Made available in DSpace on 2014-06-11T19:29:52Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-01-29Bitstream added on 2014-06-13T19:18:30Z : No. of bitstreams: 1 santos_agp_me_botfm.pdf: 577277 bytes, checksum: 1563f6178a994411a2a0b69843652490 (MD5) / A síndrome dos ovários policísticos (SOP) é uma endocrinopatia comum em mulheres no menacme, com prevalência variando entre 5 a 10%. Em vários estudos, pacientes com SOP apresentam risco aumentado para o desenvolvimento das anormalidades do metabolismo da glicose. O diabetes mellitus está entre as 10 maiores causas de mortalidade no Brasil decorrente das complicações micro e macrovasculares. Avaliar a prevalência de resistência à insulina (RI), intolerância à glicose (IG) e diabetes mellitus tipo 2 (DM) nas pacientes com diagnóstico de SOP. Foram avaliados retrospectivamente os dados clínicos, bioquímicos e ultra-sonográficos de 247 pacientes com o diagnóstico de SOP. Para a avaliação do grau de RI, utilizou-se um grupo de 101 mulheres com ciclos menstruais regulares sem hiperandrogenismo. O diagnóstico de RI foi obtido utilizando-se os seguintes valores de corte: insulinemia > 12 μIU/ml, HOMA-IR > 2,71, QUICKI < 0,333, ISI < 4,75 e relação glicemia / insulina < 6,4. O diagnóstico de IG e DM tipo 2 foi realizado por meio do teste de tolerância à glicose oral (TTGO) de acordo com os critérios do WHO, 1985 e comparado ao diagnóstico pela glicemia de jejum (ADA, 2003). Para a análise estatística dos resultados, foi utilizado o teste de qui-quadrado para a associação entre as variáveis, e para as variáveis quantitativas foram utilizadas a estatística descritiva e análise de variância seguida do método de Tukey ou t de student. As pacientes com SOP apresentaram idade entre 12 a 40 anos (24,8 ± 6,3) e índice de massa corpórea entre 18,3 a 54,9 Kg/m² (32,5 ± 7,6). O percentual de pacientes obesas foi de 64%. A RI foi detectada em 54,2% das pacientes pela relação glicemia / insulina, em 59,9% pelos índices de HOMA-IR e QUICKI, em 70,6% pelo ISI e 61,9% apresentaram insulinemia > 12 μIU/ml. A RI foi maior quanto... / The polycystic ovary syndrome (PCOS) is a common endocrinopathy in women during menacme, with a prevalence ranging from 5 to 10%. In several studies, patients with PCOS have shown increased risk for developing glucose metabolism abnormalities. Diabetes mellitus is among the 10 major causes of mortality resulting from micro and macrovascular causes in Brazil. To evaluate the prevalence of insulin resistance (IR), impaired glucose tolerance (IGT) and type-2 diabetes mellitus (DM) in patients diagnosed with PCOS. The clinical, biochemical and ultrasonographic data of 247 patients diagnosed with PCOS were retrospectively analyzed. To compare IR levels, a group of 101 women with regular cycles without hyperandrogenism was used. IR diagnosis was performed by using the following cutoff values: insulinemia > 12 μIU/ml, HOMA-IR > 2.71, QUICK < 0.333, ISI < 4.75 and glycemia / insulin ratio < 6.4. The GI and type-2 DM diagnosis was performed by means of the oral glucose tolerance test (OGTT), according to WHO criteria, 1985 and compared with fasting plasma glucose diagnosis (ADA, 2003). The results were interpreted by the chisquare test for association between variables, and descriptive statistics and analysis of variance followed by Tukey’s or Student’s t tests were used for quantitative variables... (Complete abstract clic, electronic access below)

Este estudo teve como objetivos avaliar o metabolismo de quilomícrons utilizando a metodologia da cinética plasmática de uma emulsão de quilomícrons artificiais em pacientes com síndrome dos ovários policísticos (SOP), assim como o impacto da obesidade nesta cinética. Foram estudadas 43 mulheres adultas jovens, subdivididas em 4 grupos, sendo 8 pacientes com SOP e índice de massa corporal normal [SOP-N (IMC = 22,7 ± 1,9 Kg/m2)], e 15 com IMC >=30 kg/m2 [SOP-O (IMC = 33,8 ± 3,3 kg/m2)], pareadas com 20 mulheres controles, sendo 10 com IMC normal [Controle-N (IMC = 21 ± 1,76 kg/m2)] e 10 com IMC obeso [Controle-O (IMC = 33,7± 3,1 kg/m2)]. Quando os grupos foram comparados entre si, com relação às características antropométricas, perfil lipídico e apolipoproteínas; detectou-se diferença estatisticamente significante entre IMC (P < 0,001), circunferência abdominal (CA) (P < 0,001), colesterol total (P = 0,042), HDL-colesterol (P < 0,001), LDL-colesterol (P = 0,009), triglicérides (TG) (P < 0,001) e apolipoproteína B (P < 0,001). As médias destas variáveis foram maiores nos grupos Controle- O e SOP-O, não havendo diferenças entre eles. Com relação à apolipoproteína A1 e ácidos graxos livres não houve diferença entre os grupos. A média da apolipoproteína E foi significativamente maior no grupo Controle-N, não havendo diferença ao compararmos os outros três grupos entre si. Com relação à concentração dos hormônios, as pacientes com SOP tiveram médias significativamente maiores para a testosterona total e testosterona livre (TL) (P < 0,001, P = 0,001), respectivamente. O estradiol foi menor nas pacientes com SOP (P = 0,039), não havendo o impacto da obesidade nestas variáveis hormonais. A média da globulina ligadora dos esteróides (SHBG) foi significativamente maior no grupo Controle-N, não havendo diferença ao compararmos os outros três grupos entre si. Com relação ao modelo homeostático de resistência à insulina (HOMA-IR), houve um impacto significativo da obesidade e da SOP. A média do HOMA-IR foi significativamente maior nas mulheres obesas (Controle e SOP), e nas pacientes com SOP, ao compararmos com as controles pareadas para o IMC. Com relação à cinética plasmática de emulsão de quilomícrons artificiais, não houve diferença estatisticamente significante entre os grupos, da taxa fracional de remoção plasmática de 3H-triglicérides (TFR-TG), que avalia indiretamente a lipólise das partículas de triglicérides dos quilomícrons pela lipase lipoprotéica. Com relação à média da taxa fracional de remoção plasmática de 14C- éster de colesterol (TFR-EC), houve diferenças estatisticamente significantes, sendo as médias das pacientes com SOP menores que as médias das mulheres controles (P = 0,004), sem impacto da obesidade nesta variável. Após a análise de regressão multivariada, não se observou influência de nenhuma das variáveis estudadas na TFR-EC das pacientes com SOP. Na análise de Correlação de Pearson, observamos nas pacientes com SOP, uma correlação direta entre IMC e TG (r = 0,480; P = 0,020), IMC e HOMA-IR (r = 0,687; P < 0,001), CA e TG (r = 0,574; P = 0,004), CA e HOMA-IR (r = 0,634; P = 0,001), HDL e SHBG (r = 0,481; P = 0,020), e correlação inversa entre IMC e SHBG (r = - 0,581; P = 0,004), CA e SHBG (r = - 0,629; P = 0,001), CA e HDL (r = - 0,464; P = 0,016), SHBG e TG (r = - 0,414; P = 0,050), SHBG e HOMA-IR (r = - 0.528; P = 0,010), TL e SHBG (r = - 0.510; P = 0,013). A diminuição da recaptação de remanescentes de quilomícrons, demonstrada através da diminuição da TFR-EC, é compatível com níveis circulantes maiores destes remanescentes, assim como um tempo de permanência maior na circulação, facilitando e progredindo o processo de aterosclerose. A diminuição da TFR-EC está presente na SOP, independentemente do IMC, sendo mais um fator de risco cardiovascular nas portadoras desta síndrome. / The aims of this study were to evaluate the chylomicrons metabolism using the method of plasma kinetics of an emulsion of artificial chylomicrons in patients with polycystic ovary syndrome (PCOS), as well as the impact of obesity in this kinetics. Forty-three young adult women were studied , subdivided into 4 groups: 8 of them, with PCOS and normal body mass index [ PCOS-N (BMI = 22.7 ± 1.9 kg/m2)], and 15 with BMI >=30 kg/m2 [PCOS-O (BMI = 33.8 ± 3.3 kg/m2 )] , pairwise matched with 20 controls, being 10 with normal BMI [ Control-N (BMI =21 ± 1.76 kg/m2 )] and 10 with obese BMI [Control-O (BMI = 33.7 ± 3.1 kg/m2 )]. When the groups were compared among themselves, in relation to the antropometric features, lipid profile and apolipoproteins; it was detected a statistically significant difference among BMI (P < 0.001), waist circunference (WC) (P < 0.001), total cholesterol (P = 0.042), HDL-cholesterol (P < 0.001), LDL-cholesterol (P = 0.009), triglycerides (TG) (P < 0.001) and apolipoprotein B (P < 0.001). The means of these variables were higher in the Control-O and PCOS groups and there were no differences among them. In relation to apolipoprotein A1 and to free fatty acids, there was no difference among the groups. The means of apolipoprotein E was significantly higher in the Control-N group and there was no difference when we compared the other three groups among themselves. In relation to hormone concentration, the PCOS patients had means significantly higher for total testosterone and free testosterone (P < 0.001, P = 0.001), respectively. Estradiol was lower in PCOS patients (P = 0.039), and there was no obesity impact in these hormonal variables. The means of sex hormone-binding globulin (SHBG) was significantly higher in the Control-N group, and there was no difference when we compared the other three groups among themselves. In relation to the homeostasis model assessment of insulin resistance (HOMA-IR), there was a significant impact of obesity and of PCOS. The means of HOMA-IR was significantly higher in obese women (Controls and PCOS), and in PCOS patients when compared with pairwise matched controls for BMI. In relation to the plasma kinetics of artificial chylomicrons emulsion, there was no statistically significant difference among the groups, of the plasma 3H-triglyceride fractional clearance rate (TFR-TG) , which evaluates indirectly the lipolysis of triglycerides particles of chylomicrons by the lipoprotein lipase. In relation to the means of plasma fractional clearance rate of 14C-cholesterol ester (TFR-EC), there were statistically significant differences, being the means of PCOS patients, lower than the means of controls (P = 0.004), without obesity impact in this variable. After the multivariate regression analysis, it was not observed influence of any of the variables studied in TFR-EC of PCOS patients. Using the Pearson\'s Correlation analysis, we observed in PCOS patients, a direct correlation between BMI and TG (r = 0.480; P = 0.020), BMI and HOMA-IR (r = 0.687; P < 0.001), CA and TG (r = 0.574; P = 0.004), CA and HOMA-IR (r = 0.634; P = 0.001); HDL and SHBG (r = 0.481; P = 0.020) and inverse correlation between BMI and SHBG ( r = - 0.581; P = 0.004), CA and SHBG (r = - 0.629; P = 0.001), CA and HDL (r = -0.464; P = 0.016), SHBG and TG ( r = - 0.414; P = 0.050), SHBG and HOMA-IR ( r = - 0.528; P = 0.010), TL and SHBG ( r = - 0.510; P = 0.013). The decrease of the uptake of chylomicrons remnants shown through the decrease of TFR-EC, is compatible with higher circular levels of these remnants, as well as a prolonged duration in the circulation, facilitating and proceeding to the atherosclerosis process. The decrease of TFR-EC is present in PCOS, independently of BMI, and it is one more cardiovascular risk factor for PCOS patients.

A síndrome dos ovários policísticos (SOP) e a obesidade estão associadas ao aumento do risco cardiovascular, mas não está estabelecido se tal aumento é determinado por estas condições propriamente ditas ou pelos fatores de risco cardiometabólicos a elas associados. Objetivo: determinar, em mulheres jovens e sem fatores de risco cardiometabólicos, a influência da SOP e da obesidade sobre parâmetros vasculares relacionados ao processo de aterogênese. Métodos: foram estudadas pacientes com SOP, subdivididas em portadoras de índice de massa corpórea (IMC) normal e obesas, as quais foram comparadas a mulheres sem SOP (grupo controle) pareadas para o IMC. Foram excluídas participantes tabagistas, com distúrbios do metabolismo da glicose, hipertensão arterial, LDL-C 160 mg/dL e triglicérides 250 mg/dL. Foram avaliados parâmetros clínicos, laboratoriais (perfis hormonal e metabólico) e vasculares [espessura íntimamédia da artéria carótida comum (EIM-ACC), complacência da artéria carótida comum (CP-ACC) e função endotelial da artéria braquial (DMF)], os quais foram avaliados de maneira não-invasiva através de imagens ultrasonográficas de alta-resolução. Para determinar a influência da SOP e da obesidade sobre tais parâmetros, foram formados grupos de acordo com a presença ou ausência de tais condições: grupo SOP vs grupo Controle, independentemente do IMC; grupo IMC normal vs grupo Obesidade, independentemente da presença da SOP. Resultados: Foram selecionadas 25 pacientes com SOP, sendo 10 com IMC normal (34,0 ± 3,2 kg/m2) e 15 obesas (22,4 ± 2,1 kg/m2) e 23 mulheres controles (12 com IMC normal e 11 obesas). As médias de testosterona livre das pacientes com SOP foram significativamente superiores às médias das mulheres controles, independentemente do IMC. As médias do HOMA-IR e da área sob a curva de insulina das pacientes obesas com SOP foram significativamente superiores às observadas nas pacientes com SOP portadoras de IMC normal e mulheres controles. A média da EIM-ACC das pacientes obesas com SOP foi significativamente superior à das mulheres controles com IMC normal (50,0 ± 4,0 vs 47,0 ± 3,0 mm.10-2; p<0,05). As médias da CP-ACC e da DMF foram semelhantes entre pacientes com SOP e mulheres controles, independentemente do IMC. Para avaliar a influência da SOP e da obesidade, as comparações foram, respectivamente: grupo SOP (n=25) vs grupo Controle (n=23); grupo IMC normal (n=22) vs grupo Obesidade (n=26). A faixa etária global foi de 26,0 ± 4,7 anos. Tanto a SOP quanto a obesidade influenciaram os parâmetros de resistência insulínica. A média da EIM-ACC foi maior no grupo SOP do que no grupo Controle (49,1 ± 1,0 vs 47,2 ± 1,0 mm.10-2; p<0,05) e semelhante entre os grupos IMC normal e Obesidade (49,1 ± 1,0 vs 47,3 ± 1,0 mm.10-2; NS). Não foi observada influência da SOP ou da obesidade na CP-ACC e na DMF. Os parâmetros vasculares estudados não se correlacionaram com as outras variáveis analisadas entre as pacientes com SOP e entre as mulheres controles. Conclusão: Em mulheres jovens e sem fatores de risco cardiometabólicos, a presença da SOP teve influência no aumento da EIM-ACC. Assim, a EIMACC pode ser o marcador inicial do processo de aterogênese nesse grupo de pacientes / Polycystic ovary syndrome (PCOS) and obesity are related to the increase in cardiovascular risk, but it is still not known if such risk is due to these conditions themselves or to the cardiometabolic risk factors associated with them. Objective: determine, in young women without cardiometabolic risk factors, the influence of PCOS as well as obesity on vascular parameters related to the process of atherogenesis. Methods: We studied patients with PCOS, subdivided in patients with normal body mass index (BMI) and obeses, who were compared with women without PCOS (control group) pairwise matched for BMI. We excluded smoking subjects, subjects with glucose metabolism disturbances, with arterial hypertension, LDC -L 160 mg/dl and with triglycerides 250 mg/dl. We evaluated clinical, laboratory (hormonal and metabolic profiles) and vascular parameters [common carotidy artery intima-media thickness (CCA-IMT), compliance of commom carotid artery (CP-CCA) and endothelium function of the braquial artery (FMD)], through a non-invasive method using high resolution ultrasound imaging. In order to determine the influence of PCOS and obesity on such parameters, groups were formed according to the presence or absence of such conditions: PCOS group vs Control group, independently of BMI; normal BMI group vs obesity group, independently of PCOS presence. Results: Twenty-five patients with PCOS were selected, being 10 with normal BMI (34.0 ± 3.2 kg/m²), 15 obeses (22.4 ± 2.1 kg/m²) and 23 control women (12 with normal BMI and 11 obeses). The mean values of free testosterone in PCOS patients were significantly higher than the means in controls, independently of BMI. The means of HOMA-IR and the area under the insulin curve in obese PCOS patients were significantly higher than the ones observed in PCOS patients with normal BMI and controls. The means of CCA-IMT in obese PCOS patients was significantly higher than in controls with normal BMI (50.0 ± 4.0 vs 47.0 ± 3.0 mm.10-2; p<0.05). The means of CP-CCA and FMD were similar between PCOS patients and controls, independently of BMI. To evaluate the influence of PCOS and obesity, the comparisons were respectively: PCOS group (n=25) vs Control group (n=23); normal BMI group (n=22) vs Obesity group (n=26). Global age range was 26.0 ± 4.7 years. PCOS as well as obesity influenced the insulin resistance parameters. The means of CCA-IMT was higher in PCOS group than in Control group (49.1 ± 1.0 vs 47.2 ± 1.0 mm.10-2; p<0.05) and similar between normal BMI and Obesity groups (49.1 ± 1.0 vs 47.3 ± 1.0 mm 10-2; NS). It was not observed any influence of PCOS or obesity in CP-CCA and in FMD. The vascular parameters studied did not correlate with the other variables analized between PCOS patients and controls. Conclusions: In young women without cardiometabolic risk factors, the presence of PCOS had influence on the increase of CCA-IMT. Thus, CCA-IMT might be the initial marker of the atherogenic process in this group of patients

A hiperinsulinemia e a resistência à insulina (RI) são descritas em pacientes portadoras da PCOS, independentemente do índice de massa corporal. O exercício físico parece não ser capaz de reverter completamente a RI nessas pacientes, sugerindo uma resposta sub-ótima ao estímulo do treinamento físico nessa população. Assim, o objetivo desse trabalho foi investigar os efeitos agudos do exercício aeróbio sobre a expressão de proteínas envolvidas na sinalização intracelular para captação de glicose em pacientes com PCOS comparadas a mulheres sem comorbidades e sem a PCOS (grupo CTRL). No período basal, as voluntárias realizaram avaliações do perfil lipídico, glicêmico e hormonal, capacidade física e composição corporal. Após a intervenção, as voluntárias realizaram dosagens sanguíneas para a avaliação do perfil inflamatório e glicêmico em resposta ao exercício físico. Além disso, as voluntárias foram submetidas à biopsias musculares, para analises da expressão de proteínas envolvidas na sinalização intracelular para a captação de glicose. A expressão proteica da PI3-k não demonstrou diferenças significantes em resposta à sessão aguda de exercício aeróbio no grupo PCOS. Todavia, o grupo CTRL demonstrou um aumento significante da ativação dessa proteína em resposta à sessão aguda de exercício aeróbio (p = 0.018), bem como uma tendência de diferença significante da atividade dessa proteína na condição PÓS (p = 0.073) no grupo CTRL em comparação ao grupo PCOS. A fosforilação da AS160 Thr 642 foi significante maior no grupo CTRL em resposta a sessão aguda de exercício aeróbio (p = 0.043), enquanto, uma resposta inalterada da fosforilação da AS160 Thr 642 foi observada no grupo PCOS em resposta ao exercício aeróbio agudo. O grupo CTRL apresentou um aumento da fosforilação dessa proteína significante maior que o grupo PCOS na condição PÓS (p = 0.05). Os presentes achados demonstram um prejuízo na sinalização intracelular para captação de glicose no músculo esquelético ao nível da proteína PI3-k p85 e AS160 Thr 642 em resposta ao exercício aeróbio agudo nas mulheres com PCOS comparada as mulheres CTRL. Entretanto, a translocação do GLUT-4 não está prejudicada em resposta ao exercício aeróbio agudo nas mulheres com PCOS comparada as mulheres CTRL. Esses dados sugerem que defeitos de sinalização em proteínas específicas da sinalização insulínica não impedem a efetiva translocação de GLUT-4 no músculo esquelético de pacientes com PCOS / Hyperinsulinemia and insulin resistance (IR) are described in PCOS patients regardless of body mass index. Exercise does not seem to be able to completely reverse the IR in these patients, suggesting a sub-optimal response to the stimulus of exercise training in this population . The objective of this study was to investigate the acute effect of aerobic exercise on the protein expression involved in intracellular signaling for glucose uptake in patients with PCOS compared with women without PCOS (CTRL group). At baseline, subjects underwent assessments of lipid, glucose and hormone profile, physical fitness and body composition. After the intervention, the volunteers performed blood measurements for the assessment of inflammatory markers and glycemic profile in response to acute aerobic exercise. In addition, the volunteers underwent skeletal muscle biopsies for analysis of the protein expression involved in intracellular signaling for glucose uptake. PI3-k expression showed no significant differences in response to acute exercise bout in the PCOS group. However, the CTRL group showed a significant increase in activation of this protein in response to acute exercise bout (p = 0.018) and a trend toward significant difference in activity of this protein after exercise (p = 0.073) in the CTRL group compared to the PCOS group. AS160 Thr 642 phosphorylation was significantly higher in the CTRL group in response to acute exercise bout (p = 0.043), while an unchanged response of AS160 Thr 642 phosphorylation was observed in the PCOS group in response to acute aerobic exercise. CTRL group showed an increase in phosphorylation of this larger than PCOS group significant protein in the period after the acute exercise bout (p = 0.05). The present findings demonstrate a loss in intracellular signaling for glucose uptake in skeletal muscle at the level of the protein PI3 -k p85 and AS160 Thr 642 in response to acute aerobic exercise in women with PCOS compared CTRL women. However, GLUT - 4 translocation is not impaired in response to acute aerobic exercise in women with PCOS compared CTRL women. These data suggest that specific defects of insulin signaling do not impairment the effective GLUT - 4 translocation in skeletal muscle of patients with PCOS, probably by activation of compensatory molecular mechanisms. Keywords: polycystic ovary syndrome, exercise, obesity, insulin

A síndrome dos ovários policísticos (SOP) é o distúrbio endócrino mais frequente em mulheres em idade reprodutiva. Sua etiologia é desconhecida, mas recentemente, fatores ambientais, como o excesso esteróides sexuais em fases precoces da vida, têm sido implicados na origem da SOP. Em ratas, o excesso de androgênios ou estrogênios na vida neonatal altera a função do eixo hipotálamo-hipófise-gonadal e induz alterações reprodutivas e metabólicas similares às observadas na SOP em humanos. O objetivo deste estudo foi analisar a expressão dos genes relacionados ao controle da secreção de GnRH (Gnrh, Gnrhr, Kiss1, Kiss1r e Ar) no hipotálamo de modelos animais de SOP e avaliar a correlação com a morfologia ovariana, níveis séricos de gonadotrofinas e esteróides sexuais, e a expressão de genes chaves na esteroidogênese ovariana (Cyp17a1 e Lhr). Foram utilizadas 30 ratas alocadas em igual número em três grupos. De acordo com os grupos, os animais receberam por injeção subcutânea, entre 0-3 dias de vida, os seguintes compostos: propionato de testosterona (1,25 mg) (grupo Testosterona); benzoato de estradiol (0,5 mg) (grupo Estradiol); e veículo (0,1 mL) (grupo Controle). Os animais foram pesados semanalmente a partir do nascimento até os 90 dias de vida. Ao completarem 90 dias, os animais foram eutanasiados e tiveram coletados o hipotálamo, os ovários e o sangue. Foi avaliada a expressão dos genes Gnrh, Gnrhr, Kiss1, Kiss1r e Ar no hipotálamo e Cyp17a1 e Lhr no ovário por PCR quantitativo em Tempo Real. O ovário também foi analisado morfológica e morfometricamente após coloração com hematoxilina e eosina (H.E.) e o sangue foi utilizado para a dosagem sérica dos hormônios LH, FSH, estradiol, progesterona e testosterona. A análise estatística foi realizada utilizando a análise de variância (ANOVA) complementada pelo teste de comparações múltiplas de Tukey. Os animais dos grupos Estradiol e Testosterona apresentaram 11 anovulação e maior peso corporal em relação ao grupo Controle. O gene Kiss1 encontrou-se hipoexpresso nos grupos Estradiol e Testosterona em relação ao grupo Controle (p<0,0001). No grupo Estradiol, o gene Kiss1r apresentou expressão aumentada em relação ao grupo Controle (p<0,01). O gene Gnrh não exibiu variações de expressão entre os grupos. A expressão de Gnrhr exibiu aumento no grupo Testosterona em relação ao grupo Estradiol (p<0,004). No grupo Testosterona, o gene do receptor de androgênio (Ar) apresentou expressão aumentada em relação ao grupo Controle (p<0,04). Quanto ao nível sérico de LH, o grupo Testosterona exibiu aumento em relação aos grupos Estradiol e Controle (p<0,001). O grupo Estradiol exibiu maior concentração sérica de estradiol em relação ao grupo Testosterona (p<0,01). Os níveis séricos de FSH, progesterona e testosterona não exibiram diferenças significativas entre os grupos. A expressão do gene Lhr apresentou-se aumentada nos grupos Estradiol e Testosterona em comparação ao Controle (p<0,003). O gene Cyp17a1 apresentou-se hiperexpresso no grupo Estradiol em relação aos grupos Controle e Testosterona (p<0,0001 e p<0,001, respectivamente). A contagem diferencial de folículos pré-antrais e antrais não diferiu significativamente entre os grupos. Os ovários dos grupos Estradiol e Testosterona apresentaram ausência de corpos lúteos e exibiram aumento da área intersticial e diminuição do volume do núcleo das células intersticiais, sendo todas essas alterações estatisticamente significativas (p<0,0001). Conclui-se que o excesso de estradiol ou testosterona na vida neonatal altera a fisiologia do hipotálamo e do ovário e leva a anovulação de ratas na vida adulta / Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women at reproductive age. Its etiology is unknown, but recently, environmental factors, such as excess of sex steroids in early life, have been compared to PCOS origin. In female rats, the excess of androgens or estrogens in neonatal life alters the hypothalamus-pituitary-gonadal axis function and induces to reproductive and metabolic alterations like those observed in human PCOS. The aim of this study is to analyze the expression of genes compared to GnRH secretion control (Gnrh, Gnrhr, Kiss1, Kiss1r e Ar) in the hypothalamus of animal models of PCOS and to evaluate the correlation with ovarian morphology, serum levels of gonadotropins and sex steroids and expression of key genes in ovarian steroidogenesis (Cyp17a1 e Lhr). 30 rats were used and allocated equally into three groups. According to the groups, animals received a subcutaneous injection, between 0-3 days old, of the following compounds: testosterone propionate (1.25 mg) (Testosterone group); estradiol benzoate (0.5 mg) (Estradiol group) and vehicle (0.1 mL) (Control group). Animals were weighed weekly from birth until 90 days of life. At 90 days, the animals were euthanized and were collected the hypothalamus, the ovaries and blood. We evaluated the expression of genes Gnrh, Gnrhr, Kiss1, Kiss1r and Ar in hypothalamus and Lhr and Cyp17a1 in ovary, both by quantitative Real-Time PCR. The ovary was also analyzed morphologically and morphometrically after staining with hematoxylin and eosin (H.E.) and the blood was used for evaluation of serum levels of LH, FSH, estradiol, progesterone and testosterone. Statistical analysis was performed using analysis of variance (ANOVA) complemented by Tukeys multiple comparisons test. The animals of the Testosterone and Estradiol groups had anovulation and had higher body weight compared to the Control group. The Kiss1 gene was downregulated in Estradiol and 13 Testosterone groups in relation to the Control group (p<0.0001). In Estradiol group, Kiss1r gene expression was increased in relation to the control group (p<0.01). The Gnrh gene expression did not show variations between groups. The Gnrhr expression was increased in Testosterone group in relation to Estradiol group (p<0.004). In Testosterone group, the androgen receptor gene (Ar) showed an increased expression compared to the Control group (p<0.04). Testosterone group exhibited increased serum levels of LH in comparison to Control and Estradiol groups (p<0.001). Estradiol group exhibited higher serum levels of estradiol compared to Testosterone group (p<0.01). Serum levels of FSH, progesterone and testosterone exhibited no significant differences between groups. Lhr gene expression was increased in Estradiol and Testosterone groups in comparison to the control (p<0.003). The Cyp17a1 gene was upregulated in Estradiol group compared to Testosterone and Control groups (p<0.0001 and p<0.001, respectively). The differential counting of preantral and antral follicles did not differ significantly between groups. Ovaries of the animals of Estradiol and Testosterone groups showed absence of corpora lutea and exhibited increased interstitial area and reduced interstitial cells nuclear volume, and all of these changes were statistically significant (p<0.0001). It was concluded that excess of estradiol or testosterone in neonatal life alters the hypothalamic and ovarian physiology and leads to anovulation in rats at adulthood

Orientadores: Cássia Raquel Teatin Juliato, Cristina Laguna Benetti-Pinto / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T01:05:51Z (GMT). No. of bitstreams: 1 Mayrink_Jussara_M.pdf: 620094 bytes, checksum: e3d5f6dee5c7be899f7f699f6c82fdfe (MD5) Previous issue date: 2013 / Resumo: Introdução: A síndrome dos ovários policísticos (SOP) é uma doença que acomete aproximadamente 10% das mulheres em idade reprodutiva. Está associada a diversos distúrbios metabólicos, como a resistência insulínica (RI) e a síndrome metabólica (SM). A resistência insulínica, por sua vez, está relacionada a disfunções tireoidianas (hipotireoidismo clínico e subclínico). Alguns estudos têm relacionado essas disfunções à ocorrência de SOP, bem como a maior prevalência de tireoidite crônica autoimune nessas mulheres. Entretanto, esses trabalhos ainda são escassos. Objetivos: comparar a prevalência de tireoidite crônica autoimune em mulheres com e sem SOP, comparar a presença de anticorpos antitireoidianos antiperoxidase (ATPO) e antitireoglobulina (ATG) e achados ecográficos tireoidianos sugestivos de tireoidite crônica autoimune em mulheres com e sem SOP. Sujeitos e métodos: foi um estudo de corte transversal, incluindo 130 mulheres entre 18 e 40 anos dos ambulatórios de ginecologia endocrinológica e de planejamento familiar do Departamento de Ginecologia e Obstetrícia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas - entre os meses de agosto de 2012 e agosto de 2013 -, sendo 65 com SOP, em conformidade com o Consenso de Rotterdam de 2004, e 65 mulheres com ciclos menstruais regulares e sem doenças crônicas previamente diagnosticadas. Para todas foram avaliados: índice de massa corpórea (IMC, kg/m2), graus de hirsutismo através do índice de Ferriman-Gallwey, TSH, T4L, T3L, glicemia e insulinemia de jejum, avaliação de resistência insulínica através do índice de HOMA, antiperoxidase e antitireoglobulina e ultrassom da glândula tireóide. Análise Estatística: Para análise dos dados foram usados os testes de Mann- Whitney, t de student, qui quadrado e exato de Fischer. Os dados foram apresentados como média ±DP. Resultados: As 130 mulheres participantes deste estudo eram jovens, com idade entre 18 e 40 anos e média de 27,8 ±6,9 anos no grupo com SOP e 33,5 ±5,7 anos no grupo sem SOP. As mulheres com e sem SOP apresentaram média de IMC de 34,8±8,9 e 28,4±4,8 kg/m2, respectivamente (p<0,0001). O índice de Ferriman-Gallwey para os grupos com e sem SOP foi 8±3,1 e 5±0,7, respectivamente (p<0,0001). Os valores de insulinemia, glicemia e índice de HOMA também foram significativamente maiores na presença de SOP. Em relação ao TSH, os valores para mulheres com e sem SOP foram de 2,4 ±1,8 mIU/L e 2,1±1,2 mIU/L, respectivamente (p=0,0133). Não houve diferença na ocorrência de ATPO e ATG comparando-se os dois grupos. Não houve diferença entre os grupos para o volume tireoidiano avaliado pela ecografia. Entretanto, as glândulas eram mais hipoecoicas no grupo com SOP (26,8% versus 15,4%; p=0,05). A prevalência de HSC foi de 16,9% (11/65mulheres) no grupo com SOP e 6,2% (4/65 mulheres) no grupo sem SOP. Em relação ao diagnóstico de tireoidite crônica autoimune, houve diferença significativa em sua prevalência, com 43,1% de tireoidite no grupo com SOP e 26,2% no grupo sem SOP (p=0,04). Conclusão: A maior prevalência de tireoidite crônica autoimune e de alteração na função tireoidiana (HSC) das mulheres com SOP indicam a necessidade de manter-se vigilância periódica sobre a função tireoidiana, embora não aponte a necessidade de pesquisa rotineira de anticorpos antitireoidianos / Abstract: Introduction: Polycystic ovary syndrome (PCOS) is a condition that affects approximately 10% of women of reproductive age. It's associated with various metabolic disorders such as insulin resistance (IR) and metabolic syndrome (MS). Insulin resistance, in turn, is related to thyroid dysfunction (clinical and subclinical hypothyroidism). Some studies have linked these disorders to the occurrence of PCOS as well as a higher prevalence of autoimmune thyroiditis. However, these studies are still scarce. Objectives: To compare the prevalence of autoimmune thyroiditis , the occurrence of anti -thyroid peroxidase antibodies (ATPO) and anti - thyroglobulin (ATG) and thyroid ultrasound findings suggestive of autoimmune thyroiditis in subjects with and without PCOS. Subjects and methods: It was a cross-sectional study including 130 women between 18 and 40 years of outpatient gynecological endocrinology and family planning at the Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, between the months of August 2012 and August 2013, 65 with PCOS, in accordance with the Rotterdam criteria, and 65 women with regular menstrual cycles and without previously diagnosed chronic diseases. For all evaluated: body mass index (BMI, kg/m2), degree of hirsutism by Ferriman - Summary xii Gallwey, TSH , FT4 , FT3, blood glucose and fasting insulin, assessment of insulin resistance by HOMA index, ATPO and ATG and ultrasound of the thyroid gland. Statistical analysis: For data analysis we used the Mann- Whitney test, Student's t, chi-square and exact Fisher. Data were presented as mean ± SD. Results: 130 women participating in this study were young, between 18 and 40 years, 27.8 ± 6.9 years in the PCOS group and 33.5 ± 5.7 years in the group without PCOS. Women with and without PCOS had a mean BMI of 34.8 ± 8.9 and 28.4 ± 4.8 kg/m2 , respectively ( p < 0.0001 ) . The Ferriman - Gallwey index for the groups with and without PCOS was 8 ± 5 and 3.1 ± 0.7, respectively (p < 0.0001). The amounts of insulin, glucose and HOMA index were also significantly higher in the presence of PCOS. The TSH values for women with and without PCOS were 2.4 ± 1.8 mIU / L and 2.1 ± 1.2 mIU / L, respectively (p = 0.0133). There was no difference in the occurrence of ATPO and ATG comparing the two groups. There was no difference between groups for thyroid volume measured by ultrasound. However, the glands were more hypoechoic in the PCOS group (26.8% vs. 15.4%, p = 0.05). The prevalence of SCH was 16.9 % (11/65 women) in the PCOS group and 6.2% (4/65 women) in the group without PCOS. The prevalence of autoimmune thyroiditis in the PCOS group was 43.1% and 26.2% in the group without PCOS (p = 0.04). Conclusion: The higher prevalence autoimmune thyroiditis and SCH in women with PCOS indicates the necessity of keeping surveillance on their periodic thyroid function, but do not point the necessity of routine investigation of antithyroid antibodies / Mestrado / Fisiopatologia Ginecológica / Mestra em Ciências da Saúde

Orientadores: Cristina Laguna Benetti Pinto, Cássia Raquel Teatin Juliato / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T21:48:04Z (GMT). No. of bitstreams: 1 Piccolo_VanessaRibeiroSantanaBerini_M.pdf: 1012178 bytes, checksum: 3e14c4b6d744f4a349f66711137e183d (MD5) Previous issue date: 2012 / Resumo: Introdução: A síndrome dos ovários policísticos (SOP) associa-se, em 50% a 70% dos casos, ao hiperinsulinismo, obesidade e síndrome metabólica. A relação entre resistência insulínica (RI) e função tireoidiana é ainda pouco estudada, embora se considere haver interação entre disfunção tireoidiana e metabolismo lipídico. Objetivo: avaliar a partir de que nível sérico de hormônio estimulador da tireoide (TSH) há maior prevalência de RI e a relação entre TSH e diferentes parâmetros clínicos e metabólicos em mulheres com SOP. Sujeitos e Métodos: Foi avaliada a associação do TSH e RI em 168 mulheres com SOP atendidas no ambulatório de ginecologia endócrina do Departamento de Tocoginecologia da Faculdade de Ciências Médicas, UNICAMP não hipotireoideas. Avaliaram-se também as variáveis: índice de Ferriman-Galley, índice de massa corpórea (IMC), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD), circunferência abdominal (CA), circunferência do quadril (CQ), níveis séricos de testosterona total, testosterona livre, glicemia em jejum, insulina em jejum, índice de HOMA (HOMA-IR), colesterol total, HDL colesterol (HDL) e LDL colesterol (LDL), triglicérides (TRIG). Para determinar o ponto de corte que maximize a sensibilidade e a especificidade foi empregada curva ROC para os níveis de TSH, considerando resistência insulínica quando HOMA-IR ? 2,71. As variáveis foram comparadas segundo o ponto de corte do TSH determinado pela curva ROC e pela classificação de hipotireoidismo subclínico (HSC) com valores de TSH ? 4,5 e <10mIU/L, bem como pela presença de RI. Foi estudada também a correlação das variáveis com TSH e HOMA-IR. Resultados: As 168 mulheres com SOP tinham média de idade de 24,2 ± 5,8 anos. A associação entre TSH e RI mostrou um valor de corte de TSH ? 2,77mUI/L, com sensibilidade de 47,9% e especificidade de 65,3% para correlação de RI. Os parâmetros clínicos, hormonais e metabólicos foram avaliados e comparados para TSH < 2,77mUI/L e TSH entre 2,77 e 10mUI/L, sem diferença significativa entre as variáveis estudadas. Foram então comparadas mulheres com e sem RI, com valores significativamente maiores para peso, IMC, PAS, PAD, CA e CQ entre as com RI. As mesmas variáveis foram comparadas entre mulheres com função tireoidiana normal ou HSC. Observaram-se valores significativamente maiores de prolactina (PRL) e LDL nas com HSC. Realizadas as correlações entre os parâmetros estudados, observou-se correlação positiva apenas entre TSH e LDL. O HOMA-IR mostrou correlação positiva com peso, IMC, PAS, PAD, CA, CQ e TRIG. Conclusão: Há maior associação entre a concentração de TSH ? 2,77mUI/L e a presença de RI, porém sem alteração nos parâmetros clínicos e laboratoriais que indique mudança de conduta. Porém, quanto maior a RI, observou-se piora nos parâmetros clínicos relacionados à síndrome metabólica. As mulheres com SOP e HSC apresentaram valores de LDL e PRL significativamente maiores do que nas com níveis de TSH < 4,5 mUI/L / Abstract: Introduction: Polycystic ovary syndrome (PCOS) is associated with hyperinsulinism, obesity and the metabolic syndrome in 50-70% of cases. The association between insulin resistance (IR) and thyroid function has yet to be fully clarified, although an interaction between thyroid dysfunction and lipid metabolism is recognized. Objective: To evaluate the serum level of thyroid-stimulating hormone (TSH) that results in a greater prevalence of IR and the relationship between TSH and different clinical and metabolic parameters in women with PCOS. Subjects and methods: The association of TSH and IR was evaluated in 168 women with PCOS without overt hypothyroidism attending a gynecological endocrinology outpatient clinic at the Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP). Other variables evaluated were: the Ferriman-Gallwey Index, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, hip circumference, serum levels of total testosterone, free testosterone, fasting glucose and fasting insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and triglycerides (TRIG). To determine the cut-off point that would maximize sensitivity and specificity, a receiver-operating characteristic (ROC) curve was used for TSH levels, with insulin resistance being defined as HOMA-IR ? 2.71. The variables were compared based on the cut-off point for TSH determined by the ROC curve, the classification of subclinical hypothyroidism (SCH) as defined by TSH values ? 4.5 and < 10 mIU/L, and the presence of IR. The correlation between the variables, TSH and HOMA-IR, was also assessed. Results: The mean age of the 168 women with PCOS was 24.2 ± 5.8 years. The association between TSH and IR revealed a cut-off value for TSH ? 2.77 mIU/L, with sensitivity of 47.9% and specificity of 65.3% for the correlation with IR. The clinical, hormonal and metabolic parameters were evaluated and compared for TSH levels < 2.77mIU/L and for TSH levels of 2.77 - 10mIU/L, with no statistically significant differences being found between the variables studied. The women with IR were then compared with those without IR, with significantly higher values being found for weight, BMI, SBP, DBP, waist and hip circumference among women with IR. The same variables were compared between the women with normal thyroid function and those with SCH. Significantly higher values of prolactin and LDL-c were found in the women with SCH. Evaluation of the parameters studied showed a positive correlation only between TSH and LDL-c. HOMA-IR correlated positively with weight, BMI, SBP, DBP, waist and hip circumference and TRIG. Conclusion: There is a stronger association between TSH levels ? 2.77mIU/L and the presence of IR; however, no abnormalities were found in the clinical or laboratory parameters that would warrant a change in clinical management. Nevertheless, the higher the IR, the poorer the clinical parameters related to the metabolic syndrome. The women with PCOS and SCH had significantly higher LDL-c and PRL levels compared to women with TSH levels < 4.5 mIU/L / Mestrado / Fisiopatologia Ginecológica / Mestra em Ciências da Saúde

Abstract The number of ovarian follicles declines with age resulting in a significant decrease of fertility by the age of 40. However, the age when follicle loss starts to affect ovarian endocrine function is not well recognized. The purpose of the present study was to investigate age-related ovarian/adrenal androgen secretion, which is crucial for estrogen biosynthesis in healthy women and in women with polycystic ovarian syndrome (PCOS). Another aim of the study was to compare the usefulness of different serum markers in assessing ovarian aging and in diagnosing polycystic ovaries (PCOs) and PCOS. The human chorionic gonadotropin (hCG) test was used to study the endocrine potential of ovaries/adrenals. The ovarian capacity to secrete and synthesize androgens was found to be decreased as early as at the age of 30 in regularly menstruating women. In women with PCOS, both basal and hCG-stimulated androgen levels were about 50% higher than in healthy women and they remained high until late reproductive age. Similarly to regularly menstruating women, the androgen secretion capacity in PCOS subjects decreased with age, and estradiol concentrations remained unchanged until the age of 44 years. Adrenal androgen synthesis was not changed during hCG-tests. Since serum antimüllerian hormone (AMH) and follicle stimulating hormone (FSH) levels were changed significantly after the age of 25 years in regularly menstruating women, they may be considered as useful serum markers reflecting the ovarian aging process. In women with PCOS, AMH levels were continuously 2- to 3-fold higher than in healthy women possibly reflecting high follicle number in these women. A decline in ovarian endocrine function before the age of 30 is one of the first signs of ovarian aging. However, in women with PCOS ovarian androgen secretion capacity is markedly increased and remain high throughout the reproductive years. The results of the present studies also indicate that LH/hCG does not play a role in adrenal androgen synthesis, since LH/hCG did not stimulate adrenal androgen synthesis. The measurement of AMH is a useful tool to estimate ovarian aging process as well as to diagnose PCOs/PCOS.

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders amongst women, estimated to affect one out of 10 women. Symptoms include infertility, obesity, alopecia, acne, hirsutism and menstrual irregularities. Women with the syndrome are also more likely to experience co-morbid physical and psychological conditions such as diabetes, heart disease, endometrial cancer and also depression and anxiety. PCOS has also been found to have a negative impact on quality of life. This thesis aimed to further understanding, and improve quality of life of women with PCOS in the UK. To achieve this, the thesis aimed to investigate and identify how women with PCOS in the UK perceive and define their quality of life and to further understanding of the day-to-day experience of living with PCOS. Moreover, in order to measure quality of life, it aimed to develop and validate a UK disease-specific quality of life measure for women with PCOS. It also aimed to identify, develop and test a pilot intervention to increase quality of life in women with PCOS. To achieve these aims a mixed-methods approach was taken employing a variety of data generation and collection methods including: photovoice, online Skype™ interviews; LimeSurvey and Qualtrics. The findings of this thesis emphasise that PCOS has a negative impact on quality of life; encompassing psychological, social, environmental, and physical domains of quality of life. Women with PCOS who experienced the symptoms of infertility, hirsutism, weight, alopecia, skin discolouration, skin tags and mood swings had significantly lower scores of overall quality of life than those women who did not experience the symptoms. In addition, those women with PCOS who had a diagnosis of anxiety and/or depression had reduced quality of life. The dissemination of these findings will enable health care professionals to better understand the experience of living with PCOS and its impact on quality of life. Moreover, this thesis identifies many areas for future research which will enable a better understanding of the impact of PCOS on quality of life. Finally, this thesis makes recommendations for clinical practice which include improvement of support from health care professionals for women with PCOS in order to help them better manage their symptoms, and therefore improve their overall quality of life.

Abstract Oligomenorrhea (menstrual disturbances) and hirsutism (excessive growth of body hair) are typical symptoms of polycystic ovary syndrome, a common endocrine disorder with long-term health risks among fertile-age women. Associations between body size development and polycystic ovary syndrome symptoms in a cohort design (528 symptomatic and 1479 asymptomatic women) and endocrine, metabolic and clinical characteristics of women with self-reported symptoms of oligomenorrhea or hirsutism in a nested case-control design (518 cases and 1036 controls) were investigated in this general population-based study. Gynecologic ultrasonographic examinations were performed in 196 cases and 67 controls to assess the morphology of the ovaries and its relationship to biochemical and clinical parameters. The study population was derived from the Northern Finland Birth Cohort 1966, which included all births with expected birth dates in 1966 in Northern Finland and is well representative of the general female population. Polycystic ovary syndrome symptoms in adulthood were associated with obesity, particularly abdominal obesity, in adolescence and in adulthood, but not with birth weight or being small for gestational age. Hormonal changes typical of polycystic ovary syndrome, i.e. higher circulating concentrations of testosterone, luteinizing hormone (LH) and insulin and lower levels of sex hormone-binding globulin (SHBG), were detected in women with self-reported symptoms of oligomenorrhea and/or hirsutism compared with the controls. Less favorable metabolic cardiovascular disease risk factor profiles, higher body mass index (BMI), waist-hip ratio (WHR), and triglyceride and C-reactive protein (CRP) concentrations and lower high density lipoprotein cholesterol (HDL-C) levels, were detected in women with symptoms, being the most severe among women who reported both hirsutism and oligomenorrhea. Unfavorable characteristics were pronounced in the presence of overweight or obesity. Women with symptoms more often had features characteristic of polycystic ovarian morphology associated with an endocrine and clinical profile reflecting polycystic ovary syndrome. This study shows that questioning in regard to symptoms of oligomenorrhea and hirsutism is useful in detecting women at risk of polycystic ovary syndrome and associated health risks. Avoidance of being overweight is important among young women to prevent the development of insulin resistance. Systematic follow-up of women with symptoms of oligomenorrhea and hirsutism is justified for prevention and early detection of long-term health risks.