Made available in DSpace on 2016-08-19T18:16:05Z (GMT). No. of bitstreams: 1 dissertacao Debora.pdf: 708623 bytes, checksum: e13258642ac00185a278de8f61921fca (MD5) Previous issue date: 2012-10-30 / BACKGROUND: Polycystic ovary syndrome (PCOS) has been correlated with metabolic syndrome (MS), both with common characteristics regarding the altered lipid profile, obesity, hypertension and the occurrence of cardiovascular diseases. OBJECTIVES: Identify the prevalence of Metabolic Syndrome in women with PCOS and its association with cardiovascular risk markers. METHODS: Cross-sectional, prospective. 191 women between 18 and 42 years were evaluated in the Clinic of Gynecology, University Hospital Maternal-Child Unit of the Federal University of Maranhão, leaving 82 patients with PCOS. The patients underwent a clinical evaluation and screening with detailed history, conducting biochemical and ultrasonographic examinations. To collect data, we used two sheets of protocol, with questionnaires containing identification, weight, height, among other measures, in addition to personal, family, and gynecological history. RESULTS: In women with PCOS, the presence of metabolic syndrome was observed in 21%. In this group, the significant clinical variables were age group from 26 to 32 years (59%), obesity (82%) and acanthosis nigricans (87%). Among the diagnostic criteria for MS, the most common were HDL and waist circumference change (65% and 39%, respectively). Regarding inflammatory markers, only elevated CRP was significant (p value = 0.0030). CONCLUSION: The present study showed a high prevalence of women with MS, mostly young and obese women. Their risk of cardiovascular disease was associated with increased CRP level. / Introdução: A síndrome dos ovários policísticos tem sido correlacionada com a Síndrome Metabólica, ambas com características comuns quanto à alteração do perfil lipídico, obesidade, hipertensão e a ocorrência de doenças cardiovasculares. Objetivo: Identificar a prevalência de Síndrome Metabólica em mulheres com síndrome dos ovários policísticos e sua associação com marcadores de risco cardiovascular. Metodologia: Transversal. Foram avaliadas 191 mulheres entre 18 e 42 anos atendidas no Ambulatório de Ginecologia do Hospital Universitário Unidade Materno-Infantil da Universidade Federal do Maranhão, restando 82 pacientes com síndrome dos ovários policísticos. As pacientes foram submetidas a uma triagem com avaliação clínica e anamnese detalhada, realização de exames bioquímicos e ultrassonográficos. Para a coleta de dados, foram utilizadas duas fichas de protocolo, com questionários sobre identificação, peso, altura, dentre outras medidas, além de antecedentes pessoais, familiares e ginecológicos. Resultados: Nas portadoras de síndrome dos ovários policísticos, a presença de síndrome metabólica foi constatada em 21%. Neste grupo, as variáveis clínicas significativas foram a faixa etária de 26 a 32 anos (59%), obesidade (82%) e acantose nigricans (87%). Dentre os critérios diagnósticos para síndrome metabólica, os mais freqüentes foram HDL e circunferência da cintura alterados (65% e 39%, respectivamente). Em relação aos marcadores inflamatórios, somente a PCR-US elevada foi significante (p valor = 0,0030). Conclusão: O presente estudo evidenciou alta prevalência de mulheres com SM, em sua maioria jovens e obesas. O risco das mesmas para doença cardiovascular associou-se à PCR-US aumentada.

Made available in DSpace on 2016-08-19T18:16:05Z (GMT). No. of bitstreams: 1 Dissertacao Joelma.pdf: 599807 bytes, checksum: 496d32d46e118e53ae391f662bfa6dbd (MD5) Previous issue date: 2012-10-29 / FUNDAÇÃO DE AMPARO À PESQUISA E AO DESENVOLVIMENTO CIENTIFICO E TECNOLÓGICO DO MARANHÃO / The polycystic ovary syndrome (PCOS) is considered the most common endocrine disease during the woman's reproductive life, with prevalence ranging from 5 to 10% of women of reproductive age and is characterized by chronic anovulation and hyperandrogenism, showing complex multifactorial pathogenesis. Objective: To determine the cutoff the lipid accumulation product in women with polycystic ovary syndrome. Methods: Cross-sectional study with 78 women between 18 and 42 years diagnosed with polycystic ovary syndrome according to the Rotterdam criteria directed to nutritional evaluation at the Maternal and Child Unit of the University Hospital UFMA. The interest variables were recorded in protocol form: socio-demographic, behavioral, gynecological history, personal and family history of diseases, anthropometric data (weight, height, body mass index and waist circumference), laboratory tests, imaging exams and blood pressure values. The product of lipid accumulation was calculated by the formula described by Kahn. Regarding the analysis of data normality of quantitative variables was analyzed by the Shapiro Wilk; to compare the means of the variables we used the t Student test. To check the correlation between the lipid product accumulation and cardiovascular risk markers was applied Linear Correlation coefficient (r) test. The lipid product accumulation was analyzed according to the Receiver Operating Characteristic Curve, being discriminated values of high sensitivity and specificity simultaneously. The significance level for all tests was 5%. Results: Using the Receiver Operating Characteristic curve to determine the best cutoff of predicted LAP index risk for cardiovascular disease, it was noted that the value above 39.32 cm.mmol/L representing the area under the 0.8845 of the curve. Every women who had lipid product accumulation product value above the cutoff defined also showed the highest changes in mean of risk markers analyzed of cardiovascular diseases, a statistically significant difference. Regarding the analysis of correlation between the product of lipid accumulation above the cutoff defined and risk markers for cardiovascular diseases, there was a significant correlation. Conclusion: These results demonstrate that cutoff values ≥ 39.32 cm.mmol/L of LAP index seems to indicate the increased risk for CVD and should be used as a screening tool and research for its ease of measurement and interpretation, as well as its low cost and may even have its applicability in primary health care. / A síndrome dos ovários policísticos (SOP) é considerada a endocrinopatia mais comum durante a vida reprodutiva da mulher, com prevalência que varia entre 5 a 10% das mulheres em idade fértil sendo caracterizada por anovulação crônica e hiperandrogenismo, apresentando fisiopatogenia complexa de caráter multifatorial. Objetivo: Determinar o ponto de corte do produto da acumulação lipídica em mulheres com síndrome dos ovários policísticos. Metodologia: Estudo transversal realizado com 78 mulheres entre 18 e 42 anos atendidas no Hospital Universitário Unidade Materno-Infantil da Universidade Federal do Maranhão com o diagnóstico de síndrome dos ovários policísticos de acordo com os critérios de Rotterdam. As variáveis de interesse foram registradas em ficha-protocolo com: dados sócio-demográficos, comportamentais, história ginecológica, antecedentes pessoais e familiares de patologias, dados antropométricos (peso, altura, índice de massa corporal e circunferência da cintura), exames laboratoriais, exame de imagem e valores de pressão arterial. O produto da acumulação lipídica foi calculado pela fórmula descrita por Kahn. Com relação à análise de dados a normalidade das variáveis quantitativas foi analisada pelo teste Shapiro Wilk, para comparação das médias das variáveis utilizou-se o Teste t de Student. Na verificação de Correlação entre o produto da acumulação lipídica e os marcadores de risco cardiovascular foi aplicado o teste de Correlação Linear de Pearson (r). O produto da acumulação lipídica foi submetido à análise segundo a Curva Receiver Operating Characteristic, sendo discriminados os valores de maior sensibilidade e especificidade, simultaneamente. O nível de significância para todos os testes foi de 5%. Resultados: Utilizando-se a Curva Receiver Operating Characteristic para determinar o melhor ponto de corte do produto da acumulação lipídica preditivo de risco para doença cardiovascular, notou-se que o valor acima de 39,32 cm.mmol/L, representou a área sob a curva de 0,8845. Todas as mulheres que apresentaram o valor do produto da acumulação lipídica acima do ponto de corte definido, também apresentaram as maiores alterações nas médias dos marcadores de risco de doença cardiovascular analisados, diferença estatisticamente significativa. No que concerne à análise de correlação entre o produto da acumulação lipídica acima do ponto de corte definido e os marcadores de risco para doenças cardiovasculares, houve uma correlação significativa. Conclusão: Estes resultados demonstram que valores de ponto de corte ≥ 39,32 cm.mmol/L do produto da acumulação lipídica parecem apontar risco aumentado à doença cardiovascular e pode ser utilizado como ferramenta de triagem e investigação pela sua facilidade de mensuração e interpretação, além do baixo custo, podendo ter, inclusive, sua aplicabilidade na atenção primária em saúde.

Το σύνδρομο των πολυκυστικών ωοθηκών (PCOS) είναι ίσως η συχνότερη διαταραχή των γυναικών αναπαραγωγικής ηλικίας. Οι κύριες κλινικές εκδηλώσεις του συνδρόμου είναι η υπερανδρογοναιμία και η χρόνια ανωοθυλακιορρηξία, ενώ σχετίζεται σε μεγάλο βαθμό με την παχυσαρκία και την αντίσταση στην ινσουλίνη. Η αντίσταση στην ινσουλίνη έχει ένα σημαντικό ρόλο τόσο ως αίτιο όσο και ως αποτέλεσμα του συνδρόμου. Στις γυναίκες τόσο η υπερινσουλιναιμία όσο και η υπερανδρογοναιμία σχετίζεται με αυξημένο καρδιοαγγειακό κίνδυνο. Το PCOS σχετίζεται με αυξημένο καρδιοαγγειακό κίνδυνο, ενώ τόσο η αλλαγή τρόπου ζωής και η φαρμακολογική παρέμβαση έχει δειχθεί ότι βελτιώνει την υπερανδρογοναιμία και την υπογονιμότητα και ελαττώνει τον καρδιοαγγειακό κίνδυνο. Μαζί με τους κλασικούς καρδιοαγγειακούς παράγοντες κινδύνου, αιμοδυναμικές και αιματολογικές μεταβλητές παίζουν σημαντικό ρόλο στην παθογένεση της αθηρωσκλήρυνσης. Η γλοιότητα του πλάσματος είναι σημαντική αιματολογική μεταβλητή και εξαρτάται απο μακρομόρια όπως το ινωδογόνο, οι ανοσοσφαιρίνες και οι λιποπρωτεϊνες. Ο σκοπός της παρούσης μελέτης ήταν να ερευνήσει τις μεταβολές της γλοιότητας του πλάσματος σε γυναίκες με PCOS και την συσχέτιση τους με την υπερανδρογοναιμία, την παχυσαρκία και την αντίσταση στην ινσουλίνη. Η μελέτη συμπεριέλαβε 96 ασθενείς με PCOS και 72 γυναίκες με φυσιολογική έμμηνο ρύση ως ομάδα ελέγχου. Η γλοιότητα πλάσματος ήταν 1.243±0.670 mm2/s στην ομάδα ελέγχου (n=72), και 1.250±0.079 στιν γυναίκες με PCOS (n=96) (p=0.524). Η γλοιότητα του πλάσματος εμφάνισε σημαντική συσχέτιση με BMI (b=0.315, p=0.013), Ολικές Πρωτείνες (b=0.348, p=0.005), AUCIns (b=0.320, p=0.011). Στις γυναίκες με PCOS με αντίσταση στην ινσουλίνη (PCOS-IR) η γλοιότητα του πλάσματος ήταν 1.300 ± 0.055 mm2/s, ενώ στις γυναίκες με PCOS χωρίς αντίσταση στην ινσουλίνη (PCOS-ΝIR) η γλοιότητα του πλάσματος ήταν 1.231± 0.49 mm2/s (p=0.004). Στη συνέχεια χωρίσαμε όλες τις γυναίκες με PCOS σε 2 υποομάδες: αυτές με BMI<25 και αυτές με BMI>25. Η γλοιότητα πλάσματος ήταν 1.235±0.786mm2/s στις γυναίκες με PCOS και BMI<25, και 1.273±0.756mm2/s στις γυναίκες με PCOS και BMI>25 (p=0.024). Σε νέες γυναίκες με PCOS η αύξηση της γλοιότητας του πλάσματος συσχετίσθηκε με την παχυσαρκία και την αντίσταση στην ινσουλίνη. Συμπερασματικά στις νέες γυναίκες με PCOS η γλοιότητα του πλάσματος επιδεινώθηκε από την αντίσταση στην ινσουλίνη. Καθώς η αυξημένη γλοιότητα του πλάσματος είναι ένας πρώιμος παράγοντας κινδύνου για καρδιοαγγειακή νόσο, ο κλινικός χειρισμός των νέων υπέρβαρων γυναικών με PCOS θα πρέπει πάντα να περιλαμβάνει μία μείωση του σωματικού τους βάρους και τη λελογισμένη και με προσοχή χρήση των αντισυλληπτικών δισκίων ως θεραπευτική προσέγγιση. / Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. PCOS is characterized by hirsutism, anovulation, hyperandrogenemia and is also highly associated with obesity and insulin resistance. Insulin resistance plays a significant role, both as a cause and as a result of the syndrome. Both hyperinsulinemia and androgen excess in women is associated with increased cardiovascular risk. PCOS is linked to cardiovascular disease, while, altering lifestyle or pharmacological intervention has been shown to improve hyperandrogenism and infertility and reduce cardiovascular risk. Along with classic cardiovascular risk factors, hemodynamic and hemorheologic variables play an important role in the pathogenesis of atherosclerosis. Plasma viscosity is an important hemorheologic variable and is mainly determined by several macromolecules, including fibrinogen, immunoglobulins, and large lipoproteins. Our objective was to investigate plasma viscosity in women with PCOS. The acquired data were tested for association with hyperandrogenemia, obesity and insulin resistance in PCOS patients. The study included 96 young PCOS women and 72 healthy controls. Plasma viscosity was 1.243±0.670 mm2/s in the control group and 1.250±0.079 in PCOS women (p=0.524). Total protein (B=0.348, p=0.005), AUC for Insulin (B=0.320, p=0.011) and BMI (B=0.315, p=0.013) were proven to be significantly correlated to plasma viscosity. Plasma viscosity was significantly increased in PCOS women with Insulin Resistance (IR) compared to matched for age and BMI PCOS women without IR (1.300±0.055 mm2/s versus 1.231±0.049 mm2/s) (p=0.004). Then we divided all PCOS women in two separate groups, lean PCOS with BMI<25 and obese PCOS with BMI>25. Plasma viscosity was 1.235±0.786mm2/s in PCOS women with BMI<25, in the group of women was and 1.273±0.756mm2/s in PCOS women with BMI>25 (p=0.024). Young PCOS women presented a plasma viscosity which was increased by obesity and IR. In conclusion, young PCOS women presented a plasma viscosity which was deteriorated by IR. As increased plasma viscosity is an early risk factor for cardiovascular disease, clinical management of young overweight PCOS women with IR should always include a serious reduction in body weight and the use of oral contraceptive treatment with cautious.

Disease-specific compounds (biomarkers) are analyzed in clinical laboratories to assist with diagnosing diseases. This thesis describes development and validation of liquid chromatography tandem mass spectrometry (LC-MS/MS) based tests for diagnosing a diverse group of endocrine and metabolic diseases. The analytical methods used on-line and off-line sample extraction and analytical derivatization as means of enhancing the analytical sensitivity, specificity and clinical utility. All developed methods were extensively validated and reference intervals for the biomarker concentrations were established in blood samples of healthy adults and children. Advantages of the LC-MS/MS as an analytical technique include possibility of simultaneous measurement of multiple analytes and ability of confirming their identity. In this thesis we proposed and evaluated approaches for the assessment of the specificity of analysis in the methods that use tandem mass spectrometry detection. To enhance throughput of the LC-MS/MS tests for the biomarkers that have endogenous or exogenous isomers an approach was developed for quantitation of isomers from unresolved chromatographic peaks. Using methods developed in this thesis we performed a study of the steroidogenesis in ovarian follicles of healthy women and women with polycystic ovary syndrome (PCOS). Obtained data on the steroid concentrations and associations between the steroid metabolites in the pathway would be helpful for better understanding of the ovarian pathophysiology. Potential biomarkers of PCOS were identified in the thesis; further studies will be necessary to confirm their clinical utility.

Diss. (sammanfattning) Stockholm : Karolinska institutet 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Pubarca precoce (PP), definida como o surgimento de pelos pubianos antes dos oito anos de idade em meninas após exclusão de causas secundárias, tem sido associada a maior prevalência de componentes da síndrome metabólica e desenvolvimento da síndrome dos ovários policísticos (PCOS) na adolescência. Em mulheres com PCOS, foi relatado aumento da massa ventricular esquerda (MVE) e disfunção diastólica, associados à resistência insulínica (RI). Os objetivos dos estudos foram: 1) avaliar a MVE e a função cardíaca sistólica e diastólica através de ecocardiografia em meninas com PP e controles, além de analisar a associação entre os parâmetros cardíacos com androgênios e marcadores de RI; 2) determinar a frequência da PCOS em uma coorte de meninas com PP na pós-menarca e avaliar se existem preditores para o desenvolvimento da PCOS. Variáveis clínicas, hormonais e metabólicas, ecocardiografia e composição corporal foram obtidas em 35 meninas com PP e 35 controles saudáveis pareadas pela idade (artigo 1). Trinta e quatro meninas com mais de dois anos pós-menarca da coorte de PP da Unidade de Endocrinolgia Ginecológica do Hospital de Clínicas de Porto Alegre (UEG/HCPA) foram classificadas em PCOS e não-PCOS e seus dados pré-puberais foram analisados para detectar preditores do desenvolvimento de PCOS e comparados com os de 17 meninas controles saudáveis da mesma idade (artigo 2). Após ajuste para gordura corporal total, a MVE foi maior no grupo PP (97,31 ± 33,37 vs. 81,25 ± 19,06 g, p = 0,017), bem como a onda A’ (5,66 ± 1,34 vs. 5,09 ± 0,98 cm / s, p = 0,025), uma medida da função diastólica. O índice de androgêncios livres (FAI) e gordura corporal total foram preditores independentes de maior MVE e, juntamente com HOMA-IR contribuíram com 72% da variabilidade da MVE no grupo PP (artigo 1). No segundo artigo, 44,1% das meninas com PP foram diagnosticadas com PCOS na pósmenarca. Na pré-puberdade, esse grupo apresentou maior índice de massa corporal (IMC) e HOMA-IR em relação às controles, bem como níveis mais elevados de testosterona, escore de hirsutismo e insulina em jejum quando comparadas às não-PCOS e às controles. O risco para o desenvolvimento de PCOS entre as PPs esteve associado ao IMC z-escore ≥ 2 (odds ratio [OR] = 4; intervalo de confiança 95% [IC] 1.33 – 18.66); escore de Ferriman-Galwey ≥ 4 (OR = 2,7; IC 95% 1,15-5,14); HOMA-IR ≥ 2,42 (OR = 7; IC 95% 1,39-12,0) e volume ovariano ≥ 1,17 mL (OR = 8; IC 95% 1,60-39,9) no período pré-puberal. Em conclusão, meninas com PP apresentaram maior MVE associada aos níveis de androgênios, RI e gordura corporal total. Além disso, foi encontrada alta freqüência de PCOS na coorte de PP da UEG/HCPA. Obesidade, maior escore de hirsutismo, RI e volume ovariano na pré-puberdade foram preditores de desenvolvimento da PCOS na adolescência. / Precocious pubarche (PP) in girls, defined as idiopathic appearance of pubic hair before the age of eight years, has been associated with higher prevalence of components of metabolic syndrome and post pubertal development of polycystic ovary syndrome (PCOS). Increased left ventricular mass (LVM) and diastolic dysfunction have been reported in women with PCOS associated with insulin resistance (IR). The aims of the studies were: 1) to assess LVM and cardiac systolic and diastolic function using echocardiography in girls with PP and controls, and to analyze the relationship between cardiac parameters with androgens and IR; 2) to determine the frequency of PCOS in a cohort of postmenarcheal PP girls and to assess whether possible predictors exist for development of PCOS Clinical, hormonal and metabolic profiles, echocardiography and body composition were examined in 35 PP girls and 35 healthy age-matched controls (article 1). Thirty-four postmenarcheal girls with PP of the Gynecological Endocrinology Unit, Division of Endocrinology of Hospital de Clínicas de Porto Alegre (GEU/HCPA) clinic cohort were classified as PCOS and non-PCOS and prepubertal data were analyzed to detect PCOS development predictors and compared with data of 17 age-matched controls (article 2). After adjusting for total body fat, LVM was higher in the PP group (97.31 ± 33.37 vs. 81.25 ± 19.06 g, p = 0.017) as well as A’ wave (5.66 ± 1.34 vs. 5.09 ± 0.98 cm/s, p=0.025), a measurement of diastolic function. Free androgen index (FAI) and total body fat were independent predictors of higher LVM, and together with HOMA-IR contributed with 72% of LVM variability in the PP group (article 1). In the second article, fifteen (44.1%) PP girls were classified as PCOS and had higher body mass index standard deviation score (BMI SDS) and HOMA-IR than controls, as well as higher testosterone, hirsutism score and fasting insulin than non-PCOS girls and controls in prepubertal period. The risk for PCOS development among PP girls increased with prepubertal BMI SDS ≥ 2 (odds ratio [OR] = 4; 95% confidence interval [CI] 1.33 – 18.66), Ferriman-Galwey hirsutism score ≥ 4 (OR = 2.7; 95% CI 1.15 - 5.14), HOMA-IR ≥ 2.42 (OR = 7; 95% CI 1.39 - 12.0) and ovarian volume ≥ 1.17 mL (OR= 8; 95 CI 1.60 – 39.9). In conclusion, PP girls had greater LVM associated with higher androgen levels, IR, and total body fat, occurred early in pubertal development. In addition, we found high frequency of PCOS in Southern Brazil PP cohort. Obesity, clinical androgenism, IR and ovarian volume were predictors of development of PCOS later.

A síndrome dos ovários policísticos (PCOS) é o distúrbio endócrino mais comum em mulheres em idade reprodutiva, sendo caracterizado por anovulação crônica e manifestações de hiperandrogenismo. O sobrepeso e a obesidade afetam a maioria das mulheres com PCOS e, quando presentes, podem acentuar as alterações reprodutivas e metabólicas associadas à síndrome. Dessa forma, a redução de peso através da restrição calórica é de suma importância nas mulheres com PCOS e excesso de peso. Entretanto, ainda não está estabelecido se a composição da dieta por si só pode ter efeitos significativos sobre as alterações metabólicas e hormonais da PCOS. Poucos ensaios clínicos randomizados avaliando o efeito de diferentes intervenções dietéticas foram realizados em mulheres com PCOS, sendo que os estudos existentes apresentam, em sua maioria, curta duração e pequeno tamanho amostral. Dietas com redução de carboidratos, assim como dietas com baixo índice glicêmico e carga glicêmica têm sido o principal foco de estudo em mulheres com PCOS e, embora os resultados sejam controversos, estudos demonstram superioridade desses tipos de dieta em relação a uma dieta convencional na melhora do perfil antropométrico e da sensibilidade insulínica. Por outro lado, mudanças de estilo de vida podem não ser suficientes para promover uma redução de peso significativa e intervenções farmacêuticas podem ser necessárias. O orlistat é um fármaco usado no tratamento da obesidade que age através da inibição das lipases gástricas e pancreáticas e não tem efeitos adversos sistêmicos, sendo o único fármaco antiobesidade disponível em muitos países. Dessa forma, com o objetivo de avaliar os efeitos do orlistat nas variáveis clínicas relacionadas à perda de peso, assim como comparar esses efeitos com aqueles obtidos com o uso da metformina, em mulheres com PCOS, realizou-se uma revisão sistemática e meta-análise. Os resultados dessa revisão sistemática sugerem que o orlistat leva a uma redução significativa do peso/índice de massa corporal (IMC) em mulheres com PCOS. Além disso, os resultados da meta-análise evidenciaram que o orlistat e a metformina têm efeitos similares na redução de IMC, testosterona, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) e insulina em mulheres com PCOS com sobrepeso e obesidade. Outro fator a ser considerado é o aumento do risco cardiovascular associado à PCOS. Estudos demonstram que as alterações cardiovasculares pré-clínicas são mais frequentes nesta população do que em mulheres sem a síndrome de mesma idade. A variabilidade da frequência cardíaca (VFC) é a medida das variações cíclicas dos intervalos entre as batidas cardíacas (intervalo R-R), e reflete a função cardíaca autonômica. Alterações na VFC podem refletir doença cardiovascular subclínica. A redução do consumo de gordura saturada tem um importante papel na prevenção primária e secundária de doenças cardiovasculares. Dessa forma, realizou-se um estudo com objetivo de avaliar se o consumo de ácidos graxos saturados (SFA) está associado com VFC em mulheres com PCOS. Oitenta e quatro mulheres com PCOS foram incluídas no estudo. A análise da VFC foi realizada no repouso e após teste de stress mental. As participantes foram estratificadas de acordo com a mediana do consumo de SFA (8,5% do consumo energético total), avaliado por questionário de frequência alimentar. Os resultados desse estudo indicam que o menor consumo de SFA combinado com menor consumo de carne vermelha e maior consumo de frutas, vegetais e feijões está associado com melhor VFC em resposta ao stress e níveis circulantes mais baixos de testosterona em mulheres com PCOS. / Polycystic ovary syndrome (PCOS), the most common endocrinological disorder in women of reproductive age, is characterized by hyperandrogenism and chronic anovulation. Obesity or overweight affect most of patients with PCOS and may accentuate reproductive and metabolic issues. Thus, weight reduction through calorie restriction is extremely important in overweight/obese PCOS women. However, it remains unclear whether the diet composition per se may have significant effects on metabolic and hormonal issues of PCOS. A few randomized controlled trials (RCTs) evaluating the effect of different dietary interventions have been performed in PCOS women, and most studies have short-term and small sample size. Low-carbohydrate diets as well as diets with low glycemic index and glycemic load have been the main focus of studies in PCOS women, and although the results are controversial, studies demonstrated superiority of these diets in relation to a conventional diet in improving anthropometric profile and insulin sensitivity. On the other hand, lifestyle changes may not be sufficient to promote significant weight loss, and pharmaceutical interventions may be required. Orlistat is a drug for the treatment of obesity that acts by inhibiting gastric and pancreatic lipases. Orlistat does not have systemic adverse effects and it is currently the sole anti-obesity agent available in many countries. In this way, a systematic review and meta-analysis was performed. The aim was to assess the effects of orlistat on weight loss-associated clinical variables and to compare these effects to those obtained with metformin treatment in overweight/obese women with PCOS. The results of this systematic review indicate that orlistat leads to significant reduction in weight/body mass index (BMI) in PCOS. In addition, the results of meta-analysis indicate that orlistat and metformin have similar effects in reducing BMI, HOMA, testosterone and insulin in overweight/obese PCOS women. Another point to consider is the increased cardiovascular risk associated with PCOS. Studies have demonstrated that preclinical cardiovascular disorders are more frequent in PCOS than in women without the syndrome of same age. The heart rate variability (HRV) is a measure of the time variation between heart beats (R-R interval), and reflects autonomic cardiac function. Alterations in HRV may reflect subclinical cardiovascular disease. Reduction in saturated fat intake has an important role in primary and secondary of cardiovascular disease. Thus, we performed a study assessing whether dietary saturated fatty acids (SFA) intake is associated with stress-induced HRV in patients with PCOS. Eighty-four PCOS women were included in the study. The HRV analysis was performed at rest and after mental stress test. Participants were stratified by median SFA intake (8.5% of daily energy intake), assessed by food frequency questionnaire. The results indicate that lower SFA intake is associated with more favorable stress-related HRV and lower testosterone in women with PCOS.

Abstract Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5–15% of women of reproductive age. The syndrome is characterized by menstrual irregularities, hyperandrogenism and polycystic ovaries. Infertility is a major problem in PCOS and it can be explained partially by chronic anovulatory cycles. Excess body weight and insulin resistance are common among women with PCOS, exposing them to the most common pregnancy complication, gestational diabetes mellitus (GDM) and, later in life, to a higher risk of developing glucose metabolism disorders eventually leading to outbreak of type 2 diabetes mellitus (T2DM). However, the respective roles of the syndrome per se, excess body weight and hyperandrogenism regarding the aforementioned complications are still to be clarified. The objectives were first to determine the risks of PCOS, infertility problems and decreased fertility at age 26 in women with a history of menstrual irregularity or elevated androgen levels in adolescence (at age 16). We also aimed to clarify whether PCOS per se is associated with decreased fertility and increased incidence of miscarriage, GDM, prediabetes and T2DM. Lastly, we focused on the respective roles of excess body weight and hyperandrogenism as regards the development of GDM and impaired glucose metabolism. The study populations were derived from the prospective Northern Finland Birth Cohorts 1966 and 1986, comprising all expected births in 1966 (n = 5889 females) and 1986 (n = 4567) in the two northernmost provinces of Finland. The data was complemented with fertility rates and diagnoses of GDM and T2DM from registers held by the National Institute for Health and Welfare and The Social Insurance Institution of Finland. Menstrual irregularity or elevated androgen levels in adolescence were associated at age 26 with increased risks of PCOS and infertility problems, but not with decreased fertility rates. At the end of their reproductive life women with symptoms of PCOS were not more often childless, had had a similar incidence of miscarriages but had a smaller family size compared with healthy women, and obesity further decreased family size in this group. Excess body weight and elevated androgen levels, but not PCOS per se, were independent risk factors of GDM. The increased risk of T2DM in PCOS was mainly due to excess body weight, although both factors had a synergistic effect on the development of T2DM. / Tiivistelmä Monirakkulainen munasarjaoireyhtymä (PCOS) on yleinen naisilla esiintyvä hormonaalinen häiriö, josta kärsii 5-15% lisääntymisikäisistä naisista. Kuukautiskierron häiriöt, mieshormoniylimäärä ja monirakkulaiset munasarjat ovat ominaisia oireyhtymälle. Lapsettomuus on keskeinen ongelma oireyhtymässä, mikä johtuu osittain kroonisesta ovulaatioiden epäsäännöllisyydestä tai niiden puuttumisesta. Ylipainoa ja insuliiniresistenssiä esiintyy usein oireyhtymää sairastavilla naisilla ja ne altistavat raskausajan diabeteksen puhkeamiselle. Myöhemmällä iällä PCOS-naisilla on suurentunut riski sairastua sokeriaineenvaihdunnan häiriöihin, jotka lisäävät riskiä tyypin 2 diabeteksen (T2DM) puhkeamiselle. PCOS:n, ylipainon ja mieshormoniylimäärän itsenäiset roolit edellä mainittujen häiriöiden kehittymisessä ovat kuitenkin edelleen epäselviä. Ensimmäisenä tavoitteena oli selvittää PCOS:n, lapsettomuusongelmien ja alentuneen hedelmällisyyden riskiä 26-vuotiaana naisilla, joilla todettiin kuukautiskierron häiriö tai kohonneet mieshormonipitoisuudet nuoruusiällä (16-vuotiaana). Toiseksi selvitimme, liittyykö PCOS itsessään alentuneeseen hedelmällisyyteen sekä kohonneeseen keskenmenojen, raskausdiabeteksen, diabeteksen esiasteiden ja T2DM esiintyvyyteen. Lisäksi selvitimme ylipainon ja mieshormoniylimäärän itsenäisiä rooleja raskausdiabeteksen ja muiden sokeriaineenvaihdunnan häiriöiden kehittymisessä. Tutkimusaineistoina olivat Pohjois-Suomen syntymäkohortit 1966 (n = 5889 naista) ja 1986 (n = 4567 naista), joihin sisältyivät kaikki elävänä syntyneet lapset vuosina 1966 ja 1986 kahdesta Suomen pohjoisimmasta läänistä. Tutkimusaineistoja täydennettiin hedelmällisyyslukujen ja GDM- sekä T2DM-diagnoosien osalta Terveyden ja hyvinvoinnin laitoksen ja Kansaneläkelaitoksen ylläpitämistä rekistereistä. Nuoruusiän kuukautiskierron häiriöt ja mieshormoniylimäärä olivat yhteydessä suurentuneeseen riskiin kehittää PCOS ja kärsiä lapsettomuusongelmista, mutta näiden yhteyttä alentuneisiin hedelmällisyyslukuihin 26-vuotiaana ei todettu. PCOS-oireiset naiset eivät kärsineet lapsettomuudesta lisääntymisiän aikana verrokkinaisia enemmän ja keskenmenojen esiintyvyys ei eronnut oireisten ja terveiden naisten välillä. Oireisilla naisilla oli kuitenkin pienempi perhekoko kuin verrokeilla, ja lihavuus entisestään pienensi perhekokoa oireisilla naisilla. Ylipaino ja mieshormoniylimäärä olivat itsenäisiä riskitekijöitä raskausdiabeteksen kehittymiselle. PCOS ei ollut riskitekijä raskausdiabeteksen kehittymiselle. Kohonnut T2DM-riski PCOS:ssa johtui lähinnä ylipainosta, vaikkakin molemmat tekijät olivat itsenäisiä riskitekijöitä T2DM:n kehittymiselle.

A Síndrome dos Ovários Policísticos (PCOS) é a endocrinopatia mais frequente em mulheres na idade reprodutiva, além de ser a causa mais comum de hiperandrogenismo e anovulação crônica. Diferentes fenótipos da PCOS foram identificados, e um melhor entendimento dessas diferentes apresentações clínicas se faz necessário para o reconhecimento de riscos, medidas preventivas e terapêuticas específicas para cada fenótipo. Associações entre polimorfismos de substituição de um único nucleotídeo (SNPs) em genes que codificam enzimas responsáveis pelo metabolismo androgênico e PCOS foram descritos. O anticoncepcional oral (ACO) é utilizado para o tratamento de mulheres com PCOS por seu efeito supressivo na secreção de androgênios ovarianos e melhora do hirsutismo. Entretanto, os dados na literatura são conflitantes quanto aos efeitos do ACO nos parâmetros metabólicos de mulheres com PCOS. Além disso, não está bem estabelecido se a presença de alelos polimórficos está associada com diferenças nos fenótipos da PCOS e se pode influenciar na resposta ao tratamento com ACO. Os objetivos desta tese foram investigar a influência dos SNPs -71 AG no gene AKR1C3 e SNP50 no gene CYP19 gene (substituição de G por A) na resposta de mulheres com PCOS ao tratamento com ACO e verificar se o SNP50 está associado com fenótipos da PCOS. Cento e sessenta e duas mulheres com PCOS foram estratificadas em PCOS clássicas (hiperandrogenismo e disfunção ovulatória, c-PCOS) e PCOS ovulatórias (hiperandrogenismo, ciclos ovulatórios, aparência policística dos ovários, ov-PCOS) e uma subamostra de 51 mulheres (que não apresentavam resistência insulínica evidente) completaram 6 meses de tratamento com ACO (20 ug etinilestradiol e 75 ug gestodeno, 21/28 dias por ciclo). A presença ou ausência dos alelos polimórficos foram consideradas para expressar os resultados que avaliaram os SNPs -71 AG e SNP50. O escore de hirsutismo foi similar em c-PCOS e ov-PCOS, e as diferenças nos parâmetros hormonais e metabólicos observadas foram independentes da presença do alelo A do SNP50. Após os 6 meses de tratamento com ACO, como era esperado, os níveis de testosterona total e o escore clínico de hirsutismo diminuíram, enquanto os níveis da globulina carreadora de hormônios sexuais aumentaram. Houve uma pequena redução da pressão arterial sistólica e do hormônio luteinizante. As medidas de insulina e do índice HOMA permaneceram inalteradas após o tratamento. Houve um aumento dos níveis de lipídios, mas os valores permaneceram dentro dos limites da normalidade. Nenhuma das alterações observadas esteve associada com a presença dos alelos polimórficos dos SNPs -71 AG ou SNP50. As conclusões são de que o ACO é uma alternativa eficaz para o tratamento dos sintomas do hiperandrogenismo, sem comprometimento dos parâmetros metabólicos, pelo menos naquelas mulheres sem resistência insulínica prévia ao tratamento. Os SNPs -71AG no gene AKR1C3 e SNP50 no gene CYP19 não contribuem para as melhoras observadas com o uso do ACO. Além disso, o SNP50 parece não estar associado com as diferenças existentes entre os fenótipos clássico e ovulatório da PCOS. / Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women at reproductive age, and also the most common cause of hyperandrogenism and chronic anovulation. Different phenotypes of PCOS have been identified, and a better knowledge of these clinical symptoms is necessary to recognize risks, prevention, and treatment strategies for each phenotype. Associations between single nucleotide polymorphisms (SNPs) in genes that codify enzymes responsible for the androgenic metabolism and PCOS have been described. The oral contraceptive pill (OCP) is used to treat women with PCOS due to the suppressive effect on ovarian androgen secretion, with consequent amelioration of hirsutism. However, data are conflicting in literature regarding the effects of OCP on metabolic variables in PCOS. Besides that, it is not well established whether the presence of polymorphic alleles is associated with PCOS phenotypes and whether can influence on the response to OCP treatment. The aims of this thesis were to investigate the influence of the SNPs -71 AG at AKR1C3 gene and SNP50 of CYP19 gene (G to A substitution) on the response of PCOS to treatment with oral contraceptive pills and to assess whether the SNP50 is associated with PCOS phenotypes. A hundred sixty two hirsute women were stratified into a classic PCOS group (hyperandrogenism and ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS), and a subsample of 51 women (without evidences of insulin resistance) completed a 6-month OCP trial (20 ug ethinylestradiol plus 75 ug gestodene, 21/28 days per cycle). We considered the presence or absence of the polymorphic alleles to express results and to perform the comparisons regarding the SNPs -71 AG and SNP50. Hirsutism score was similar in c-PCOS and ov-PCOS, and the differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A for SNP50. After 6 months of OCP treatment, as expected, total testosterone and hirsutism score declined, while sex hormone binding globulin increased. There was a slight reduction in systolic blood pressure and luteinizing hormone levels. Insulin and homeostasis model assessment remained unchanged after treatment. There was an increase in lipids, but the values remained at the normal range. None of these changes were associated with the presence of polymorphic alleles for -71 AG or SNP50 polymorphisms. We conclude that OCP is an alternative to ameliorate androgenic symptoms without compromising metabolic parameters, at least in women without insulin resistance before treatment. The -71AG SNP of AKR1C3 gene and the SNP50 of CYP19 gene did not contribute to the improvements observed. Besides that, SNP50 may not be associated to the existing differences between classic and ovulatory PCOS phenotypes.