Abstract The aim was to evaluate in vitro cytotoxicity and genotoxicity of Bio-C Repair (BCR), compared to Endosequence BC Root Repair (ERRM), MTA Angelus (MTA-Ang), and MTA Repair HP (MTA-HP). MC3T3 osteoblastic cells were exposed to extracts of the repairing bioceramic cements. After 1, 3, and 7 days, cytotoxicity and genotoxicity were evaluated by MTT and Micronucleus tests, respectively. Cells not exposed to biomaterials were used as a negative control. Data were compared using ANOVA two-way, followed by the Tukey Test (α=5%). MTA-Ang and MTA-HP showed no difference in relation to control regarding cytotoxicity in any experimental times. BCR and ERRM reduced cell viability after 3 and 7 days (p<0.05); however, the reduction caused by BCR was less than that caused by ERRM. Considering the micronucleus formation, all biomaterials caused an increase after 3 and 7 days (p<0.05), being greater for the BCR and ERRM groups. It can be concluded that BCR is non-cytotoxic in osteoblastic cells, as well as MTA-Ang e MTA Repair HP. BCR and ERRM showed greater genotoxicity than others tested biomaterials.

Resumo O objetivo foi avaliar in vitro a citotoxicidade e genotoxicidade do Bio-C Repair (BCR), em comparação com o Endosequence BC Root Repair (ERRM), MTA Angelus (MTA-Ang) e MTA Repair HP (MTA-HP). As células osteoblásticas MC3T3 foram expostas aos extratos dos cimentos biocerâmicos reparadores. Após 1, 3 e 7 dias, a citotoxicidade e a genotoxicidade foram avaliadas pelos testes MTT e Micronúcleo, respectivamente. Células não expostas aos biomateriais foram utilizadas como controle negativo. Os dados foram comparados por ANOVA de dois fatores, seguido do Teste de Tukey (p = 5 %). MTA-Ang e MTA-HP não apresentaram diferença em relação ao controle quanto à citotoxicidade em nenhum dos tempos experimentais. BCR e ERRM reduziram a viabilidade celular após 3 e 7 dias (p < 0,05); no entanto, a redução causada pelo BCR foi menor que aquela causada pelo ERRM. Todos os biomateriais causaram aumento na formação de micronúcleos após 3 e 7 dias (p < 0,05), sendo maior para os grupos BCR e ERRM. O BCR não é citotóxico em células osteoblásticas, assim como cimentos MTA-Ang e MTA Repair HP. BCR e ERRM apresentaram maior genotoxicidade do que outros biomateriais testados.

ABSTRACT Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called “hook effect”. Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

Objective This study aimed to get the genotypic and allelic frequencies of rs1801282 in 179 volunteer donors and 154 patients with Metabolic syndrome (MetS) in Brasilia, Brazil and also examine the association with anthropometric, biochemical and hemodynamic variables in the latter group. MetS comprises a group of diseases resulting from insulin resistance, in-creased risk of type 2 diabetes and atherosclerotic cardiovascular disease. MetS is defined by the presence of increased visceral fat, atherogenic dyslipidemia (elevated triglycerides (TGL)), with decreased high density lipoprotein (HDL) and increased low density lipoprotein (LDL) levels, hypertension (BPH) and disturbances in glucose homeostasis representing a significant burden across the world due to the alarming increase in the incidence over the last decades besides their significant morbidity and mortality. Peroxisome proliferator activated receptor-gamma (PPARg) has been mentioned as a candidate gene for determining the risk of MetS. It is a member of the nuclear receptors superfamily and a ligand-activated transcription factor, which regulates the expression of genes involved in the network lipogenesis and adipogenesis, insulin sensitivity, energy balance, inflammation, angiogenesis and atherosclerosis. Among the PPARG genetic variants, single nucleotide polymorphism rs1801282 has been the most extensively studied one since it was first described by Yen and cols. in 1997. This polymorphism is characterized by the replacement of a proline (CCC) to an alanine (GCA) at codon 12 of exon B, due to the exchange of a cytosine with a guanine. The Ala allele frequency varies in different ethnic groups.Materials and methods DNA was extracted using Chelex-100 method and determinations of genotypes were performed by allele-specific chain reaction.Results The distribution of genotype frequency of the MetS group was not statistically different from the frequency in the donor population at large. In the first group, genotype frequency was CC to 0.869 and 0.103 for CG, while allelic frequencies were 0.948 for C and 0.052 for G allele. In the group of donors, the genotype and allele frequencies were 0.882 for CC, 0.117 to CG; and 0.941 to 0.059 for G and C, respectively. GG genotype was not found in any of the two groups. The genotype distribution and allele frequencies were in Hardy-Weinberg equilibrium. No marker could be detected from the analysis of anthropometric, biochemical and hemodynamic variables in the MetS group.Conclusion Our data suggest that this polymorphism is not correlated with predisposition to MetS. The results obtained on a small sample of the population of Brasilia, corroborate the data reported in the literature on the prevalence of this polymorphism in PPAR in populations of different ethnic origins.

OBJETIVO: Investigar a associação do alelo T do polimorfismo de nucleotídeo único (SNP) rs7903146 do TCF7L2 com a ocorrência de DM2 em uma amostra de indivíduos acompanhados no Hospital Universitário de Brasília. SUJEITOS E MÉTODOS: O SNP 7903146 do TCF7L2 foi genotipado por PCR alelo-específica em 113 pacientes portadores de DM2 e em 139 controles não diabéticos em Brasília, Brasil. RESULTADOS: Foi observada associação significativa do alelo T do SNP rs7903146 do TCF7L2 com a ocorrência de DM2 (razão de chances de 3,92 para o genótipo TT utilizando o modelo genético recessivo, p = 0,003; e de 1,5 para o alelo T, p = 0,032). CONCLUSÃO: Esse resultado reforça os achados prévios de associação consistente desse fator genético com o risco de diabetes em populações de origens étnicas diversas. Arq Bras Endocrinol Metab. 2012;56(8):479-84

OBJECTIVE:To investigate the association of the T allele of the single nucleotide polymorphism (SNP) rs7903146 of TCF7L2 with the occurrence of T2D in a sample of subjects followed up at the Brasilia University Hospital. SUBJECTS AND METHODS: The SNP rs7903146 of TCF7L2 was genotyped by allele-specific PCR in 113 patients with known T2D and in 139 non-diabetic controls in Brasilia, Brazil. RESULTS:We found that the T allele of the SNP rs7903146 of TCF7L2 was significantly associated with T2D risk (odds ratio of 3.92 for genotype TT in the recessive genetic model, p = 0.004 and 1.5 for T allele, p = 0.032). CONCLUSION:These results reinforce previous findings on the consistent association of this genetic factor and the risk of T2D in populations of diverse ethnic backgrounds. Arq Bras Endocrinol Metab. 2012;56(8):479-84

OBJETIVO: Este estudo relata o processo de adaptação da versão brasileira do questionário QoL-AGHDA (Quality of Life - Assessment of Growth Hormone Deficiency in Adults) para pacientes com deficiência do hormônio de crescimento (DGH). MATERIAIS E MÉTODOS: A tradução adotou a metodologia de duplo painel. O questionário foi testado por intermédio de entrevistas direcionadas com 16 pacientes com DGH. No estágio final, dados de 120 pacientes com DGH (81 com teste/reteste) foram analisados para consistência interna, confiabilidade teste/reteste, validade convergente e validade entre grupos conhecidos. RESULTADOS: Os grupos de tradução foram bem-sucedidos e a versão final foi adaptada seguindo sugestões obtidas das entrevistas com os 16 pacientes. O coeficiente alfa de Cronbach foi 0,90, confiabilidade teste/reteste 0,88, escores QoL-AGHDA se correlacionaram com o NHP (p < 0,01) e também com a saúde geral relatada pelos pacientes (p < 0,01). CONCLUSÕES: A adaptação do QoL-AGHDA para a população brasileira foi bem-sucedida, e a nova versão demonstrou ser válida e confiável.

OBJECTIVE: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients. MATERIALS AND METHODS: The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups. RESULTS: The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01). CONCLUSIONS: The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.

O câncer diferenciado de tireoide raramente ocorre em associação a nódulos hiperfuncionantes. Foi descrito aqui o caso de uma paciente de 47 anos de idade que desenvolveu sintomas de hipertireoidismo associados a um nódulo tireoidiano palpável. A cintilografia da tireoide mostrou tratar-se de um nódulo autônomo, e a biópsia por punção aspirativa por agulha fina foi sugestiva de carcinoma papilar. Os achados laboratoriais foram consistentes com o diagnóstico de hipertireoidismo. A paciente foi submetida à tireoidectomia e um carcinoma papilar de 3,0 x 3,0 x 2,0 cm, variante folicular, foi descrito por exame histopatológico. O tecido tireoidiano circunjacente era normal. No pós-operatório a paciente recebeu 100 mCi de 131I, e a cintilografia de corpo inteiro mostrou apenas captação residual. Nenhuma metástase foi identificada ao longo de cinco anos de acompanhamento. Nódulos quentes raramente albergam doença maligna, e este caso demonstrou que, quando ocorre carcinoma, o prognóstico parece ser muito bom, sem evidência de disseminação metastática em longo prazo.

Differentiated thyroid cancer rarely occurs in association with hyperfunctioning nodules. We describe a case of a 47-year-old woman who developed symptoms of hyperthyroidism associated with a palpable thyroid nodule. Thyroid scintigraphy showed an autonomous nodule, and fine-needle aspiration biopsy was suggestive of papillary carcinoma. Laboratorial findings were consistent with the diagnosis of hyperthyroidism. The patient underwent thyroidectomy and a papillary carcinoma of 3.0 x 3.0 x 2.0 cm, follicular variant, was described by histological examination. The surrounding thyroid tissue was normal. Postoperatively, the patient received 100 mCi of 131I, and whole body scans detected only residual uptake. No evidence of metastasis was detected during five years of follow-up. Hot thyroid nodules rarely harbor malignancies, and this case illustrated that, when a carcinoma occurs the prognosis seems to be very good with no evidence of metastatic dissemination during a long-term follow-up.

A resistência ao hormônio tireoideano (RHT) é uma doença rara, causada por variável hiporresponsividade dos tecidos aos hormônios tireoideanos, usualmente causada por mutações no receptor beta do hormônio tireoideano (TRβ). Descrevemos uma grande família brasileira portadora de uma nova mutação afetando o gene do TRβ, induzindo RHT. Uma paciente de 14 anos de idade apresentou concentrações plasmáticas elevadas de T4 e T3 livres, associadas a TSH não-suprimido e bócio questionável. O diagnóstico de RHT foi estabelecido pela identificação da mutação I431V no gene do TRβ. Dezesseis parentes assintomáticos da probanda também são afetados pela mutação. Estudos funcionais mostram que a mutação I431V exerce efeito dominante negativo sobre o TR selvagem, basicamente, por prejudicar a liberação do correpressor SMRT ligante-dependente. A presença desta mutação reduz a potência, mas não afeta a eficácia da ação do hormônio tireoideano, o que está de acordo com a apresentação clínica de eumetabolismo dos indivíduos afetados.

Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). We describe a large Brazilian family harboring a novel mutation affecting TRβ gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRβ gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRβ, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.

Avaliamos as características clínico-laboratoriais de 73 pacientes com síndrome de Cushing (SC) endógena, assim distribuídos: 46 (63%) com doença de Cushing (DC), 21 (28,7%) com tumores adrenais (TA) e 6 (8,2%) com a síndrome do ACTH ectópico (SAE). A freqüência de manifestações clássicas do hipercortisolismo foi similar, independentemente da etiologia da SC. Em 100% dos casos de SC, observaram-se níveis do cortisol sérico (CS) > 1,8 µg/dL após supressão com doses baixas de dexametasona (DMS), além de elevação do cortisol à meia-noite (sérico ou salivar). Contudo, o cortisol livre urinário foi normal em 11,5% dos pacientes. Os níveis de ACTH mostraram-se suprimidos nos pacientes com TA, normais ou elevados na DC e sempre elevados na SAE. No teste de supressão noturna com 8 mg de DMS, supressão do CS > 50% foi observada em 78,2% dos casos de DC e 33,3% dos casos de SAE, enquanto uma supressão > 80% foi exclusiva da DC. Após estímulo com CRH ou DDAVP, um incremento do ACTH > 35% aconteceu em 81% dos indivíduos com DC e em 16,6% daqueles com SAE, ao passo que um incremento do ACTH > 50% restringiu-se à DC. A combinação de incremento do ACTH > 35 e supressão do CS > 50% foi também exclusiva da DC. A ressonância magnética visualizou 100% dos macroadenomas e 59,4% dos microadenomas hipofisários nos casos de DC. Em 10 pacientes submetidos ao cateterismo bilateral do seio petroso inferior, um gradiente centro-periferia de ACTH > 3 pós-CRH ou DDAVP teve sensibilidade de 90% e especificidade de 100% para a doença de Cushing.

We studied clinical and laboratorial features of 73 patients with endogenous Cushing’s syndrome, subdivided as follows: 46 (63%) with Cushing’s disease (CD), 21 (28.7%) with an adrenal tumor and 6 (8.2%) with ectopic ACTH secretion (EAS). The rate of typical manifestations of hypercortisolism was similar regardless its etiology. In 100% of cases of Cushing’s syndrome we observed serum cortisol levels greater than 1.8 µg/dL in low-dose dexamethasone (DMS) suppression tests, as well as elevation of serum or salivary midnight cortisol. However, urinary free cortisol was normal in 11.5% of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and always high in EAS. In the 8-mg overnight DMS suppression test, serum cortisol suppression > 50% was observed in 78.2% of cases of CD and in 33.3% of subjects with EAS, while an 80% suppression was only seen in CD. After stimulation with CRH or DDAVP an ACTH increase > 35% occurred in 81% of individuals with CD and 16.6% of those with EAS, while an ACTH increase > 50 achieved 100% specificity. Moreover, the combination of serum cortisol suppression > 50% and an ACTH increase > 35% in both tests only occurred in Cushing’s disease. Pituitary magnetic resonance imaging identified 100% of macroadenomas and 59.4% of microadenomas in patients with CD. Among 10 patients that underwent bilateral inferior petrosal sinus sampling, a central-to-peripheral ACTH gradient > 3 after CRH or DDAVP had 90% sensitivity and 100% specificity for Cushing’s disease.

Macroprolactinemia caracteriza-se pelo predomínio no soro de uma prolactina (PRL) de alto peso molecular e baixa atividade biológica que não requer tratamento. A prevalência de macroprolactinemia foi avaliada em 115 pacientes consecutivos com hiperprolactinemia. Entre eles, 19 (16,5%) tinham exclusivamente macroprolactinemia, 4 (3,5%) síndrome dos ovários policísticos, 7 (6,1%) acromegalia, 8 (6,9%) hiperprolactinemia idiopática, 10 (8,7%) hipotiroidismo primário, 14 (12,2%) adenomas clinicamente não-funcionantes, 20 (17,4%) hiperprolactinemia farmacológica e 33 (28,7%) prolactinomas. O diagnóstico de macroprolactinemia foi estabelecido pela obtenção de uma recuperação da PRL < 30% após tratamento do soro com polietilenoglicol. Dentre os 19 pacientes com macroprolactinemia isolada, 16 (84,2%) eram mulheres e 12 (63,2%) eram assintomáticos, enquanto 4 (21%) tinham oligomenorréia e 3 (15,8%), galactorréia. Em contraste, apenas 11,5% dos indivíduos com outras causas de hiperprolactinemia eram assintomáticos (p< 0,001). Os níveis de PRL nos casos de macroprolactinemia variaram de 45,1 a 404 ng/mL (média de 113,3 ± 94,5), mas em 15 (78,9%) foram < 100 ng/mL. Nossos achados demonstram que macroprolactinemia é uma condição freqüente e, assim, sugerimos que seja rotineiramente pesquisada em pacientes com hiperprolactinemia.

Macroprolactinemia is characterized by the predominance in the serum of macroprolactin, a prolactin (PRL) with high molecular mass and low biological activity that does not need treatment. The prevalence of macroprolactinemia was evaluated in 115 consecutive patients with hyperprolactinemia. Among them, 19 (16.5%) had solely macroprolactinemia, 4 (3.5%) polycystic ovary syndrome, 7 (6.1%) acromegaly, 8 (6.9%) idiopathic hyperprolactinemia, 10 (8.6%) primary hypothyroidism, 14 (12.2%) clinically non-functioning pituitary adenomas, 20 (17.4%) drug-induced hyperprolactinemia and 33 (28.7%) prolactinomas. The diagnosis of macroprolactinemia was established by the demonstration of a PRL recovery < 30% after treatment of sera with polyethylene glycol. Among the 19 patients with isolated macroprolactinemia, 16 (84.2%) were female and 12 (63.2%) were asymptomatic, while 4 (21%) presented with oligomenorrhea and 3 (15.8%) with galactorrhea. In contrast, only 11.5% of individuals with other causes of hyperprolactinemia were asymptomatic (p< 0.001). Prolactin levels in cases of macroprolactin ranged from 45.1 to 404 ng/mL (mean 113.3 ± 94.5) but in 15 (78.9%) were < 100 ng/mL. Our findings demonstrate that macroprolactinemia is a common condition and, therefore, we suggest that it should be routinely screened in patients with hyperprolactinemia.

Lesões hipofisárias clinicamente inaparentes são demonstradas através da ressonância magnética em aproximadamente 10% da população geral adulta, caracterizando os chamados incidentalomas hipofisários. A história natural dessas lesões ainda não está completamente estabelecida. Embora sejam tipicamente pequenos (< 10mm no seu maior diâmetro) e clinicamente silenciosos, alguns incidentalomas hipofisários podem secretar hormônios ou causar efeitos de massa por compressão sobre estruturas vizinhas. Além disso, uma minoria dessas lesões, principalmente aquelas com mais de 10mm (macroincidentalomas) podem crescer com o tempo; assim, o seguimento a longo prazo se faz necessário. Intervenções terapêuticas estão indicadas para os incidentalomas funcionantes (uso de agonistas dopaminérgicos ou ressecção transesfenoidal) ou para aqueles que causem efeitos de massa ou aumentem de tamanho durante o seguimento (ressecção transesfenoidal). Significante extensão supra-selar ou hipopituitarismo podem ser indicações adicionais para o tratamento cirúrgico, mesmo na ausência de compressão quiasmática.

Clinically unsuspected pituitary lesions are demonstrated by magnetic resonance imaging in approximately 10% of the general adult population, characterizing the so-called pituitary incidentalomas. Their natural history is not yet completely established. Despite being typically small (<10mm in the greatest diameter) and clinically silent, some pituitary incidentalomas may be hormonally active or cause mass effects by compressing neighboring structures. Furthermore, a minority of these lesions, particularly those greater than 10mm (macroincidentalomas) may grow over time; hence, longterm follow-up is necessary. Therapeutic interventions are indicated for lesions that are hormonally active (use of dopamine agonists or transsphenoidal resection) or for those that cause mass effects or increase in size during the follow-up (transsphenoidal resection). Significant suprasellar extension or hypopituitarism may be additional indications for surgical treatment even in the absence of chiasm compression.