Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF. Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women. Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups. Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.

Numerous epidemiological studies show a strong association between low birth weight and later life hypertension and metabolic disease. Excessive in utero exposure to glucocorticoids (‘stress hormones’) has been hypothesized to be important in such developmental ‘programming’, acting via crucial physiological, gene expression or structural changes in the developing fetus. Normally, the fetus is protected from the high levels of maternal glucocorticoids by an enzymic placental barrier, 11 betahydroxysteroid dehydrogenase type 2 (11β-HSD2). In the placenta, 11β-HSD2 efficiently converts active maternal glucocorticoids (cortisol in humans; corticosterone in rodents) to physiologically inactive 11-keto forms. In previous studies in rats, maternal administration of dexamethasone, a synthetic glucocorticoid which is minimally metabolized by 11β-HSD2, or carbenoxolone, a potent inhibitor of 11 β-hydroxysteroid dehydrogenase, increased glucocorticoid load to the fetus. This resulted in lower offspring birthweight and later life hypertension and hyperglycemia — important components of the metabolic syndrome. These programming effects were seen when dexamethasone was administered selectively during the third week of gestation. We have used this well-validated model of programming to dissect the molecular mechanisms that mediate the programming of hypertension. In accord with previous observations, administration of dexamethasone (100μg/kg/day) to pregnant rats during the last week of pregnancy significantly reduced offspring birthweight by 10%. Moreover, the 9 month-old adult offspring had systolic hypertension (9% rise) accompanied by significant hypokalemia (10% fall K+). The coexistence of hypertension and hypokalemia suggested that prenatal overexposure to dexamethasone might increase mineralocorticoid activity in the kidney. Intriguingly, although offspring of dexamethasone-treated dams had 46% lower plasma renin concentrations (consistent with intravascular fluid volume expansion), 24-hour total urinary aldosterone levels were significantly reduced compared to controls (reduction of 56%). Maternal dexamethasone treatment was associated with a permanent decrease in 11β- HSD2 mRNA and activity in the kidney of the offspring (45% and 36% respectively). 11β-HSD2 plays an important role in regulation of renal sodium reabsorption (and thereby blood pressure) by acting as a pre-receptor barrier to MR access, preventing glucocorticoids from activating MR in the distal nephron. Thus, the decrease in renal 11β-HSD2 activity would allow greater endogenous glucocorticoids to activate MR, likely accounting for the low-renin, low-aldosterone hypokalemic hypertensive phenotype observed in these offspring. Other components of mineralocorticoid or glucocorticoid signaling pathways, including mineralocorticoid receptor (MR), glucocorticoid receptor (GR) and 11-beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) were not altered in the offspring kidney by prenatal glucocorticoid exposure. Dexamethasone-programmed offspring also showed exaggerated mineralocorticoid activity with increased kalliuresis in response to exogenously administered corticosterone, suggesting that the decrease in renal 11β-HSD2 is functionally important. In this respect, our rat model resembles the syndrome of apparent mineralocorticoid excess where reduced 11β-HSD2 allows illicit activation of MR by glucocorticoids, resulting in excessive sodium reabsorption, hypertension and hypokalemia. We also studied the effects of maternal dexamethasone on offspring erythropoietin expression in the kidney. This followed from previous observations that identified the hepatocyte nuclear factor 4 alpha (HNF4α) as a key gene up-regulated in dexamethasone-programmed offspring liver, where it might be involved in mediating hyperglycemia. HNF4α is also expressed in the kidney. The role of HNF4α in the kidney is not fully understood, but has been implicated in regulation of erythropoietin synthesis. As in the liver, prenatal exposure to dexamethasone caused a significant increase (64% increase) in renal HNF4α expression. The increase in renal HNF4α mRNA was observed early (in one week old offspring) and persisted into adulthood. This was associated with significantly elevated levels of erythropoietin in circulation (110% increase). Moreover, animals that were exposed to prenatal dexamethasone had significantly increased red blood cell mass (7% increase), presumably as a result of upregulation of erythropoietin.

A pubarca precoce (PP) é definida como o desenvolvimento de pêlos pubianos antes dos 8 anos de idade em meninas e 9 anos de idade em meninos. Embora a PP não interfira diretamente com os eventos da puberdade, algumas evidências sugerem que estas meninas tenham maior risco para desenvolver, mais tarde, a Síndrome dos Ovários Policísticos (PCOS). A 17ß-hidroxiesteróide desidrogenase tipo 5 (17ßHSD5) é a principal responsável pela conversão de androstenediona em testosterona. Variações no gene que codifica para essa enzima, em especial os polimorfismos de nucleotídeo único (SNPs), podem estar relacionados com hiperandrogenismo e PCOS. A vitamina D, além dos efeitos sobre metabolismo ósseo, parece modular outras ações extra-esqueléticas, incluindo secreção e sensibilidade tecidual à insulina. A Vitamina D vem sendo associada com resistência insulínica e variantes do gene do receptor da vitamina D (VDR), vem sendo estudadas em populações de risco como no diabetes. No entanto, pouco se sabe sobre o envolvimento destes polimorfismos na PP. Os objetivos do presente trabalho foram: Avaliar os níveis de 25-hidroxivitamina D; determinar a frequência dos polimorfismos FokI, BsmI, ApaI e TaqI do gene do VDR e do SNP-71AG do gene da 17ßHSD5; verificar se existe associação entre esses polimorfismos com variáveis antropométricas, metabólicas e hormonais em uma amostra de pacientes com PP e controles do sul do Brasil. Foram arroladas 36 meninas com PP e 197 controles saudáveis. As genotipagens foram realizadas por PCR em tempo real para os SNPs -71AG, BsmI e FokI e por PCR-RFLP para os SNPs ApaI e TaqI. O SNP -71 AG do gene da 17ßHSD5 apresentou distribuição genotípica de 52,4% AA, 39,1% AG e 8,6% GG, sendo a frequência dos alelos A:G de 0,72:0,28. Analisando os dois grupos, verificamos uma maior freqüência do alelo variante (G) no grupo de meninas com PP quando comparadas aos controles (0,37 e 0,26, respectivamente), no entanto sem diferença estatística (p=0,054); não foram verificadas associações do polimorfismo com os dados clínicos e hormonais. As meninas com PP apresentaram níveis séricos de 25(OH)D inferiores aos das meninas controles (18,08±8,32 versus 21,27±7,03; p=0,032). Na análise dos polimorfismos, observou-se que o genótipo polimórfico GG do SNP ApaI TG, apresentou uma frequência maior em PP (30,6%) do que nas controles (16,2%) (Odds Ratio: 2,269; 95% Intervalo de Confiança: 1,015 – 5,076; p=0,042). Este genótipo foi também associado com níveis mais baixos de estradiol (35,30 (14,80 – 50,48) versus 12,22 (6,49 – 23,69); p=0,030) e testosterona total (0,52 (0,39 – 0,84) versus 0,20 (0,11 – 0,47); p=0,009) nas meninas com PP, mas não foi associado com os níveis de 25(OH)D. Por outro lado, verificou-se associação entre a presença dos polimorfismos TaqI TC (genótipo TC+CC) e BsmI GA (genótipo GA+AA) e níveis séricos de 25(OH)D mais elevados no grupo de meninas saudáveis (19,86±7,16 versus 22,55±6,69, p=0,007; 19,53±6,94 versus 22,88±6,76, p=0,001, respectivamente). Em conclusão, os dados deste estudo indicam que: 1) houve maior freqüência do alelo variante G SNP -71 AG do gene da 17βHSD5, com uma associação limítrofe desse alelo com o diagnóstico clínico de PP; 2) o polimorfismo ApaI TG associou-se com PP e parece estar modulando os processos esteroidogênicos nas meninas com PP; 3) houve uma interação entre os polimorfismos TaqI TC e BsmI GA e concentrações circulantes de vitamina D em meninas do sul do Brasil. / Precocious pubarche (PP) is usually defined as the development of pubic hair before the age of 8 in girls and age of 9 in boys. Although the PP does not interfere directly in puberty events, some evidence suggests that these girls have higher risk for the development of Polycystic Ovary Syndrome (PCOS) at later ages. The Type 5 17β-Hydroxysteroid Dehydrogenase (17ßHSD5) is the principal responsible for the conversion of androstenedione to testosterone. Variations in the gene encoding for this enzyme, especially Single Nucleotide polymorphisms (SNPs), may be related with hyperandrogenism, and PCOS. Besides the effects on bone metabolism, vitamin D appears to modulate other extra-skeletal actions, including secretions and tissue sensitivity to insulin. Vitamin D has been associated with insulin resistance and variants in the vitamin D receptor (VDR) gene, have been studied in populations at risk of Diabetes. However, little is known about these polymorphisms in the PP. The aims of this work were: to evaluate the levels of the 25-hydroxyvitamin D; to determine the polymorphisms FokI, BsmI, ApaI and TaqI in VDR gene and SNP -71AG in 17ßHSD5 gene frequencies; to asses if exist association between this SNPs and anthropometric, metabolic and hormonal characteristics in patients with PP and controls of the southern Brazil. Were enrolled 36 girls with PP and 197 healthy controls. Genotypic analyzes were evaluated by Real Time for the SNPs -71AG, BsmI and FokI and by PCR-RFLP for the ApaI e TaqI polymorphisms. Genotype frequency for SNP -71 AG of the 17ßHSD5 gene was 52.4% AA, 39.1% AG and 8.6% GG, A:G allelic frequency was 0.72:0.28. Analyzing both groups, higher frequency of the variant allele (G) in patient PP than controls (0.37 e 0.26, respectively) was found but without statistical difference (p=0.054); there were no associations between this polymorphism and clinical and hormonal features. PP girls have serum levels of 25(OH)D lower than those from control group (18.08±8.32 versus 21.27±7.03; p=0.032). The polymorphism analyze was observed that genotype GG of the SNP ApaI TG showed a higher frequency in PP (30.6%) than controls (16.2%) (Odds Ratio: 2.269; 95% confidence interval: 1.015 – 5.076; p=0.042). The same genotype was associated with lower estradiol (35.30 (14.80 – 50.48) versus 12.22 (6.49 – 23.69); p=0.030) and total testosterone levels (0.52 (0.39 – 0.84) versus 0.20 (0.11 – 0.47); p=0.009), in girls with PP. There were no association between this polymorphism and serum 25(OH)D. On the other hand, there was association between the presence of the polymorphisms TaqI TC (TC + CC genotype) and BsmI GA (GA + AA genotype) and higher serum 25(OH)D in the group of healthy girls (19.86 ± 7.16 versus 6.69 ± 22:55 , p = 0.007; 19:53 ± 6.94 versus 22.88 ± 6.76, p = 0.001, respectively). In conclusion, data from this study indicate that: 1) there was a higher frequency of the variant allele G of the SNP -71 AG of the 17ßHSD5 gene, with a borderline association of this allele with the clinical diagnosis of PP; 2) ApaI TG polymorphism is associated with PP and seems to modulate the processes steroidogenesis in girls with PP; 3) there was an interaction between the polymorphisms TaqI TC and BsmI GA and vitamin D concentrations in girls from southern Brazil.

A pubarca precoce (PP) é definida como o desenvolvimento de pêlos pubianos antes dos 8 anos de idade em meninas e 9 anos de idade em meninos. Embora a PP não interfira diretamente com os eventos da puberdade, algumas evidências sugerem que estas meninas tenham maior risco para desenvolver, mais tarde, a Síndrome dos Ovários Policísticos (PCOS). A 17ß-hidroxiesteróide desidrogenase tipo 5 (17ßHSD5) é a principal responsável pela conversão de androstenediona em testosterona. Variações no gene que codifica para essa enzima, em especial os polimorfismos de nucleotídeo único (SNPs), podem estar relacionados com hiperandrogenismo e PCOS. A vitamina D, além dos efeitos sobre metabolismo ósseo, parece modular outras ações extra-esqueléticas, incluindo secreção e sensibilidade tecidual à insulina. A Vitamina D vem sendo associada com resistência insulínica e variantes do gene do receptor da vitamina D (VDR), vem sendo estudadas em populações de risco como no diabetes. No entanto, pouco se sabe sobre o envolvimento destes polimorfismos na PP. Os objetivos do presente trabalho foram: Avaliar os níveis de 25-hidroxivitamina D; determinar a frequência dos polimorfismos FokI, BsmI, ApaI e TaqI do gene do VDR e do SNP-71AG do gene da 17ßHSD5; verificar se existe associação entre esses polimorfismos com variáveis antropométricas, metabólicas e hormonais em uma amostra de pacientes com PP e controles do sul do Brasil. Foram arroladas 36 meninas com PP e 197 controles saudáveis. As genotipagens foram realizadas por PCR em tempo real para os SNPs -71AG, BsmI e FokI e por PCR-RFLP para os SNPs ApaI e TaqI. O SNP -71 AG do gene da 17ßHSD5 apresentou distribuição genotípica de 52,4% AA, 39,1% AG e 8,6% GG, sendo a frequência dos alelos A:G de 0,72:0,28. Analisando os dois grupos, verificamos uma maior freqüência do alelo variante (G) no grupo de meninas com PP quando comparadas aos controles (0,37 e 0,26, respectivamente), no entanto sem diferença estatística (p=0,054); não foram verificadas associações do polimorfismo com os dados clínicos e hormonais. As meninas com PP apresentaram níveis séricos de 25(OH)D inferiores aos das meninas controles (18,08±8,32 versus 21,27±7,03; p=0,032). Na análise dos polimorfismos, observou-se que o genótipo polimórfico GG do SNP ApaI TG, apresentou uma frequência maior em PP (30,6%) do que nas controles (16,2%) (Odds Ratio: 2,269; 95% Intervalo de Confiança: 1,015 – 5,076; p=0,042). Este genótipo foi também associado com níveis mais baixos de estradiol (35,30 (14,80 – 50,48) versus 12,22 (6,49 – 23,69); p=0,030) e testosterona total (0,52 (0,39 – 0,84) versus 0,20 (0,11 – 0,47); p=0,009) nas meninas com PP, mas não foi associado com os níveis de 25(OH)D. Por outro lado, verificou-se associação entre a presença dos polimorfismos TaqI TC (genótipo TC+CC) e BsmI GA (genótipo GA+AA) e níveis séricos de 25(OH)D mais elevados no grupo de meninas saudáveis (19,86±7,16 versus 22,55±6,69, p=0,007; 19,53±6,94 versus 22,88±6,76, p=0,001, respectivamente). Em conclusão, os dados deste estudo indicam que: 1) houve maior freqüência do alelo variante G SNP -71 AG do gene da 17βHSD5, com uma associação limítrofe desse alelo com o diagnóstico clínico de PP; 2) o polimorfismo ApaI TG associou-se com PP e parece estar modulando os processos esteroidogênicos nas meninas com PP; 3) houve uma interação entre os polimorfismos TaqI TC e BsmI GA e concentrações circulantes de vitamina D em meninas do sul do Brasil. / Precocious pubarche (PP) is usually defined as the development of pubic hair before the age of 8 in girls and age of 9 in boys. Although the PP does not interfere directly in puberty events, some evidence suggests that these girls have higher risk for the development of Polycystic Ovary Syndrome (PCOS) at later ages. The Type 5 17β-Hydroxysteroid Dehydrogenase (17ßHSD5) is the principal responsible for the conversion of androstenedione to testosterone. Variations in the gene encoding for this enzyme, especially Single Nucleotide polymorphisms (SNPs), may be related with hyperandrogenism, and PCOS. Besides the effects on bone metabolism, vitamin D appears to modulate other extra-skeletal actions, including secretions and tissue sensitivity to insulin. Vitamin D has been associated with insulin resistance and variants in the vitamin D receptor (VDR) gene, have been studied in populations at risk of Diabetes. However, little is known about these polymorphisms in the PP. The aims of this work were: to evaluate the levels of the 25-hydroxyvitamin D; to determine the polymorphisms FokI, BsmI, ApaI and TaqI in VDR gene and SNP -71AG in 17ßHSD5 gene frequencies; to asses if exist association between this SNPs and anthropometric, metabolic and hormonal characteristics in patients with PP and controls of the southern Brazil. Were enrolled 36 girls with PP and 197 healthy controls. Genotypic analyzes were evaluated by Real Time for the SNPs -71AG, BsmI and FokI and by PCR-RFLP for the ApaI e TaqI polymorphisms. Genotype frequency for SNP -71 AG of the 17ßHSD5 gene was 52.4% AA, 39.1% AG and 8.6% GG, A:G allelic frequency was 0.72:0.28. Analyzing both groups, higher frequency of the variant allele (G) in patient PP than controls (0.37 e 0.26, respectively) was found but without statistical difference (p=0.054); there were no associations between this polymorphism and clinical and hormonal features. PP girls have serum levels of 25(OH)D lower than those from control group (18.08±8.32 versus 21.27±7.03; p=0.032). The polymorphism analyze was observed that genotype GG of the SNP ApaI TG showed a higher frequency in PP (30.6%) than controls (16.2%) (Odds Ratio: 2.269; 95% confidence interval: 1.015 – 5.076; p=0.042). The same genotype was associated with lower estradiol (35.30 (14.80 – 50.48) versus 12.22 (6.49 – 23.69); p=0.030) and total testosterone levels (0.52 (0.39 – 0.84) versus 0.20 (0.11 – 0.47); p=0.009), in girls with PP. There were no association between this polymorphism and serum 25(OH)D. On the other hand, there was association between the presence of the polymorphisms TaqI TC (TC + CC genotype) and BsmI GA (GA + AA genotype) and higher serum 25(OH)D in the group of healthy girls (19.86 ± 7.16 versus 6.69 ± 22:55 , p = 0.007; 19:53 ± 6.94 versus 22.88 ± 6.76, p = 0.001, respectively). In conclusion, data from this study indicate that: 1) there was a higher frequency of the variant allele G of the SNP -71 AG of the 17ßHSD5 gene, with a borderline association of this allele with the clinical diagnosis of PP; 2) ApaI TG polymorphism is associated with PP and seems to modulate the processes steroidogenesis in girls with PP; 3) there was an interaction between the polymorphisms TaqI TC and BsmI GA and vitamin D concentrations in girls from southern Brazil.

A pubarca precoce (PP) é definida como o desenvolvimento de pêlos pubianos antes dos 8 anos de idade em meninas e 9 anos de idade em meninos. Embora a PP não interfira diretamente com os eventos da puberdade, algumas evidências sugerem que estas meninas tenham maior risco para desenvolver, mais tarde, a Síndrome dos Ovários Policísticos (PCOS). A 17ß-hidroxiesteróide desidrogenase tipo 5 (17ßHSD5) é a principal responsável pela conversão de androstenediona em testosterona. Variações no gene que codifica para essa enzima, em especial os polimorfismos de nucleotídeo único (SNPs), podem estar relacionados com hiperandrogenismo e PCOS. A vitamina D, além dos efeitos sobre metabolismo ósseo, parece modular outras ações extra-esqueléticas, incluindo secreção e sensibilidade tecidual à insulina. A Vitamina D vem sendo associada com resistência insulínica e variantes do gene do receptor da vitamina D (VDR), vem sendo estudadas em populações de risco como no diabetes. No entanto, pouco se sabe sobre o envolvimento destes polimorfismos na PP. Os objetivos do presente trabalho foram: Avaliar os níveis de 25-hidroxivitamina D; determinar a frequência dos polimorfismos FokI, BsmI, ApaI e TaqI do gene do VDR e do SNP-71AG do gene da 17ßHSD5; verificar se existe associação entre esses polimorfismos com variáveis antropométricas, metabólicas e hormonais em uma amostra de pacientes com PP e controles do sul do Brasil. Foram arroladas 36 meninas com PP e 197 controles saudáveis. As genotipagens foram realizadas por PCR em tempo real para os SNPs -71AG, BsmI e FokI e por PCR-RFLP para os SNPs ApaI e TaqI. O SNP -71 AG do gene da 17ßHSD5 apresentou distribuição genotípica de 52,4% AA, 39,1% AG e 8,6% GG, sendo a frequência dos alelos A:G de 0,72:0,28. Analisando os dois grupos, verificamos uma maior freqüência do alelo variante (G) no grupo de meninas com PP quando comparadas aos controles (0,37 e 0,26, respectivamente), no entanto sem diferença estatística (p=0,054); não foram verificadas associações do polimorfismo com os dados clínicos e hormonais. As meninas com PP apresentaram níveis séricos de 25(OH)D inferiores aos das meninas controles (18,08±8,32 versus 21,27±7,03; p=0,032). Na análise dos polimorfismos, observou-se que o genótipo polimórfico GG do SNP ApaI TG, apresentou uma frequência maior em PP (30,6%) do que nas controles (16,2%) (Odds Ratio: 2,269; 95% Intervalo de Confiança: 1,015 – 5,076; p=0,042). Este genótipo foi também associado com níveis mais baixos de estradiol (35,30 (14,80 – 50,48) versus 12,22 (6,49 – 23,69); p=0,030) e testosterona total (0,52 (0,39 – 0,84) versus 0,20 (0,11 – 0,47); p=0,009) nas meninas com PP, mas não foi associado com os níveis de 25(OH)D. Por outro lado, verificou-se associação entre a presença dos polimorfismos TaqI TC (genótipo TC+CC) e BsmI GA (genótipo GA+AA) e níveis séricos de 25(OH)D mais elevados no grupo de meninas saudáveis (19,86±7,16 versus 22,55±6,69, p=0,007; 19,53±6,94 versus 22,88±6,76, p=0,001, respectivamente). Em conclusão, os dados deste estudo indicam que: 1) houve maior freqüência do alelo variante G SNP -71 AG do gene da 17βHSD5, com uma associação limítrofe desse alelo com o diagnóstico clínico de PP; 2) o polimorfismo ApaI TG associou-se com PP e parece estar modulando os processos esteroidogênicos nas meninas com PP; 3) houve uma interação entre os polimorfismos TaqI TC e BsmI GA e concentrações circulantes de vitamina D em meninas do sul do Brasil. / Precocious pubarche (PP) is usually defined as the development of pubic hair before the age of 8 in girls and age of 9 in boys. Although the PP does not interfere directly in puberty events, some evidence suggests that these girls have higher risk for the development of Polycystic Ovary Syndrome (PCOS) at later ages. The Type 5 17β-Hydroxysteroid Dehydrogenase (17ßHSD5) is the principal responsible for the conversion of androstenedione to testosterone. Variations in the gene encoding for this enzyme, especially Single Nucleotide polymorphisms (SNPs), may be related with hyperandrogenism, and PCOS. Besides the effects on bone metabolism, vitamin D appears to modulate other extra-skeletal actions, including secretions and tissue sensitivity to insulin. Vitamin D has been associated with insulin resistance and variants in the vitamin D receptor (VDR) gene, have been studied in populations at risk of Diabetes. However, little is known about these polymorphisms in the PP. The aims of this work were: to evaluate the levels of the 25-hydroxyvitamin D; to determine the polymorphisms FokI, BsmI, ApaI and TaqI in VDR gene and SNP -71AG in 17ßHSD5 gene frequencies; to asses if exist association between this SNPs and anthropometric, metabolic and hormonal characteristics in patients with PP and controls of the southern Brazil. Were enrolled 36 girls with PP and 197 healthy controls. Genotypic analyzes were evaluated by Real Time for the SNPs -71AG, BsmI and FokI and by PCR-RFLP for the ApaI e TaqI polymorphisms. Genotype frequency for SNP -71 AG of the 17ßHSD5 gene was 52.4% AA, 39.1% AG and 8.6% GG, A:G allelic frequency was 0.72:0.28. Analyzing both groups, higher frequency of the variant allele (G) in patient PP than controls (0.37 e 0.26, respectively) was found but without statistical difference (p=0.054); there were no associations between this polymorphism and clinical and hormonal features. PP girls have serum levels of 25(OH)D lower than those from control group (18.08±8.32 versus 21.27±7.03; p=0.032). The polymorphism analyze was observed that genotype GG of the SNP ApaI TG showed a higher frequency in PP (30.6%) than controls (16.2%) (Odds Ratio: 2.269; 95% confidence interval: 1.015 – 5.076; p=0.042). The same genotype was associated with lower estradiol (35.30 (14.80 – 50.48) versus 12.22 (6.49 – 23.69); p=0.030) and total testosterone levels (0.52 (0.39 – 0.84) versus 0.20 (0.11 – 0.47); p=0.009), in girls with PP. There were no association between this polymorphism and serum 25(OH)D. On the other hand, there was association between the presence of the polymorphisms TaqI TC (TC + CC genotype) and BsmI GA (GA + AA genotype) and higher serum 25(OH)D in the group of healthy girls (19.86 ± 7.16 versus 6.69 ± 22:55 , p = 0.007; 19:53 ± 6.94 versus 22.88 ± 6.76, p = 0.001, respectively). In conclusion, data from this study indicate that: 1) there was a higher frequency of the variant allele G of the SNP -71 AG of the 17ßHSD5 gene, with a borderline association of this allele with the clinical diagnosis of PP; 2) ApaI TG polymorphism is associated with PP and seems to modulate the processes steroidogenesis in girls with PP; 3) there was an interaction between the polymorphisms TaqI TC and BsmI GA and vitamin D concentrations in girls from southern Brazil.

Ziel der Untersuchungen war, zur Klärung der Ursachen einer während der letzten Jahrzehnte erhöhten Frequenz sowohl von PCOS als auch von IO beizutragen. Es war zu ermitteln, ob hormonelle Verschiebungen bei den Patienten nachweisbar und diese durch genetische und epigenetische Faktoren erklärbar sind. Ausgehend von dem Postulat, daß verminderte 21-OH- und 3beta-HSD-Aktivitäten als prädisponierende Faktoren von PCOS und IO angesehen werden, waren hormonanalytische Untersuchungen zur Ermittlung partieller 21-OH- bzw. 3beta-HSD-Defizienzen durchgeführt worden. Den eigenen Erfahrungen und Darstellungen der internationalen Literatur entsprechend befaßt sich ein Teil der Methodik mit der Entwicklung einer neuen, der üblichen 17alfa-OHP-Messung überlegenen Methode zur Ermittlung von 21-OH-Defizienzen durch 21-DOF-Bestimmung nach ACTH-Test im Blutplasma. Wir erhielten bei vier von 21 PCOS-Patientinnen und drei von acht Patienten mit IO erhöhte 21-DOF-, 21-DOF/F- bzw. 17alfa-OHP-Werte nach ACTH-Test, die auf partielle 21-OH-Defizienzen hinweisen. Zusätzlich wurden bei 12 PCOS-Patientinnen erhöhte basale DHEAS- oder DHEAS/F-Werte gefunden, die als Hinweise auf partielle 3beta-HSD-Defizienzen oder 17,20-Lyase-Hyperaktivität gedeutet wurden. In der Stichprobe der IO waren DHEAS oder DHEAS/F-Werte bei vier Patienten erhöht. Da bei vier der 12 Patientinnen mit PCOS und zwei von vier Patienten mit IO genetisch und endokrinologisch gleichzeitig eine partielle 21-OH-Defizienz nachgewiesen wurde, kann bei diesen Patienten eine partielle 3beta-HSD-Defizienz weitgehend ausgeschlossen werden. Es wurden molekulargenetische Untersuchungen für die 14 häufigsten Mutationen in CYP21 bei Cohorten mit AGS, PCOS und IO durchgeführt. Die Untersuchung der AGS-Patienten sollte dazu dienen, ein effizientes und schnelles System der Mutationssuche für diagnostische Zwecke zu etablieren. Es wurden die häufigsten, phänotypisch wirksamen Mutationen in CYP21 bei der Mehrzahl dieser Patientengruppe im homozygoten bzw. compound heterozygoten Zustand gefunden und eine deutliche Genotyp-Phänotyp-Korrelation festgestellt. Auch bei Patientinnen mit PCOS sowie bei IO, bei denen partielle 21-OH-Defizienzen nachweisbar waren, wurden Mutationen in CYP21 gefunden. Die hierbei heterozygot vorliegenden Mutationen waren dieselben, die homozygot oder compound heterozygot bei schweren Formen des AGS gefunden wurden. Es ergab sich eine Korrelation molekulargenetischer und hormonanalytischer Befunde bei AGS, PCOS sowie IO. Allerdings konnten bei der Mehrzahl der Fälle mit PCOS und mit IO weder Mutationen noch hormonelle Auffälligkeiten hinsichtlich partieller 21-OH-Defizienzen gefunden werden. Die jedoch bei vielen Patientinnen gefundenen erhöhten DHEAS- und DHEAS/F-Werte stimmen mit Untersuchungen überein, die parallel starke Zunahmen der Häufigkeit der Hemmung des Enzyms 3ß-HSD bzw. der Aktivierung der 17,20-Lyase bei PCOS-Patientinnen und der Prävalenz des PCOS selbst bei nach 1955 geborenen Frauen und von Spermatogenesestörungen bei nach 1960 geborenen Männern fanden. Die Ursache hierfür wird in der Beeinflussung der adrenalen und gonadalen Steroidhormonsynthese vor allem durch das Umweltteratogen DDT und seine Metaboliten gesehen. Weiterhin wurde der Umweltfaktor Streß diskutiert. Für die Ätiopathogenese der untersuchten Fertilitätsstörungen werden materno-fetale Mechanismen postuliert, worauf unsere sowohl molekulargenetischen als auch hormonanalytischen Befunde hinweisen. Insgesamt bestätigen die Ergebnisse unserer Arbeit die These, daß Leben auf der Interaktion von Genen und Umweltfaktoren beruht und daß Hormone dabei als Mediatoren wirken. In gen- oder umweltbedingten unphysiologischen Konzentrationen können sie während kritischer Entwicklungsphasen des neuroendokrinen Systems als Teratogene wirken und zu lebenslangen Reproduktionsstörungen führen. / This paper describes a mutational and hormonal screening in a cohort of 21 patients ultrasonically diagnosed with PCO. Our data show single heterozygous base pair CYP21 mutations in 4 patients. The four women with PCOS and CYP21 mutations also displayed clear signs of partial 21-hydroxylase deficiency through a significant rise in 21DOF or 17alfa-OHP plasma levels after ACTH stimulation. Azziz et al. have reported several heterozygous mutations in hyperandrogenic women with LO-CAH. Other studies report several heterozygous point mutations in hyperandrogenic woman who, however, were not examined for polycystic ovaries.The correlation between the hormone profiles and genetic screening results found with our patients underscores the latter s usefulness with PCOS patients. In contrast to the hormone profile, genetic screening is not influenced by external factors. The frequency of heterozygous CYP21 mutations is higher (19%) than in the normal population (5-8%), suggesting a link with PCOS in some cases. The ratio of LH/FSH was significantly raised in 43% of the cases. Most importantly, basal plasma DHEA-S levels and DHEA-S/F ratios were clearly increased, higher than the means +2SD in controls. This suggests a partial 3beta-hydroxysteroid dehydrogenase deficiency or 17,20 lyase hyperactivity. Other authors, however, were not able to find mutations in the corresponding genes. This could be explained by the fact that the DDT metabolite o,p DDD is a strong inhibitor of 3beta-HSD, and that DDT and its metabolites may be able to activate the 17,20 lyase, a cytochrome P450 enzyme. Furthermore, DDT has some oestrogen activity, and its perinatal administration can produce a PCOS-like syndrome in rats. Very significantly, there has not only been an approximately fourfold increased prevalence of PCO in women borne since 1955 in eastern Germany, following a massive prenatal exposure to DDT, but also a notable shift in the hormone profiles of those affected. A predominance of 3beta-HSD deficiencies and 17,20 lyase hyperactivity (70%) vs. 21-hydroxylase deficiency (23%) has emerged, in contrast with 21-hydroxylase deficiencies in 70% vs. 3beta-HSD deficiencies or 17,20 lyase hyperactivity in 14% for those born earlier than 1955. Similar results were obtained in this study for women with PCOS born since 1955, suggesting that the prenatal exposure of high amounts of DDT and its metabolites indeed appear to be responsible - at least in part - for the major increase in PCO and PCOS.

This thesis examines the influence of stress on the activity of hippocampal CA1 area. The main task was to determine whether the stress load affects the changes of the local metabolism of glucocorticoids, and whether the levels of corticosteroid receptors in the CA1 hippocampus are modulated in response to stress. In order to answer these questions, the experiments were carried out using three different rat strains - Fisher, Lewis and Wistar which differ in their activities of hypothalamic-pituitary-adrenal axis. Our results demonstrate that stress has no effect on expression of MR mRNA. Conversely, stress reduces the levels of GR mRNA in CA1 area of the dorsal hippocampus. Moreover, we confirmed that the Lewis and Wistar rats didn't change metabolism of glucocorticoids after stress response. By the Fisher rats increased levels of 11β-HSD1 mRNA expression and therefore increased the metabolism of corticosterone.

Stress is a widespread phenomenon in the western society of these days. It is a risky factor for health and well-being of the majority of people. Based on these facts, it is the main subject for the field of "stress physiology" research, which aims to study processes occurring during stress response and tries to elucidate mechanisms leading to stress-induced health impairment. The first aim of this thesis was to describe effects of psycho-social stress on organism. The second aim was to find out if can stress applied in juvenile age affect the stress response in adulthood. If so, how is the role of glucocorticoid-metabolism enzyme 11β-HSD1 in this influence? To answer these questions, two different animal models inducing stress response in the laboratory rat were used. The first one is the model of mild social stress based on the resident-intruder paradigm. Our results show efficancy of this model. Fisher 344 male rats treated under this model for seven consecutive days show highly elevated plasma corticosterone concentrations and elevated expression of the glucocorticoid receptor gene in the pituitary. Behavioral analysis demonstrates a decreased social behavioral profile of the intruders, suggesting submisive social position of these animals in the resident-intruder paradigm. The second model used is...

Introdução: A deficiência da 21-hidroxilase (21-OHD) é um frequente erro herdado do metabolismo que resulta no comprometimento da síntese do cortisol e/ou aldosterona e aumento da produção de andrógenos. A doença é caracterizada por uma diversidade fenotípica, variando desde virilização pré-natal da genitália externa de fetos femininos e pós-natal em ambos os sexos, com ou sem perda de sal, até quadros assintomáticos. Em seu tratamento é necessária reposição com glicocorticoide para se evitar a insuficiência adrenocortical e os sinais de virilização. Um fino ajuste na dose diária do glicocorticoide é essencial para se evitar sub ou supertratamento, com o objetivo de preservar o potencial de estatura final e fertilidade. Entretanto, tem sido observada maior frequência de obesidade e outras comorbidades metabólicas nestes pacientes; porém, a prevalência destas complicações ainda não é conhecida, bem como se estariam associadas à exposição ao glicocorticoide e/ou com fatores genéticos. Objetivos: avaliar a frequência de obesidade e de síndrome metabólica (SM) em pacientes com 21OHD; caracterizar a distribuição alélica dos polimorfismos dos genes do receptor de glicocorticoide (NR3C1) e da enzima 11beta-hidroxiesteróide desidrogenase tipo I (HSD11B1), e correlacionar a distribuição destes polimorfismos com a presença das complicações metabólicas. Métodos: Foram selecionados 109 pacientes (60 PS/49 VS), sendo 41 crianças e adolescentes (idade média 11,4 ± 3,9 anos) e 68 adultos (idade média 28,4 ± 9 anos) em tratamento com glicocorticoide e com adequado controle hormonal. Pacientes com a forma PS também receberam fludrocortisona. Adequado controle foi caracterizado por concentração normal de atividade plasmática de renina e de andrógenos de acordo com o sexo e idade nos últimos 2 anos. A obesidade nos adultos foi definida pelo IMC >= 30 kg/m² e em crianças e adolescentes pelo IMC acima do percentil 95. Síndrome metabólica foi definida segundo o critério do National Cholesterol Education Program em adultos e crianças. História familiar de hipertensão arterial, diabetes, dislipidemia, obesidade e/ou doença cardiovascular também foi avaliada. Foram mensuradas glicemia, lipoproteínas, triglicérides, colesterol total e insulina. Os alelos BclI, A3669G, ER22/23EK e N363S do gene NR3C1 e o alelo 4436InsA do gene HSD11B1 foram genotipados e as análises de associação com os fenótipos foram realizadas por meio dos testes Chi-quadrado, t-studant e análise de regressão. As análises de correlação foram feitas utilizando o teste de correlação de Pearson. Resultados: Obesidade foi observada em 31,7% das crianças e 23,5% dos adultos. Síndrome metabólica foi observada em 14,6% das crianças e 7,3% dos adultos. A prevalência dos componentes da SM foi maior no grupo dos obesos quando comparada a de pacientes não obesos (crianças e adultos). Não houve correlação significante entre o IMC, sexo, forma clínica da 21-OHD, duração da terapia e dose de GC. História familiar positiva para obesidade, hipertensão, dislipidemia e doença cardiovascular foi mais frequente nos pacientes obesos quando comparada a de pacientes não obesos, em adultos e crianças. Os polimorfismos BclI, A3669G e 4436InsA foram identificados em 23,2%, 9,7% e 14,6% dos alelos das crianças, respectivamente, e nos adultos em 26,4%, 9,6% e 18,4% dos alelos, respectivamente. A variante A3669G foi associada à maiores concentrações de LDL-c em crianças quando comparada aos carreadores do alelo selvagem. Os pacientes adultos carreadores do polimorfismo BclI apresentaram maior IMC, circunferência abdominal e PAS quando comparados aos carreadores do alelo selvagem. Não observamos diferenças estatisticamente significantes no perfil metabólico entre pacientes carreadores e não carreadores do polimorfismo 4436InsA (adultos e crianças). Conclusão: observamos que pacientes 21-OHD possuem maior prevalência de obesidade, e o grupo pediátrico maior prevalência de SM em relação à população de referência, sendo ambas independentes da dose de glicocorticoide e do tempo do tratamento. A presença de perfil metabólico adverso esteve associada à obesidade e à predisposição genética, tais como história familiar e variantes genéticas do receptor de glicocorticoide / Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is a common autosomal recessive disorder that leads to decreased glucocorticoid secretion, with or without mineralocorticoid deficiency, and increased androgen production. The disease is characterized by phenotypic variability, including a severe form with prenatal virilization of the external genitalia in female fetuses and postnatal virilization in both sexes, with or without salt loss. Current therapy aims to provide adequate glucocorticoid (GC) replacement and to suppress the abnormal androgen secretion; mineralocorticoid replacement aims to control the renal salt balance to avoid adrenal crisis. Nevertheless, these therapeutic goals are difficult to achieve in practice due to the complexity of replicating the physiologic cortisol circadian rhythm. Increased prevalence of obesity, insulin resistance, hypertension and adverse lipid profile have been observed among CAH patients under GC therapy; however, the extent of its prevalence and also whether it is associated with the GC dose or with genetic factors are not known. Objectives: to evaluate the obesity and metabolic syndrome (SM) frequencies in 21-OHD patients; to characterize the allelic distribution of the NR3C1 and HSD11B1 polymorphisms, and to correlate with the metabolic profile. Methods: One hundred and nine patients (60SW/49SV) were selected, 41 being children and adolescents (mean age 11.4 ± 3.9 yrs) and 68 adults (mean age 28.4 ± 9 yrs) all of whom received GC treatment and had adequate hormonal control. SW patients also received fludrocortisone. Adequate hormonal control was characterized by normal plasmatic rennin activity and androgen levels according to age and sex for at least two years. Blood fasting was used to obtain glucose, lipoproteins, triglycerides, total cholesterol and insulin levels. Obesity in the adult group was defined by BMI >= 30 kg/m², and in the young group by BMI > 95th percentile. Metabolic syndrome was defined by the NCEP ATPIII criteria. Family history of the hypertension, diabetes, dyslipidemia, obesity and/or cardiovascular disease was also evaluated. The BclI, A3669G, ER22/23EK and N363S alleles of the NR3C1 gene and 4436InsA of the HSD11B1 gene were genotyped and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Correlation analyses were performed by Pearson correlation test. Results: obesity was observed in 31.7% of children and 23.5% of adults. SM was observed in 14.6% of young and 7.3% of adult patients. SM prevalence was higher in the obese group than the nonobese group (children and adults). There was no significant correlation between GC dose and BMI, sex, clinical form or treatment duration. Prevalence of family history of obesity, hypertension, dyslipidemia and cardiovascular disease was higher in the obese than in non-obese patients (children and adults). The BclI, A3669G and 4436InsA polymorphisms were found in 23.2%, 9.7% and 14.6% of the alleles in children, respectively and in 26.4%, 9.6% and 18.4% of the alleles in adults. The A3669G variant was associated to increased LDL-c levels in comparison with noncarriers in the young group. The BclI adult carriers presented higher BMI, abdominal circumference and systolic blood pressure in comparison with noncarriers. Statistically significant differences were not observed in the metabolic profile between carriers and non-carriers of the 4436InsA polymorphism (children and adults). Conclusion: in the present study, which analyzed the clinical and metabolic profile of 21-OHD patients, high obesity prevalence, independent of GC dose and treatment duration, was observed. Adverse metabolic profile was mainly associated with obesity and genetic predisposition, such as family history and NR3C1 polymorphisms

Introdução: A deficiência da 21-hidroxilase (21-OHD) é um frequente erro herdado do metabolismo que resulta no comprometimento da síntese do cortisol e/ou aldosterona e aumento da produção de andrógenos. A doença é caracterizada por uma diversidade fenotípica, variando desde virilização pré-natal da genitália externa de fetos femininos e pós-natal em ambos os sexos, com ou sem perda de sal, até quadros assintomáticos. Em seu tratamento é necessária reposição com glicocorticoide para se evitar a insuficiência adrenocortical e os sinais de virilização. Um fino ajuste na dose diária do glicocorticoide é essencial para se evitar sub ou supertratamento, com o objetivo de preservar o potencial de estatura final e fertilidade. Entretanto, tem sido observada maior frequência de obesidade e outras comorbidades metabólicas nestes pacientes; porém, a prevalência destas complicações ainda não é conhecida, bem como se estariam associadas à exposição ao glicocorticoide e/ou com fatores genéticos. Objetivos: avaliar a frequência de obesidade e de síndrome metabólica (SM) em pacientes com 21OHD; caracterizar a distribuição alélica dos polimorfismos dos genes do receptor de glicocorticoide (NR3C1) e da enzima 11beta-hidroxiesteróide desidrogenase tipo I (HSD11B1), e correlacionar a distribuição destes polimorfismos com a presença das complicações metabólicas. Métodos: Foram selecionados 109 pacientes (60 PS/49 VS), sendo 41 crianças e adolescentes (idade média 11,4 ± 3,9 anos) e 68 adultos (idade média 28,4 ± 9 anos) em tratamento com glicocorticoide e com adequado controle hormonal. Pacientes com a forma PS também receberam fludrocortisona. Adequado controle foi caracterizado por concentração normal de atividade plasmática de renina e de andrógenos de acordo com o sexo e idade nos últimos 2 anos. A obesidade nos adultos foi definida pelo IMC >= 30 kg/m² e em crianças e adolescentes pelo IMC acima do percentil 95. Síndrome metabólica foi definida segundo o critério do National Cholesterol Education Program em adultos e crianças. História familiar de hipertensão arterial, diabetes, dislipidemia, obesidade e/ou doença cardiovascular também foi avaliada. Foram mensuradas glicemia, lipoproteínas, triglicérides, colesterol total e insulina. Os alelos BclI, A3669G, ER22/23EK e N363S do gene NR3C1 e o alelo 4436InsA do gene HSD11B1 foram genotipados e as análises de associação com os fenótipos foram realizadas por meio dos testes Chi-quadrado, t-studant e análise de regressão. As análises de correlação foram feitas utilizando o teste de correlação de Pearson. Resultados: Obesidade foi observada em 31,7% das crianças e 23,5% dos adultos. Síndrome metabólica foi observada em 14,6% das crianças e 7,3% dos adultos. A prevalência dos componentes da SM foi maior no grupo dos obesos quando comparada a de pacientes não obesos (crianças e adultos). Não houve correlação significante entre o IMC, sexo, forma clínica da 21-OHD, duração da terapia e dose de GC. História familiar positiva para obesidade, hipertensão, dislipidemia e doença cardiovascular foi mais frequente nos pacientes obesos quando comparada a de pacientes não obesos, em adultos e crianças. Os polimorfismos BclI, A3669G e 4436InsA foram identificados em 23,2%, 9,7% e 14,6% dos alelos das crianças, respectivamente, e nos adultos em 26,4%, 9,6% e 18,4% dos alelos, respectivamente. A variante A3669G foi associada à maiores concentrações de LDL-c em crianças quando comparada aos carreadores do alelo selvagem. Os pacientes adultos carreadores do polimorfismo BclI apresentaram maior IMC, circunferência abdominal e PAS quando comparados aos carreadores do alelo selvagem. Não observamos diferenças estatisticamente significantes no perfil metabólico entre pacientes carreadores e não carreadores do polimorfismo 4436InsA (adultos e crianças). Conclusão: observamos que pacientes 21-OHD possuem maior prevalência de obesidade, e o grupo pediátrico maior prevalência de SM em relação à população de referência, sendo ambas independentes da dose de glicocorticoide e do tempo do tratamento. A presença de perfil metabólico adverso esteve associada à obesidade e à predisposição genética, tais como história familiar e variantes genéticas do receptor de glicocorticoide / Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is a common autosomal recessive disorder that leads to decreased glucocorticoid secretion, with or without mineralocorticoid deficiency, and increased androgen production. The disease is characterized by phenotypic variability, including a severe form with prenatal virilization of the external genitalia in female fetuses and postnatal virilization in both sexes, with or without salt loss. Current therapy aims to provide adequate glucocorticoid (GC) replacement and to suppress the abnormal androgen secretion; mineralocorticoid replacement aims to control the renal salt balance to avoid adrenal crisis. Nevertheless, these therapeutic goals are difficult to achieve in practice due to the complexity of replicating the physiologic cortisol circadian rhythm. Increased prevalence of obesity, insulin resistance, hypertension and adverse lipid profile have been observed among CAH patients under GC therapy; however, the extent of its prevalence and also whether it is associated with the GC dose or with genetic factors are not known. Objectives: to evaluate the obesity and metabolic syndrome (SM) frequencies in 21-OHD patients; to characterize the allelic distribution of the NR3C1 and HSD11B1 polymorphisms, and to correlate with the metabolic profile. Methods: One hundred and nine patients (60SW/49SV) were selected, 41 being children and adolescents (mean age 11.4 ± 3.9 yrs) and 68 adults (mean age 28.4 ± 9 yrs) all of whom received GC treatment and had adequate hormonal control. SW patients also received fludrocortisone. Adequate hormonal control was characterized by normal plasmatic rennin activity and androgen levels according to age and sex for at least two years. Blood fasting was used to obtain glucose, lipoproteins, triglycerides, total cholesterol and insulin levels. Obesity in the adult group was defined by BMI >= 30 kg/m², and in the young group by BMI > 95th percentile. Metabolic syndrome was defined by the NCEP ATPIII criteria. Family history of the hypertension, diabetes, dyslipidemia, obesity and/or cardiovascular disease was also evaluated. The BclI, A3669G, ER22/23EK and N363S alleles of the NR3C1 gene and 4436InsA of the HSD11B1 gene were genotyped and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Correlation analyses were performed by Pearson correlation test. Results: obesity was observed in 31.7% of children and 23.5% of adults. SM was observed in 14.6% of young and 7.3% of adult patients. SM prevalence was higher in the obese group than the nonobese group (children and adults). There was no significant correlation between GC dose and BMI, sex, clinical form or treatment duration. Prevalence of family history of obesity, hypertension, dyslipidemia and cardiovascular disease was higher in the obese than in non-obese patients (children and adults). The BclI, A3669G and 4436InsA polymorphisms were found in 23.2%, 9.7% and 14.6% of the alleles in children, respectively and in 26.4%, 9.6% and 18.4% of the alleles in adults. The A3669G variant was associated to increased LDL-c levels in comparison with noncarriers in the young group. The BclI adult carriers presented higher BMI, abdominal circumference and systolic blood pressure in comparison with noncarriers. Statistically significant differences were not observed in the metabolic profile between carriers and non-carriers of the 4436InsA polymorphism (children and adults). Conclusion: in the present study, which analyzed the clinical and metabolic profile of 21-OHD patients, high obesity prevalence, independent of GC dose and treatment duration, was observed. Adverse metabolic profile was mainly associated with obesity and genetic predisposition, such as family history and NR3C1 polymorphisms