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

O exercício físico é intervenção de primeira linha e parece melhorar os sintomas da síndrome dos ovários policísticos (SOP). Porém, os mecanismos dessas alterações ainda são pouco entendidos. O objetivo desse estudo foi avaliar os efeitos do exercício voluntário sobre os aspectos metabólicos e reprodutivos de modelos murinos de SOP induzida por dihidrotestosterona (DHT) ou letrozol (LET). Péletes de DHT ou LET foram utilizados para a indução de SOP experimental em camundongas pré-puberes. Os camundongos controles receberam péletes sem substância ativa. Cinco semanas após a exposição aos compostos teve início o exercício voluntário em rodas de corrida. Foram avaliados peso, composição corporal, tolerância à insulina e à glicose e o ciclo estral. Os grupos experimentais foram: controle (n=9), DHT (n=10), LET (n=9), DHT+exercício (EX) (n=9) e LET+EX (n=10). Após 4-5 semanas de exercício, os animais foram eutanasiados e os tecidos adiposos inguinal e mesentérico foram utilizados para análises morfológicas e moleculares. O grupo DHT apresentou aumento do peso corporal, aumento da proporção de grandes adipócitos mesentéricos e ciclo estral anormal. O grupo LET apresentou aumento do peso corporal e massa gorda, diminuição da sensibilidade à insulina, aumento da população de adipócitos pequenos, aumento da expressão de genes relacionados à lipólise na gordura mesentérica e ciclo estral anormal. O exercício reduziu a massa gorda e a expressão de genes da via NOTCH no tecido adiposo inguinal e mesentérico, e restaurou a morfologia alterada dos adipócitos mesentéricos, e a expressão de genes da via do NOTCH foi negativamente correlacionada com a expressão de genes da via de browning (transformação da gordura branca em gordura de fenótipo marrom) nos grupos DHT+EX e LET+EX. Em conclusão, o exercício restaurou a morfologia dos adipócitos mesentéricos em modelos animais de SOP induzida por DHT e LET, melhorou a sensibilidade à insulina, aumentou a expressão mesentérica de genes relacionados à lipólise e melhorou o ciclo estral em modelo animal de SOP induzida por LET. Esses benefícios podem ser atribuídos, pelo menos em parte, pela inibição de genes da via do NOTCH e pela modulação das vias de browning e lipólise no tecido adiposo / Exercise is the first line treatment and it seems to improve the symptoms of polycystic ovary syndrome (PCOS), but the mechanisms of these alterations are still poorly understood. The objective of this study was to evaluate the effects of voluntary exercise on metabolic and reproductive aspects of PCOS mouse models induced by dihydrotestosterone (DHT) or letrozole (LET). DHT or LET pellets were used for the induction of experimental PCOS in prepubertal mice. Control mice received placebo pellets. Five weeks after exposure to the substances, voluntary exercise on running wheels began. Body weight, body composition, insulin and glucose tolerance, and estrous cycle were evaluated. The experimental groups were control (n = 9), DHT (n = 10), LET (n = 9), DHT+exercise (EX) (n = 9) and LET+EX (n = 10). After 4-5 weeks of exercise, the animals were euthanized and the inguinal and mesenteric fat depots were collected for morphological and molecular analyzes. The DHT group showed increased body weight, increased proportion of large mesenteric adipocytes and abnormal estrous cycle. The LET group presented increased body weight and fat mass, decreased insulin sensitivity, increased population of small adipocytes, increased expression of genes related to lipolysis in mesenteric fat and abnormal estrous cycle. Exercise reduced fat mass and NOTCH pathway gene expression in inguinal and mesenteric adipose tissue, and restored the altered morphology of mesenteric adipocytes, and NOTCH pathway gene expression was negatively correlated with gene expression of the browning (transformation from white fat to brown-like fat) markers in both DHT+EX and LET+EX groups. In conclusion, the exercise restored the mesenteric adipocyte morphology in the DHT- and LET-induced PCOS mouse models, and the insulin sensitivity, the mesenteric expression of genes related to lipolysis, and improved the estrous cycle in the LET-induced PCOS mouse model. These benefits may be attributed, at least in part, to the inhibition of NOTCH pathway genes and the modulation of browning and lipolysis pathways in the adipose tissue

VIEIRA, TMB. Qualidade de Vida em Mulheres Obesas e com Síndrome dos Ovários Policísticos. 2010. 65 fls. Dissertação (Mestrado) - Faculdade de Medicina de Ribeirão Preto. Universidade de São Paulo. Ribeirão Preto. 2010. A síndrome dos ovários policísticos (SOP) é uma das desordens endócrinas mais comuns na idade reprodutiva, sendo a sua prevalência de 6 a 10% na população feminina. A SOP associada à obesidade pode agravar a saúde física e mental com um impacto negativo no funcionamento bio-psico-social. Os distúrbios metabólicos e as manifestações clínicas do hiperandrogenismo, comuns em mulheres com SOP tem levado ao aumento dos distúrbios psicológicos e redução na qualidade de vida (QV). Alguns estudos têm mostrado uma piora da QV na SOP, mas não fazem distinção sobre os efeitos que a própria obesidade pode acarretar a QV, uma vez que mais de 50% das pacientes SOP apresentam sobrepeso e obesidade. O presente estudo objetivou avaliar se há diferença na QV de pacientes com SOP obesas comparadas a controles obesas com ciclos ovulatórios. Foram incluídas 35 obesas com SOP e 28 obesas com ciclos ovulatórios, com idade entre 20 e 40 anos, IMC 30 e que aceitaram assinar o TCLE. Utilizou-se para a caracterização da população o questionário sócio-demográfico, médico, reprodutivo e somatométrico e para a avaliação da qualidade de vida, o questionário SF-36, que avalia os componentes da saúde física e os componentes da saúde mental. As pacientes com SOP mostraram melhor escore no que diz respeito ao domínio da capacidade funcional (73,43±20,57 vs 59,46±22,08) (p=0,01). Para os demais domínios não houve diferenças significativas entre os grupos. Nossos resultados sugerem que o aumento de androgênios comum em obesas com SOP possa estar associado à melhor capacidade funcional. / VIEIRA, TMB. Quality of Life of Obese Women With Polycystic Ovary Syndrome. 2010. 65 fls. Dissertation (Master). Faculdade de Medicina de Ribeirão Preto. Universidade de São Paulo, Ribeirão Preto, 2010. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders occurring during reproductive age, with a prevalence of 6 to 10% in the female population. PCOS associated with obesity can affect physical and mental health, with a negative impact on biopsychosocial functioning. The metabolic disorders and clinical manifestations of hyperandrogenism, common among women with PCOS, have led to an increase in psychological disorders and a reduction of quality of life (QL). Some studies have shown a worsening of QL in PCOS but without distinguishing between the effects that obesity itself may have on QL, since more than 50% of patients with PCOS are overweight or obese. The objective of the present study was to determine whether there is a difference in the QL of obese patients with PCOS compared to obese controls with ovulatory cycles. The study was conducted on 35 obese women with PCOS and 28 obese women with ovulatory cycles aged 20 to 40 years, with a BMI 30, who gave written informed consent to participate. A sociodemographic, medical, reproductive and somatometric questionnaire was used to characterize the population and QL was assessed with the SF-36 questionnaire, which evaluates the components of physical and mental health. The patients with PCOS had a better score regarding the functional capacity domain (73,43±20,57 vs 59,46±22,08) (p=0,01), whereas no significant differences were observed beween groups regarding the remaining domains. The present results suggest that the increase in androgens commonly occurring among obese women with PCOS may be associated with their better functional capacity.

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.

INTRODUÇÃO: A matriz extracelular no endométrio fornece vasta gama de sinais envolvidos em diferentes processos celulares, tais como morte celular e proliferação. Neste sentido, os glicosaminoglicanos e os proteoglicanos, juntamente com os fatores de crescimento, modulam várias etapas da angiogênese, proliferação celular e remodelação do estroma, o que pode ser importante para o fluxo menstrual regular e a redução dos processos proliferativos. Além disso, são importantes para a adequada interação maternofetal. OBJETIVO: Avaliar a concentração de ácido hialurônico, das enzimas de biossíntese do ácido hialurônico - hialurônico sintases (HAS1, HAS2 e HAS3) e dos pequenos proteoglicanos ricos em leucina (decorim, biglicam, lumicam e fibromodulina) no endométrio de pacientes com síndrome dos ovários policísticos (SOP) e de mulheres eumenorreicas. MÉTODOS: Foram analisadas 20 amostras de endométrio, 10 provenientes de pacientes com SOP e 10 de mulheres com ciclos menstruais regulares na fase proliferativa do ciclo, com idade variando entre 20 e 35 anos, atendidas na Divisão de Clínica Ginecológica do Hospital das Clínicas da FMUSP (HC-FMUSP). A determinação do perfil e da concentração do ácido hialurônico foi efetuada por método bioquímico de ensaio fluorimétrico (ELISA-like). A sua localização no tecido endometrial, assim como as dosagens das enzimas sintases (HAS1, HAS2 e HAS3) e dos pequenos proteoglicanos ricos em leucina (decorim, biglicam, lumicam e fibromodulina e), foi feita por imunoistoquímica e \"western blotting\". Para a análise dos resultados foi utilizado o teste t de student (p<=0,05). Os cálculos foram realizados com auxílio do programa SPSS versão13 (SPSS, Chicago, IL). RESUTADOS: Houve maior concentração de ácido hialurônico no endométrio de mulheres eumenorreicas na fase proliferativa do ciclo menstrual do que no das com síndrome dos ovários policísticos. Com relação às sintases do ácido hialurônico, observou-se maior reatividade de HAS1 e HAS2 e menor reatividade de HAS3 no endométrio de mulheres com SOP em relação às mulheres com ciclos menstruais regulares na fase proliferativa. Quanto aos pequenos proteoglicanos ricos em leucina notou-se maior imunorreatividade de decorim e lumicam no endométrio de pacientes com SOP. CONCLUSÕES: As pacientes com SOP apresentam menor concentração de ácido hialurônico e maior reatividade ao decorim e lumicam em relação às mulheres com ciclos regulares na fase proliferativa. Esses dados sugerem que nas pacientes com SOP, o endométrio seria menos receptivo e teria mecanismos para evitar a proliferação excessiva / INTRODUCTION: Endometrium extracellular matrix provides wide range of signals at different cellular levels like cell death and proliferation. In this regard, glycosaminoglycans and proteoglycans, along with growth factors, modulate various stages of angiogenesis, cell proliferation and remodeling of the stroma, which can be important for regulating menses and reducing the proliferative processes. Additionally, it is important for proper fetal-maternal interactions. OBJECTIVE: Evaluate hyaluronic acid concentration, the enzymes of hyaluronic acid synthases (HAS1, HAS2 and HAS3) and small leucine-rich proteoglycans (decorin, lumican, fibromodulim and biglycan) in the endometrium of patients with polycystic ovary syndrome (PCOS) and eumenorrheic women. METHODS: A total of 20 endometrial samples from 10 patients with PCOS and 10 women with regular menstrual cycles in the proliferative phase, with ages ranging between 20 and 35 years, attended at Gynecology Division of Clinical Hospital of the FMUSP (HC-USP). Profile determination and the concentration of hyaluronic acid were performed by biochemical method of fluorimetric assay (ELISA-like). Its location in the endometrial tissue as well as the dosage of enzymes synthases (HAS1, HAS2 and HAS3) and small leucine-rich proteoglycans (decorin, lumican, fibromodulim and biglycan) was done by immunohistochemistry and western blotting. To analyze the results Student t test was used (p < 0.05). The calculations were performed with software SPSS version 13. RESULTS: A higher concentration of hyaluronic acid in eumenorrheic women endometrium in proliferative phase when compared with polycystic ovary syndrome. Regarding hyaluronic acid synthases, there was a higher HAS1 and HAS2 reactivity and lower HAS3 reactivity in the PCOS endometrium compared to women with regular menstrual cycles in the proliferative phase. Decorin and lumican showed higher immunoreactivity in PCOS endometrium. CONCLUSIONS: PCOS patients have a lower concentration of hyaluronic acid and greater reactivity to decorin and lumican than eumenorrheic women in proliferative phase. These data suggest that in patients with PCOS, the endometrium would be less receptive and have mechanisms to prevent excessive proliferation

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder encompassing reproductive and metabolic phenotypes. Genetic analysis, targeting candidate genes has to date proven unsuccessful in the search for a truly dominant genetic link. Another hypothesis to explain the etiology of PCOS is that of fetal programming in the context of developmental origins of health and disease. Extensive animal studies, validated by human data, support the fetal origins hypothesis of PCOS and highlight that PCOS may arise due to excess androgen exposure in fetal life. Previous reports from our laboratory found metabolic dysfunction in 11 month old prenatally androgenised females (d62-102 of fetal life), which included pancreatic and hepatic alterations. The pancreatic alterations seemed to result from gene expression changes induced in fetal life. Therefore, chapter 3 focuses on the gluconeogenic response in the day 90 fetus following maternal androgenisation from day 62 of gestation. Interestingly hepatic gluconeogenic enzymes, specifically phosphoenolpyruvate caboxykinase (PEPCK) and glucose 6 phosphatase (G6PC), were not altered. However they were decreased in the kidney, in a sex specific manner with PEPCK significantly decreased (P<0.01) and G6PC showing a strong trend toward reduction (P=0.056) in females only. This chapter progresses to explore regulatory pathways involved in gluconeogenic regulation. It seems probable that the female specific increase in circulating testosterone (P<0.001), with increased renal androgen reception (P<0.01), may be accountable for the altered expression of gluconeogenic enzymes in the kidney. Chapter 4 investigates why testosterone concentrations were not increased in the male fetus, after maternal androgenisation, by focusing on the site of testosterone production, the fetal testis. Results demonstrate that the day 90 fetus is capable of responding to prenatal androgenisation by decreasing luteinising hormone (P<0.01) and thus testicular testosterone production, such that there was a global down regulation in steroidogenic enzyme expression, in vivo testosterone production (P<0.001) and Leydig cell morphology was altered (P<0.001). As prenatal androgenisation is administered through the maternal route and placental aromatisation may occur, a novel method whereby the fetus was directly injected was utilised to assess the effects of control oil (C), testosterone (TP) or diethylstilboestrol (DES) on the fetal testis. Unlike DES, direct fetal injection with TP mimics the results found from maternal androgenisation. When the testis are examined at a later date, day 112, ten days after androgen treatment ceases, Leydig cell morphology and steroidogenic gene expression return to control values, although fascinatingly, an overshoot of in vivo testosterone production (P<0.01) was observed. When the maternal androgenisation window is extended to begin at day 30 of fetal life, further changes are noted including increased circulating testosterone (P<0.01), a strong trend toward decreased testis weight (P=0.0519) and altered expression of Sertoli and germ cell specific markers. These studies are followed up by assessing the legacy effect of testosterone on the peripubertal male testis in Chapter 5. At ten weeks of postnatal life, males, exposed to androgens from day 62-102 of fetal life had reduced testis weight (P<0.05). However, functional or cellular alterations were not observed and by 12 weeks of age, when LH had normalised, testicular weight and stimulated testosterone secretion of prenatally TP-treated males was comparable to controls. This highlights the remarkable plasticity of the testis and the unremarkable legacy of altered prenatal androgen exposure. The legacy effect of testosterone on the fetal ovary is examined in Chapter 6. Previous studies from our laboratory found minor functional alterations but no structural alterations in the fetal ovary at day 90 following androgenisation from day 62. However, as this was at a time of a highly androgenic environment we assessed the function and morphology of the ovary ten days after the removal of testosterone at day 112. In marked contrast to the normalisation of the male gonad, we observe structural changes with an increase in recruited follicles from the primordial to primary stage in the testosterone treated group (P<0.01). The chapter continues with an investigation of pathways involved in the altered follicular dynamics that may account for the change in follicular recruitment. Furthermore, the functional changes which were previously noted in the day 90 ovary were also examined in response to direct exogenous steroid treatment including, C, TP, DES and dexamethasone (DEX) and also when the window of maternal androgenisation was extended to begin at day 30. Interesting changes are observed such that the direct fetal injection treatments induce similar changes to each other, regardless of the steroid, whilst maternal androgenisation induces a different response. This highlights the complexity of the pathways involved in female gonadal development.

OBJECTIVE: To examine the likelihood of self-reporting a diagnosis for PCOS with the presentation of menstrual irregularity in a diverse, multiethnic population, based on data collected between August 9th, 2017 and October 24th, 2017 for the pilot of the Ovulation and Menstruation (OM) Study at Boston University School of Medicine. BACKGROUND: Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder among reproductive age women. It is typically diagnosed by variable combinations of menstrual irregularity, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. An alternative is its diagnosis as one of exclusion due to similarities in presentation to other endocrine disorders. As a result, PCOS may often be misdiagnosed and mismanaged in the course of a patient’s care, further exacerbated by a poor understanding of the syndrome, a lack of easily available resources, and patient frustration with clinician interactions. The early identification of key hallmarks of the disorder, such as menstrual irregularity, and awareness of its linkage to PCOS, could lead to early diagnosis and intervention. METHODS: 248 participants enrolled and participated in the Ovulation and Menstruation (OM) Health Study’s as members of its pilot cohort. Inclusion criteria were women ages 18-45 currently experiencing menstrual periods without a history of chemotherapy, radiation, or surgical menopause. Participants completed the relevant sections of the OM Study survey related to demographics, menstrual cycle patterns, and history of PCOS. Demographic questions pertained to the age, race/ethnicity, country of birth, and education levels of the participants. The menstrual cycle questions provided information regarding the age of menarche, length and pattern of menses and the menstrual cycle overall. The questions regarding history of PCOS ascertained the presence of an official or self-diagnosis for PCOS for the participant, and the age at which this was determined. The descriptive measures were presented for comparison before determining the concurrence of the presence of menstrual irregularity and the diagnosis of PCOS across demographic categories and calculating an associated prevalence ratio. RESULTS: Among women reporting a history of menstrual irregularity for 3 months or greater, PCOS was the second-highest self-reported cause for menstrual irregularity, with 20.7% of participants endorsing it as the cause for their irregularity. The presence of menstrual irregularity for 3 or more months was also more likely to be present in concurrence with a clinician diagnosis, or to a lesser extent, a self-diagnosis, for PCOS. Participants were also far more likely to have a clinician diagnosis for PCOS if they were White, US-born, young, or educated. The same applied for the likelihood of a self-diagnosis with the exception of age. CONCLUSIONS: The association between menstrual cycle irregularities and likelihood of being diagnosed with PCOS is supported by the data and appears to be influenced by demographic factors such as race/ethnicity, age, and education.

INTRODUÇÃO: A matriz extracelular no endométrio fornece vasta gama de sinais envolvidos em diferentes processos celulares, tais como morte celular e proliferação. Neste sentido, os glicosaminoglicanos e os proteoglicanos, juntamente com os fatores de crescimento, modulam várias etapas da angiogênese, proliferação celular e remodelação do estroma, o que pode ser importante para o fluxo menstrual regular e a redução dos processos proliferativos. Além disso, são importantes para a adequada interação maternofetal. OBJETIVO: Avaliar a concentração de ácido hialurônico, das enzimas de biossíntese do ácido hialurônico - hialurônico sintases (HAS1, HAS2 e HAS3) e dos pequenos proteoglicanos ricos em leucina (decorim, biglicam, lumicam e fibromodulina) no endométrio de pacientes com síndrome dos ovários policísticos (SOP) e de mulheres eumenorreicas. MÉTODOS: Foram analisadas 20 amostras de endométrio, 10 provenientes de pacientes com SOP e 10 de mulheres com ciclos menstruais regulares na fase proliferativa do ciclo, com idade variando entre 20 e 35 anos, atendidas na Divisão de Clínica Ginecológica do Hospital das Clínicas da FMUSP (HC-FMUSP). A determinação do perfil e da concentração do ácido hialurônico foi efetuada por método bioquímico de ensaio fluorimétrico (ELISA-like). A sua localização no tecido endometrial, assim como as dosagens das enzimas sintases (HAS1, HAS2 e HAS3) e dos pequenos proteoglicanos ricos em leucina (decorim, biglicam, lumicam e fibromodulina e), foi feita por imunoistoquímica e \"western blotting\". Para a análise dos resultados foi utilizado o teste t de student (p<=0,05). Os cálculos foram realizados com auxílio do programa SPSS versão13 (SPSS, Chicago, IL). RESUTADOS: Houve maior concentração de ácido hialurônico no endométrio de mulheres eumenorreicas na fase proliferativa do ciclo menstrual do que no das com síndrome dos ovários policísticos. Com relação às sintases do ácido hialurônico, observou-se maior reatividade de HAS1 e HAS2 e menor reatividade de HAS3 no endométrio de mulheres com SOP em relação às mulheres com ciclos menstruais regulares na fase proliferativa. Quanto aos pequenos proteoglicanos ricos em leucina notou-se maior imunorreatividade de decorim e lumicam no endométrio de pacientes com SOP. CONCLUSÕES: As pacientes com SOP apresentam menor concentração de ácido hialurônico e maior reatividade ao decorim e lumicam em relação às mulheres com ciclos regulares na fase proliferativa. Esses dados sugerem que nas pacientes com SOP, o endométrio seria menos receptivo e teria mecanismos para evitar a proliferação excessiva / INTRODUCTION: Endometrium extracellular matrix provides wide range of signals at different cellular levels like cell death and proliferation. In this regard, glycosaminoglycans and proteoglycans, along with growth factors, modulate various stages of angiogenesis, cell proliferation and remodeling of the stroma, which can be important for regulating menses and reducing the proliferative processes. Additionally, it is important for proper fetal-maternal interactions. OBJECTIVE: Evaluate hyaluronic acid concentration, the enzymes of hyaluronic acid synthases (HAS1, HAS2 and HAS3) and small leucine-rich proteoglycans (decorin, lumican, fibromodulim and biglycan) in the endometrium of patients with polycystic ovary syndrome (PCOS) and eumenorrheic women. METHODS: A total of 20 endometrial samples from 10 patients with PCOS and 10 women with regular menstrual cycles in the proliferative phase, with ages ranging between 20 and 35 years, attended at Gynecology Division of Clinical Hospital of the FMUSP (HC-USP). Profile determination and the concentration of hyaluronic acid were performed by biochemical method of fluorimetric assay (ELISA-like). Its location in the endometrial tissue as well as the dosage of enzymes synthases (HAS1, HAS2 and HAS3) and small leucine-rich proteoglycans (decorin, lumican, fibromodulim and biglycan) was done by immunohistochemistry and western blotting. To analyze the results Student t test was used (p < 0.05). The calculations were performed with software SPSS version 13. RESULTS: A higher concentration of hyaluronic acid in eumenorrheic women endometrium in proliferative phase when compared with polycystic ovary syndrome. Regarding hyaluronic acid synthases, there was a higher HAS1 and HAS2 reactivity and lower HAS3 reactivity in the PCOS endometrium compared to women with regular menstrual cycles in the proliferative phase. Decorin and lumican showed higher immunoreactivity in PCOS endometrium. CONCLUSIONS: PCOS patients have a lower concentration of hyaluronic acid and greater reactivity to decorin and lumican than eumenorrheic women in proliferative phase. These data suggest that in patients with PCOS, the endometrium would be less receptive and have mechanisms to prevent excessive proliferation

O exercício físico é intervenção de primeira linha e parece melhorar os sintomas da síndrome dos ovários policísticos (SOP). Porém, os mecanismos dessas alterações ainda são pouco entendidos. O objetivo desse estudo foi avaliar os efeitos do exercício voluntário sobre os aspectos metabólicos e reprodutivos de modelos murinos de SOP induzida por dihidrotestosterona (DHT) ou letrozol (LET). Péletes de DHT ou LET foram utilizados para a indução de SOP experimental em camundongas pré-puberes. Os camundongos controles receberam péletes sem substância ativa. Cinco semanas após a exposição aos compostos teve início o exercício voluntário em rodas de corrida. Foram avaliados peso, composição corporal, tolerância à insulina e à glicose e o ciclo estral. Os grupos experimentais foram: controle (n=9), DHT (n=10), LET (n=9), DHT+exercício (EX) (n=9) e LET+EX (n=10). Após 4-5 semanas de exercício, os animais foram eutanasiados e os tecidos adiposos inguinal e mesentérico foram utilizados para análises morfológicas e moleculares. O grupo DHT apresentou aumento do peso corporal, aumento da proporção de grandes adipócitos mesentéricos e ciclo estral anormal. O grupo LET apresentou aumento do peso corporal e massa gorda, diminuição da sensibilidade à insulina, aumento da população de adipócitos pequenos, aumento da expressão de genes relacionados à lipólise na gordura mesentérica e ciclo estral anormal. O exercício reduziu a massa gorda e a expressão de genes da via NOTCH no tecido adiposo inguinal e mesentérico, e restaurou a morfologia alterada dos adipócitos mesentéricos, e a expressão de genes da via do NOTCH foi negativamente correlacionada com a expressão de genes da via de browning (transformação da gordura branca em gordura de fenótipo marrom) nos grupos DHT+EX e LET+EX. Em conclusão, o exercício restaurou a morfologia dos adipócitos mesentéricos em modelos animais de SOP induzida por DHT e LET, melhorou a sensibilidade à insulina, aumentou a expressão mesentérica de genes relacionados à lipólise e melhorou o ciclo estral em modelo animal de SOP induzida por LET. Esses benefícios podem ser atribuídos, pelo menos em parte, pela inibição de genes da via do NOTCH e pela modulação das vias de browning e lipólise no tecido adiposo / Exercise is the first line treatment and it seems to improve the symptoms of polycystic ovary syndrome (PCOS), but the mechanisms of these alterations are still poorly understood. The objective of this study was to evaluate the effects of voluntary exercise on metabolic and reproductive aspects of PCOS mouse models induced by dihydrotestosterone (DHT) or letrozole (LET). DHT or LET pellets were used for the induction of experimental PCOS in prepubertal mice. Control mice received placebo pellets. Five weeks after exposure to the substances, voluntary exercise on running wheels began. Body weight, body composition, insulin and glucose tolerance, and estrous cycle were evaluated. The experimental groups were control (n = 9), DHT (n = 10), LET (n = 9), DHT+exercise (EX) (n = 9) and LET+EX (n = 10). After 4-5 weeks of exercise, the animals were euthanized and the inguinal and mesenteric fat depots were collected for morphological and molecular analyzes. The DHT group showed increased body weight, increased proportion of large mesenteric adipocytes and abnormal estrous cycle. The LET group presented increased body weight and fat mass, decreased insulin sensitivity, increased population of small adipocytes, increased expression of genes related to lipolysis in mesenteric fat and abnormal estrous cycle. Exercise reduced fat mass and NOTCH pathway gene expression in inguinal and mesenteric adipose tissue, and restored the altered morphology of mesenteric adipocytes, and NOTCH pathway gene expression was negatively correlated with gene expression of the browning (transformation from white fat to brown-like fat) markers in both DHT+EX and LET+EX groups. In conclusion, the exercise restored the mesenteric adipocyte morphology in the DHT- and LET-induced PCOS mouse models, and the insulin sensitivity, the mesenteric expression of genes related to lipolysis, and improved the estrous cycle in the LET-induced PCOS mouse model. These benefits may be attributed, at least in part, to the inhibition of NOTCH pathway genes and the modulation of browning and lipolysis pathways in the adipose tissue

VIEIRA, TMB. Qualidade de Vida em Mulheres Obesas e com Síndrome dos Ovários Policísticos. 2010. 65 fls. Dissertação (Mestrado) - Faculdade de Medicina de Ribeirão Preto. Universidade de São Paulo. Ribeirão Preto. 2010. A síndrome dos ovários policísticos (SOP) é uma das desordens endócrinas mais comuns na idade reprodutiva, sendo a sua prevalência de 6 a 10% na população feminina. A SOP associada à obesidade pode agravar a saúde física e mental com um impacto negativo no funcionamento bio-psico-social. Os distúrbios metabólicos e as manifestações clínicas do hiperandrogenismo, comuns em mulheres com SOP tem levado ao aumento dos distúrbios psicológicos e redução na qualidade de vida (QV). Alguns estudos têm mostrado uma piora da QV na SOP, mas não fazem distinção sobre os efeitos que a própria obesidade pode acarretar a QV, uma vez que mais de 50% das pacientes SOP apresentam sobrepeso e obesidade. O presente estudo objetivou avaliar se há diferença na QV de pacientes com SOP obesas comparadas a controles obesas com ciclos ovulatórios. Foram incluídas 35 obesas com SOP e 28 obesas com ciclos ovulatórios, com idade entre 20 e 40 anos, IMC 30 e que aceitaram assinar o TCLE. Utilizou-se para a caracterização da população o questionário sócio-demográfico, médico, reprodutivo e somatométrico e para a avaliação da qualidade de vida, o questionário SF-36, que avalia os componentes da saúde física e os componentes da saúde mental. As pacientes com SOP mostraram melhor escore no que diz respeito ao domínio da capacidade funcional (73,43±20,57 vs 59,46±22,08) (p=0,01). Para os demais domínios não houve diferenças significativas entre os grupos. Nossos resultados sugerem que o aumento de androgênios comum em obesas com SOP possa estar associado à melhor capacidade funcional. / VIEIRA, TMB. Quality of Life of Obese Women With Polycystic Ovary Syndrome. 2010. 65 fls. Dissertation (Master). Faculdade de Medicina de Ribeirão Preto. Universidade de São Paulo, Ribeirão Preto, 2010. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders occurring during reproductive age, with a prevalence of 6 to 10% in the female population. PCOS associated with obesity can affect physical and mental health, with a negative impact on biopsychosocial functioning. The metabolic disorders and clinical manifestations of hyperandrogenism, common among women with PCOS, have led to an increase in psychological disorders and a reduction of quality of life (QL). Some studies have shown a worsening of QL in PCOS but without distinguishing between the effects that obesity itself may have on QL, since more than 50% of patients with PCOS are overweight or obese. The objective of the present study was to determine whether there is a difference in the QL of obese patients with PCOS compared to obese controls with ovulatory cycles. The study was conducted on 35 obese women with PCOS and 28 obese women with ovulatory cycles aged 20 to 40 years, with a BMI 30, who gave written informed consent to participate. A sociodemographic, medical, reproductive and somatometric questionnaire was used to characterize the population and QL was assessed with the SF-36 questionnaire, which evaluates the components of physical and mental health. The patients with PCOS had a better score regarding the functional capacity domain (73,43±20,57 vs 59,46±22,08) (p=0,01), whereas no significant differences were observed beween groups regarding the remaining domains. The present results suggest that the increase in androgens commonly occurring among obese women with PCOS may be associated with their better functional capacity.