOS who live in different Latin American countries than in women without PCOS living in the same region. Additional studies assessing metabolic comorbidities, such as diabetes, and distinct PCOS phenotypes in different Latin American countries are warranted and may produce invaluable information for primary and secondary prevention of PCOS in the region

Metabolic profile of women with PCOS in Brazil : a systematic review and meta-analysis

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disease affecting women of reproductive age and associated with reproductive and metabolic dysfunction. Few studies are available regarding metabolic traits in Brazilian women with PCOS. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding metabolic traits and comorbidities in Brazilian women with polycystic ovary syndrome (PCOS). Methods: We systematically searched PubMed, Cochrane Central Register of Controlled Trials, and Embase for cross-sectional, case–control, or cohort studies focusing on populations of different regions from Brazil, published until July 31, 2019. Studies were selected if they reported PCOS diagnostic criteria. Studies without a control group were included if they presented relevant metabolic data. Results: Of 4856 studies initially identified, 27 were included in the systematic review and 12 were included in the meta-analysis, for a total of 995 women with PCOS defined by Rotterdam criteria and 2275 controls from different regions of Brazil. Obesity, metabolic syndrome and IGT were prevalent, and standard mean differences for BMI (SMD 0.67, 95% CI, 0.29, 1.05), waist circumference (SMD 0.22, 95% CI 0.02, 0.41), systolic (SMD 0.66, 95% CI 0.30, 1.01) and diastolic blood pressure (SMD 0.55, 95% CI 0.24, 0.87), glucose (SMD 0.21, 95% CI 0.04, 0.38) and HOMA (SMD 0.78, 95% CI 0.52, 1.04) were significantly higher in Brazilian women with PCOS compared to controls. Lipid profile was more adverse in PCOS vs. non-PCOS women. Between-study heterogeneities were low/moderate for glucose and HOMA and moderate/high for the other variables. Conclusions: The data of this systematic review and meta-analysis indicate that Brazilian women with PCOS have a worse metabolic profile than women without PCOS with no important regional differences. The prevalence of metabolic changes is intermediate in Brazil vs. other countries

Association between global leukocyte DNA methylation and cardiovascular risk in postmenopausal women

BACKGROUND: Genetic studies to date have not provided satisfactory evidence regarding risk polymorphisms for cardiovascular disease (CVD). Conversely, epigenetic mechanisms, including DNA methylation, seem to influence the risk of CVD and related conditions. Because postmenopausal women experience an increase in CVD, we set out to determine whether global DNA methylation was associated with cardiovascular risk in this population. METHODS: In this cross sectional study carried out in a university hospital, 90 postmenopausal women without prior CVD diagnosis (55.5 ± 4.9 years, 5.8 [3.0–10.0] years since menopause) were enrolled. DNA was extracted from peripheral leukocytes and global DNA methylation levels were obtained with an ELISA kit. Cardiovascular risk was estimated by the Framingham General Cardiovascular Risk Score (10-year risk) (FRS). Clinical and laboratory variables were assessed. Patients were stratified into two CVD risk groups: low (FRS: <10 %, n = 69) and intermediate/high risk (FRS ≥10 %, n = 21). RESULTS: Age, time since menopause, blood pressure, total cholesterol, and LDL-c levels were higher in FRS ≥10 % group vs. FRS <10 % group. BMI, triglycerides, HDL-c, HOMA-IR, glucose and hsC-reactive protein levels were similar in the two groups. Global DNA methylation (% 5mC) in the overall sample was 26.5 % (23.6–36.9). The FRS ≥10 % group presented lower global methylation levels compared with the FRS <10 % group: 23.9 % (20.6–29.1) vs. 28.8 % (24.3–39.6), p = 0.02. This analysis remained significant even after adjustment for time since menopause (p = 0.02). CONCLUSIONS: Our results indicate that lower global DNA methylation is associated with higher cardiovascular risk in postmenopausal women

C-reactive protein gene rs1205 polymorphism is associated with low-grade chronic inflammation in postmenopausal women

Background: Cardiovascular disease is the leading cause of death in postmenopausal women, and inflammation is a key mechanism involved in the pathogenesis of atherosclerosis. High-sensitivity C-reactive protein (hs-CRP) has been used as a biomarker of inflammation. Considering that CRP gene rs1205 polymorphism has been associated with hs-CRP circulating levels, we evaluated whether rs1205 genotypes influence the presence of low-grade chronic inflammation, acting as a marker of cardiovascular risk. Methods We performed a cross-sectional study with biobanked blood samples from 327 postmenopausal women with no evidence of clinical disease. Genotyping for rs1205 C > T SNP of the CRP gene was done by real-time polymerase chain reaction with allelic discrimination assays. Results Mean age was 55.6 ± 5.6 years. Mean body mass index (BMI) was 27.3 ± 4.7. Participants were divided according to hs-CRP levels: ≥3 mg/l (low-grade chronic inflammation) or < 3 mg/l. The frequency of allele C at rs1205 was 74.2% in the hs-CRP ≥ 3 mg/l group vs. 59% in the hs-CRP < 3 mg/l. In a multivariable model, higher prevalence of hs-CRP ≥ 3 mg/l was associated with CC genotype (PR 1.53; 95%CI 1.07–2.18; p = 0.018) and waist circumference ≥ 88 cm (PR 2.45; 95%CI 1.66–3.60; p < 0.001). Conclusions CRP rs1205 CC homozygotes may be at higher risk of a low-grade chronic inflammatory status compared to individuals carrying the T allele

Association between global leukocyte DNA methylation and cardiovascular risk in postmenopausal women

BACKGROUND: Genetic studies to date have not provided satisfactory evidence regarding risk polymorphisms for cardiovascular disease (CVD). Conversely, epigenetic mechanisms, including DNA methylation, seem to influence the risk of CVD and related conditions. Because postmenopausal women experience an increase in CVD, we set out to determine whether global DNA methylation was associated with cardiovascular risk in this population. METHODS: In this cross sectional study carried out in a university hospital, 90 postmenopausal women without prior CVD diagnosis (55.5 ± 4.9 years, 5.8 [3.0–10.0] years since menopause) were enrolled. DNA was extracted from peripheral leukocytes and global DNA methylation levels were obtained with an ELISA kit. Cardiovascular risk was estimated by the Framingham General Cardiovascular Risk Score (10-year risk) (FRS). Clinical and laboratory variables were assessed. Patients were stratified into two CVD risk groups: low (FRS: <10 %, n = 69) and intermediate/high risk (FRS ≥10 %, n = 21). RESULTS: Age, time since menopause, blood pressure, total cholesterol, and LDL-c levels were higher in FRS ≥10 % group vs. FRS <10 % group. BMI, triglycerides, HDL-c, HOMA-IR, glucose and hsC-reactive protein levels were similar in the two groups. Global DNA methylation (% 5mC) in the overall sample was 26.5 % (23.6–36.9). The FRS ≥10 % group presented lower global methylation levels compared with the FRS <10 % group: 23.9 % (20.6–29.1) vs. 28.8 % (24.3–39.6), p = 0.02. This analysis remained significant even after adjustment for time since menopause (p = 0.02). CONCLUSIONS: Our results indicate that lower global DNA methylation is associated with higher cardiovascular risk in postmenopausal women

Gene ligado a obesidade e massa gorda (fat mass and obesity associated; fto), menopausa e fatores de risco cardiovascular em mulheres na pós-menopausa

Obesidade é uma doença crônica multifatorial que no Brasil atinge cerca de 12,4% dos homens e 16,9% das mulheres com mais de 20 anos. No período pós menopáusico, as mulheres apresentam uma série de alterações fisiológicas, entre elas alteração na distribuição de gordura corporal, sobretudo um aumento na região abdominal. A obesidade apresenta uma etiologia poligênica e diversos genes vêm sendo estudados, entre eles o gene ligado a obesidade e massa gorda (FTO) que já se mostrou fortemente associado com a obesidade/IMC. Mas em relação a parâmetros metabólicos e marcadores de risco cardiovascular, os estudos ainda são bastante controversos dependendo da população em estudo. Com esses dados nosso trabalho buscou a associação entre os polimorfismos rs9939609 e rs8050136 do gene FTO com variáveis metabólicas e de risco cardiovascular em mulheres na pós menopausa. Nosso estudo mostrou que no SNP rs9939609, o genótipo homozigoto para o alelo A está associado com aumento da relação cintura quadril, índice de acumulação lipídica (LAP), que é um marcador de risco cardiovascular, que é um marcador de risco cardiovascular e hipertensão. Enquanto que no SNP rs8050136, o genótipo em homozigose para o alelo A foi associado com pressão arterial diastólica e LAP. Tanto o genótipo polimórfico do SNP rs9939609 e selvagem do rs8050136 foram associados com alteração nos níveis de glicose plasmática. Deste modo, podemos concluir que o polimorfismo rs9939609 no gene do FTO pode ser um preditor de maior risco cardiovascular em mulheres na menopausa

Avaliação de polimorfismos em genes relacionados à obesidade e diabetes em mulheres com a síndrome dos ovários policísticos e associação com variáveis metabólicas e hormonàis

A síndrome dos ovários policísticos (PCOS) representa uma das endocrinopatias mais frequentes em mulheres em idade reprodutiva, cujas principais características clínicas são anovulação crônica e manifestações de hiperandrogenismo. Em conjunto com os distúrbios reprodutivos, as pacientes com PCOS apresentam, frequentemente, obesidade e resistência insulínica (RI). Além disso, mulheres com PCOS apresentam maior risco para diabetes tipo 2, dislipidemia e hipertensão arterial e a presença da obesidade pode exacerbar os distúrbios metabólicos associados com a síndrome. A patogênese da PCOS está ligada a maior susceptibilidade ambiental bem como fatores genéticos e esses fatores podem influenciar a apresentação clínica da doença. Variantes genéticas, como polimorfismos de troca de um único nucleotídeo (SNP) vem sendo associadas com alterações metabólicas e clínicas. SNPs no gene TCF7L2 já foram descritos associados ao DM2 2 e RI. Estudos até o presente momento apresentam resultados controversos em relação a variáveis metabólicas e sua associação com os SNPs deste gene em pacientes com PCOS. Outros genes também vem sendo estudados e sabendo que a resistência à insulina e obesidade são característica frequentes de pacientes com a PCOS, o gene FTO surgiu como um possível locus a ser estudado, já que diversos estudos mostram uma associação com esses fatores em outras populações. Até o presente momento estudos mostram dados controversos, possivelmente associados a diferenças entre etnias. Além disso, estudos em uma população latino americana de mulheres com PCOS ainda não foram relatados na literatura. No presente estudo, observamos que os polimorfismos do gene do TCF7L2 rs7903146 e rs11196236 bem como seus haplótipos, não estão associados com a PCOS, mas que a paciente ser portadora de pelo menos um alelo de risco mostra uma variação positiva de 5,87 cm na cintura, 10,7 mg/dl no colesterol total e 10,3mg/dL no LDL-c. Além disso, para verificar a associação do polimorfismo rs7903146 com PCOS realizamos um meta análise, incluindo 1892 mulheres com PCOS e 2695 controles. Os resultados sugerem que o polimorfismo no gene do TCF7L2 não está associado com o risco aumentando de desenvolver PCOS em difefentes etnias (Asiáticas e não Asiáticas). No que se refere ao gene do FTO, os polimorfismos estudados também não foram associados com PCOS, mas os resultados mostram um aumento nos níveis de glicose nas pacientes que possuíam pelo menos um alelo de risco tanto para o polimorfismo rs9939609 quanto para o rs8050136. Estes resultados em conjunto sugerem que a PCOS por ser uma doença multifatorial e multigênica é difícil encontrar um único SNP responsável pelo fenótipo completo da PCOS, mas os estudos de associação em diferentes genes podem contribuir com o melhor entendimento dos diferentes fenótipos, principalmente nas características metabólicas destas pacientes.The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive age women, whose main clinical features are chronic anovulation and hyperandrogenism. Together with reproductive disorders, patients with PCOS frequently have obesity and insulin resistance (IR). In addition, women with PCOS have a higher risk for type 2 diabetes, dyslipidemia and hypertension and the presence of obesity may exacerbate the metabolic disturbances associated to the syndrome. The pathogenesis of PCOS is linked to greater environmental susceptibility and genetic factors and these aspects may influence the clinical presentation of the disease. Genetic variants as single nucleotide polymorphisms (SNPs) have been associated to metabolic and clinical changes. SNPs in the TCF7L2 gene have been described in association with DM2 2 and IR. Studies to date are controversial in relation to metabolic variables and their association with the SNPs of this gene in patients with PCOS. Other genes have also been studied and knowing that insulin resistance and obesity are common characteristic in patients with PCOS, the FTO gene has emerged as a possible locus to be studied. Several studies show an association with these factors in other populations. So far studies show controversial data, possibly associated to differences among ethnic groups. In addition, studies in a Latin American women population with PCOS have not been reported in the literature. We have found out that the gene TCF7L2, polymorphisms rs7903146 and rs11196236 and their haplotypes show no differences between genotypes and haplotypes for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dl in total cholesterol (P trend=0.03), and 10.3 mg/dl in LDL-C (P trend=0.01) was recorded. Also, to verify the association of rs7903146 polymorphism with PCOS we conducted a metaanalysis including 1892 women with PCOS and 2695 controls. The results suggest that polymorphism in the gene TCF7L2 is not associated to the increased risk of developing PCOS in different ethnicities (Asian and non- Asian). As regards the FTO gene, the studied polymorphisms were not associated to PCOS, but the results show an increase in glucose levels in patients who had at least one risk allele for the polymorphism rs8050136 and rs9939609. These results together, suggest that PCOS being a multifactorial and multigenic disease is difficult to find a single SNP responsible for the complete phenotype of PCOS, but association studies in different genes can contribute to a better understanding of the different phenotypes, especially in metabolic characteristics of these patients

Avaliação de polimorfismos em genes relacionados à obesidade e diabetes em mulheres com a síndrome dos ovários policísticos e associação com variáveis metabólicas e hormonàis

A síndrome dos ovários policísticos (PCOS) representa uma das endocrinopatias mais frequentes em mulheres em idade reprodutiva, cujas principais características clínicas são anovulação crônica e manifestações de hiperandrogenismo. Em conjunto com os distúrbios reprodutivos, as pacientes com PCOS apresentam, frequentemente, obesidade e resistência insulínica (RI). Além disso, mulheres com PCOS apresentam maior risco para diabetes tipo 2, dislipidemia e hipertensão arterial e a presença da obesidade pode exacerbar os distúrbios metabólicos associados com a síndrome. A patogênese da PCOS está ligada a maior susceptibilidade ambiental bem como fatores genéticos e esses fatores podem influenciar a apresentação clínica da doença. Variantes genéticas, como polimorfismos de troca de um único nucleotídeo (SNP) vem sendo associadas com alterações metabólicas e clínicas. SNPs no gene TCF7L2 já foram descritos associados ao DM2 2 e RI. Estudos até o presente momento apresentam resultados controversos em relação a variáveis metabólicas e sua associação com os SNPs deste gene em pacientes com PCOS. Outros genes também vem sendo estudados e sabendo que a resistência à insulina e obesidade são característica frequentes de pacientes com a PCOS, o gene FTO surgiu como um possível locus a ser estudado, já que diversos estudos mostram uma associação com esses fatores em outras populações. Até o presente momento estudos mostram dados controversos, possivelmente associados a diferenças entre etnias. Além disso, estudos em uma população latino americana de mulheres com PCOS ainda não foram relatados na literatura. No presente estudo, observamos que os polimorfismos do gene do TCF7L2 rs7903146 e rs11196236 bem como seus haplótipos, não estão associados com a PCOS, mas que a paciente ser portadora de pelo menos um alelo de risco mostra uma variação positiva de 5,87 cm na cintura, 10,7 mg/dl no colesterol total e 10,3mg/dL no LDL-c. Além disso, para verificar a associação do polimorfismo rs7903146 com PCOS realizamos um meta análise, incluindo 1892 mulheres com PCOS e 2695 controles. Os resultados sugerem que o polimorfismo no gene do TCF7L2 não está associado com o risco aumentando de desenvolver PCOS em difefentes etnias (Asiáticas e não Asiáticas). No que se refere ao gene do FTO, os polimorfismos estudados também não foram associados com PCOS, mas os resultados mostram um aumento nos níveis de glicose nas pacientes que possuíam pelo menos um alelo de risco tanto para o polimorfismo rs9939609 quanto para o rs8050136. Estes resultados em conjunto sugerem que a PCOS por ser uma doença multifatorial e multigênica é difícil encontrar um único SNP responsável pelo fenótipo completo da PCOS, mas os estudos de associação em diferentes genes podem contribuir com o melhor entendimento dos diferentes fenótipos, principalmente nas características metabólicas destas pacientes.The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive age women, whose main clinical features are chronic anovulation and hyperandrogenism. Together with reproductive disorders, patients with PCOS frequently have obesity and insulin resistance (IR). In addition, women with PCOS have a higher risk for type 2 diabetes, dyslipidemia and hypertension and the presence of obesity may exacerbate the metabolic disturbances associated to the syndrome. The pathogenesis of PCOS is linked to greater environmental susceptibility and genetic factors and these aspects may influence the clinical presentation of the disease. Genetic variants as single nucleotide polymorphisms (SNPs) have been associated to metabolic and clinical changes. SNPs in the TCF7L2 gene have been described in association with DM2 2 and IR. Studies to date are controversial in relation to metabolic variables and their association with the SNPs of this gene in patients with PCOS. Other genes have also been studied and knowing that insulin resistance and obesity are common characteristic in patients with PCOS, the FTO gene has emerged as a possible locus to be studied. Several studies show an association with these factors in other populations. So far studies show controversial data, possibly associated to differences among ethnic groups. In addition, studies in a Latin American women population with PCOS have not been reported in the literature. We have found out that the gene TCF7L2, polymorphisms rs7903146 and rs11196236 and their haplotypes show no differences between genotypes and haplotypes for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dl in total cholesterol (P trend=0.03), and 10.3 mg/dl in LDL-C (P trend=0.01) was recorded. Also, to verify the association of rs7903146 polymorphism with PCOS we conducted a metaanalysis including 1892 women with PCOS and 2695 controls. The results suggest that polymorphism in the gene TCF7L2 is not associated to the increased risk of developing PCOS in different ethnicities (Asian and non- Asian). As regards the FTO gene, the studied polymorphisms were not associated to PCOS, but the results show an increase in glucose levels in patients who had at least one risk allele for the polymorphism rs8050136 and rs9939609. These results together, suggest that PCOS being a multifactorial and multigenic disease is difficult to find a single SNP responsible for the complete phenotype of PCOS, but association studies in different genes can contribute to a better understanding of the different phenotypes, especially in metabolic characteristics of these patients