ABSTRACT Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

Objectives To describe population reference values for shoes size, and to identify possible disproportional foot growth during GH therapy.Materials and methods Construction of percentile chart based on 3,651 controls (male: 1,838; female: 1,813). The GH treated group included 13 children with idiopathic short stature (ISS) and 50 children with normal height, but with height prediction below their target height; male: 26 and female: 37 mean ± SD age 13.3 ± 1.9 and 12.9 ± 1.5 years, respectively. GH (0.05 mg/kg/day) was used for 3.2 ± 1.6 years, ranging from 1.0-10.3 years. Height expressed as SDS, target height (TH) SDS, self-reported shoes size and target shoes size (TSS) SDS were recorded.Results Reference values were established showed as a foot SDS calculator available online at www.clinicalcaselearning.com/v2. Definitive shoes size was attained in controls at mean age of 13y in girls and 14y in boys (average values 37 and 40, respectively). In the study group, shoes size was -0.15 ± 0.9 and -0.02 ± 1.3 SDS, with target feet of 0.08 ± 0.8 and -0.27 ± 0.7 SDS in males and females, respectively. There was a significant positive correlation between shoes size and familial TSS, between shoes size and height and between TSS and TH. There was no correlation between duration of GH treatment and shoes size. Our data suggest that during long-term treatment with GH, patients maintain proportional growth in shoes size and height, and the expected correlation with the familial target.Conclusions We conclude that there is no excessive increase in the size of foot as estimated by the size of shoes in individuals under long term GH therapy.

OBJECTIVE: To investigate the influence of (CA)n repeats in the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene on birth size in children who are small or adequate-sized for gestational age and to correlate these polymorphisms with serum insulin-like growth factor 1 levels and insulin sensitivity in children who are small for gestational age, with and without catch-up growth. PATIENTS AND METHODS: We evaluated 439 infants: 297 that were adequate-sized for gestational age and 142 that were small for gestational age (66 with and 76 without catch-up). The number of (CA)n repeat in the insulin-like growth factor 1 gene and a variable number of tandem repeats in the insulin gene were analyzed using GENESCAN software and polymerase chain reaction followed by enzymatic digestion, respectively. Clinical and laboratory data were obtained from all patients. RESULTS: The height, body mass index, paternal height, target height and insulin-like growth factor 1 serum levels were higher in children who were small for gestational age with catch-up. There was no difference in the allelic and genotypic distributions of both polymorphisms between the adequate-sized and small infants or among small infants with and without catch-up. Similarly, the polymorphisms were not associated with clinical or laboratory variables. CONCLUSION: Polymorphisms of the (CA)n repeats of the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene, separately or in combination, did not influence pre- or postnatal growth, insulin-like growth factor 1 serum levels or insulin resistance.

O tratamento da hiperplasia adrenal congênita (HAC) por deficiência da 21-hidroxilase forma clássica é habitualmente realizado com acetato de hidrocortisona. A hidrocortisona oral, em nosso meio, só está disponível em farmácias de manipulação. A prednisolona possui solução oral estável, comercialmente disponível, e tem como vantagem poder ser utilizada em dose única diária. O objetivo desse estudo foi comparar a eficácia da prednisolona aos resultados obtidos com o acetato de hidrocortisona. Foram estudados 15 pacientes, idade cronológica média (DP) de 7,2 anos (3,6), em dois períodos consecutivos de um ano, inicialmente utilizando a hidrocortisona (17,5 mg/m²/dia, divididos em três doses), seguida do uso de prednisolona (3 mg/m²/dia, dose única matinal). A avaliação dos tratamentos foi realizada por meio das variações do escore Z de estatura para idade cronológica (deltaZE), do escore Z de estatura para a idade óssea (deltaZEIO) e do escore Z do Índice de massa corporal (IMC) (deltaZIMC), bem como os valores da androstenediona em cada período. Não houve diferença na deltaZE, na deltaZEIO e na deltaZIMC entre os dois períodos, assim como nos valores de androstenediona. Concluiu-se que a prednisolona em dose única diária apresenta eficácia semelhante à obtida com a hidrocortisona utilizada três vezes ao dia, podendo ser considerada uma opção terapêutica nos pacientes com HAC por deficiência da 21-hidroxilase.

Hydrocortisone acetate is usually employed in the treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. In Brazil, however, oral hydrocortisone acetate is only available from manipulation pharmacies. Prednisolone has stable oral pharmaceutical formulations commercially available, with the advantage of a single daily dose. The aim of this study was to compare the efficacy of oral prednisolone and oral hydrocortisone in the treatment of CAH due to 21-hydroxylase deficiency. Fifteen patients with mean (SD) chronological age of 7.2 (3.6) years, were evaluated in two consecutive 1-year periods. In the first year, hydrocortisone (17.5mg/m²/day, divided in three doses) was used in the treatment, followed by the use of prednisolone (3 mg/m²/day, once in the morning) in the second year. The comparison between the two treatments was assessed after a one-year treatment period by: variation of height standard deviation score (SDS) (delta Height SDS), variation of height SDS according to bone age (delta BA SDS), variation of body mass SDS (delta BMI SDS) and serum levels of androstenedione. No significant difference was observed in relation to the delta Height SDS, delta BA SDS and delta BMI SDS. No significant difference was observed in the serum levels of androstenedione. We conclude that the efficacy of prednisolone administered once a day orally is comparable to the oral use of hydrocortisone three times a day. Oral prednisolone may be an option for patients with CAH due to 21-hydroxylase deficiency.

As potências antiinflamatória e imunossupressora dos glicocorticóides (GC) já foram bem estabelecidas previamente. No entanto, os GC também possuem atividade reguladora da proliferação celular e da morte celular programada (apoptose). O objetivo deste estudo foi determinar a potência relativa de diferentes GC na modulação da sobrevida celular. Linfoblastos cortico-sensíveis (linhagem celular CEM-C7/14) foram mantidos em cultura prolongada e submetidos ao tratamento com GC por 48h, em doses variando entre 10-8 e 10-5 molar. O índice de sobrevida celular foi quantificado pelo teste MTT (DimetilTiazol-Tetrezolium). Para cada GC avaliado, foram realizados pelo menos quatro experimentos em quadruplicata. A resposta celular aos diferentes GC foi analisada através do teste estatístico ANOVA on Ranks, enquanto a resposta ao mesmo GC em concentrações diferentes foi analisada pelo teste ANOVA for repeated measures. O EC50 de cada GC foi calculado utilizando-se o software GraphPad Prism 3.0. Durante o uso de concentrações baixas (10-8 e 10-7 molar), observou-se sobrevida semelhante dos linfoblastos após tratamento com hidrocortisona ou metilprednisolona. Nestas mesmas concentrações baixas, a sobrevida celular foi menor quando utilizou-se dexametasona, betametasona, budesonida ou mometasona. A mometasona e a metilprednisolona foram os dois GC que determinaram maior redução da sobrevida linfoblástica. Nossos resultados sugerem que as potências antiproliferativa e pró-apoptótica dos GC sejam diferentes dos efeitos antiinflamatórios e imunossupressores previamente estabelecidos para estes GC.

Relative antiinflammatory and immunosuppressive potencies of glucocorticoids (GC) were previously well defined. Nonetheless, GC also regulate cell proliferation and programmed death (apoptosis). The aim of this study was to determine the relative potency of different GC on the modulation of cell survival. The GC-sensitive lymphoblast cell line CEM-c7/14 was submitted to 48h-exposure to GC (dose-response curve from 10-8 to 10-5M). Cell survival was analyzed employing the DimethylTiazol-Tetrazolium (MTT) test. For each GC at least 4 experiments were performed in quadruplicate. Responses to different GC at the same molarity were analyzed by ANOVA on Ranks. Cell responses to the same GC in different concentrations were tested by repeated measures ANOVA. The EC50 for each GC was calculated with the GraphPad Prism 3.0 software. The use of low concentrations (10-8 and 10-7M) of hydrocortisone and methylprednisolone determined a similar effects on cell survival, which was less prominent than that observed with betamethasone, budesonide or momethasone. Momethasone was the most potent GC, inducing the most intense dexamethasone reduction on cell survival at the lowest concentration (10-8M). Momethasone and methylprednisolone were the two GC with the strongest impact on cell survival. Our findings suggest that antiproliferative and apoptotic potencies of GC are different from those previously reported antiinflammatory and immunosuppressive actions.

Embora o diagnóstico da Doença de Graves (DG) na infância e adolescência seja relativamente fácil, seu tratamento ainda é controverso. Pode-se utilizar fármacos anti-tireoideanos (MMZ ou PTU), porém a incidência de efeitos adversos nessa faixa etária é maior que nos adultos e a taxa de remissão é baixa, mesmo com o uso prolongado. A cirurgia é pouco indicada como tratamento inicial, sendo realizada mais freqüentemente após recidiva do tratamento medicamentoso e/ou devido aos seus efeitos adversos. A utilização da radioiodoterapia na infância e adolescência vem crescendo. Com doses adequadas, ocorre o desenvolvimento de hipotireoidismo em cerca de 90% dos casos num período de 3 a 6 meses. Os dados iniciais sugerem que o tratamento em crianças acima de 5 anos não parece estar associado a maior risco de carcinoma de tireóide. A prevalência de efeitos adversos é menor que na cirurgia. Pacientes que apresentam fatores clínicos ou laboratoriais de pior prognóstico evolutivo podem ter seu tratamento medicamentoso encurtado, sendo a indicação da radioiodoterapia realizada mais precocemente.

While the diagnosis of Graves' disease in childhood and adolescence is relatively straightforward, its treatment remains controversial. The first choice therapy is the use of anti-thyroid drugs, although side effects are more frequent than in adults and remission is low. Surgery is not usually indicated as initial treatment. Instead, it is generally recommended after recidive of the disease or due to side effects of medical treatment. The use of radioiodine therapy is increasing in this age group, especially in North America, and control of the hyperthyroidism is achieved in 3 to 6 months in 90% of the cases. There is no evidence that radioiodine therapy is associated with a higher risk of thyroid cancer, and the occurrence of side effects is lower than surgery. Based on the positive results obtained with this therapy, patients with poor responsiveness to medical treatment should be considered for early radioiodine therapy.

Objetivo: determinar a secreção de TSH em crianças com síndrome de Down, sem quadro clínico-laboratorial clássico de hipotireoidismo. Métodos: analisou-se 14 crianças com síndrome de Down e idade média de 3,4 (±1,8) anos. Excluiu-se pacientes com sintomas clássicos de hipotireoidismo ou hipertireoidismo, ou que apresentassem anticorpos antitireóide positivos. Os pacientes foram comparados a um grupo controle de 16 pacientes com idade média de 11,8 (±3,8) anos e diagnóstico de baixa estatura familial ou atraso constitucional do crescimento. Foram determinadas as concentrações de TSH, T3, T4, T4L e prolactina no tempo basal e após estímulo com TRH. Pacientes com síndrome de Down, subdivididos quanto ao TSH basal, foram comparados em relação às concentrações basais de T3, T4, T4L e prolactina. Resultados: os valores basais de TSH e de prolactina foram significativamente maiores no grupo com síndrome de Down. Após estímulo com TRH, o pico de TSH foi maior no grupo com síndrome de Down. Tanto o número de pacientes com TSH basal > 5 µU/ml, quanto o número dos que apresentaram hiper-resposta ao estímulo com TRH (pico de TSH > 30 µU/ml), foi maior no grupo com síndrome de Down. Conclusões: freqüentemente, crianças portadoras de síndrome de Down apresentam elevação do TSH basal, mesmo na presença de valores basais normais de hormônios tireoidianos e anticorpos antitireóide negativos. A maioria dessas crianças (65%) apresenta hiper-resposta ao teste de estímulo com TRH. Nossos achados demonstram que nem todas as crianças com síndrome de Down e TSH elevado apresentam quadro clássico de hipotireoidismo, sugerindo nesses pacientes uma secreção anômala de TSH de origem hipotalâmica.

Objective: to determine the thyroid stimulating hormone (TSH) secretion in children with Down syndrome (DS), who do not present clinical and laboratory evidence of classical hypothyroidism and concomitant undetectable antibodies. Methods: fourteen children with DS with a mean age of 3.4 (±1.8) years were studied. Patients with classical hypothyroidism or hyperthyroidism or those with positive antithyroid antibodies were excluded. The DS group was compared to a control group of 16 children with a mean age of 11.8 (±3.8) years, diagnosed as having familial short stature or constitutional growth delay. Both groups underwent hormonal measurements at basal condition to determine serum TSH, T3, T4, free T4 and prolactin concentrations and after stimulation with thyrotropin releasing hormone (TRH). Thyroid hormones concentrations were also compared when children with DS were subdivided into two groups according to their basal TSH levels. Results: basal TSH and prolactin levels were significantly higher in DS group. After stimulation with TRH, TSH peak was higher in the DS group. The number of patients presenting basal TSH levels higher than 5 µU/mL and TSH peaks higher than 30 µU/mL were significantly higher in the DS group. Conclusions: children with Down syndrome present frequent increase in basal TSH concentrations, despite the presence of normal basal thyroid hormones levels and negative antithyroid antibodies. Most of them (65%) show early intense response after TRH stimulation. Our data demonstrate that in spite of the absence of classic hypothyroidism and/or antithyroid antibodies, an abnormal pattern of TSH secretion occurred in patients with Down syndrome, possibly related to hypothalamic dysfunction.