RESUMO
IGF-I and IGF-II (IGFs) form higher molecular weight complexes with specific binding proteins (IGFBP-1 to -6). These complexes are referred to as binary complexes consisting of IGF-I or IGF-II and one IGFBP, or as ternary complexes each consisting of either of IGF-I or IGF-II, IGFBP-3 or -5, and an acid-labile subunit known as ALS. Ternary complex formation restricts the IGFs to the circulation and prolongs their half-life. Recently, the development of an animal model for ALS deficiency (the ALS-KO mouse) and the identification of a patient with an inactivating mutation in the IGFALS gene have provided the opportunity to assess the physiological role of this protein in the circulating IGF system. ALS deficiency has no effect on fetal growth in both the ALS-KO mice and the ALS-deficient patients. A modest reduction in post-natal growth in the null ALS mice and in the ALS-deficient patients was observed. The plasma concentrations of IGF-I and IGFBP-3 were markedly reduced both in ALS-KO mice and in the ALS-deficient patients. Basal GH levels remained normal in the ALS-KO mice and moderately increased in the ALS-deficient patients. Insulin-resistance was present in the ALS-deficient patients but not in the ALS-KO mice. Reduced bone mineral density (BMD) was present in mice and human ALS deficiency. Phenotypic features of complete ALS deficiency, that are very similar in mouse and human, include: a) the inability to form ternary complex, b) the small growth impairment in spite of the marked reduction in circulating IGF-I, and c) the reduction in BMD. On the other hand, insulin resistance and pubertal delay were observed only in human ALS deficiency. These findings underlie the important physiological role of ALS in the maintenance of the circulating IGF-I reservoir. Both models will be useful in identifying the respective roles of plasma and locally derived IGF-I in regulating metabolism and growth of specific tissues.
Assuntos
Proteínas de Transporte/genética , Glicoproteínas/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Fator de Crescimento Insulin-Like I/genética , Animais , Humanos , Camundongos , Camundongos Knockout , FenótipoRESUMO
We have studied the effect of estradiol (E2) on the GH-insulin-like growth factor (GH-IGF) axis in 15 prepubertal GH deficiency (GHD) children and 44 prepubertal or early pubertal children with idiopathic short stature (SS). All of them received a daily dose of micronized E2 (1 or 2 mg) or placebo, for 3 days, before a sequential arginine-clonidine test. In SS children, GH maximal responses were 17.8+/-10.9 on placebo and 27.9+/-14.5 microg/L on estrogen (P < 0.0001). The lower 95% confidence limits for GH maximal response changed from 3.7 microg/L (without E2) to 8.3 microg/L (on E2). In GHD children, no significant stimulatory effect of estrogen on GH levels was observed. After placebo, a cut-off limit of 3.7 microg/L (the lower 95% confidence interval limit) resulted in 73% sensitivity, 95% specificity, and an overall 90% diagnostic efficiency. After E2, a cut-off limit of 8.3 microg/L resulted in a sensitivity of 87%, a specificity of 98%, and a diagnostic efficiency of 95%. After placebo, 68% of SS showed normal IGF-I levels, and the mean did not change on E2 (13.7+/-6.3 vs. 14.3+/-6.8 nmol/L, not significant). In 93% of SS, IGF binding protein (IGFBP)-3 levels were normal during placebo. On E2, mean IGFBP-3 did not change (2.63+/-0.70 vs. 2.70+/-0.70 mg/L, not significant). In 14 of 15 GHD patients, IGF-I values were below normal on placebo, and the mean of the group did not change after E2. During placebo, 13 of 15 GHD children presented low IGFBP-3 values. During E2, there was a small significant increase in IGFBP-3 values (1.06+/-0.58 vs. 1.20+/-0.69 mg/L, P < 0.02). The highest diagnostic efficiencies for IGF-I and IGFBP-3 were observed during placebo (75% and 91%, respectively). We conclude that GH stimulation tests after E2 priming had the highest diagnostic efficiency. Our findings suggest that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and abnormal GH status in SS children.
Assuntos
Estatura , Estradiol , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Intervalos de Confiança , Diagnóstico Diferencial , Feminino , Transtornos do Crescimento/sangue , Transtornos do Crescimento/fisiopatologia , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Placebos , Sensibilidade e EspecificidadeRESUMO
Kidney function, growth velocity, weight/height ratio, body composition, lipid profile, and bone mass were studied in a randomized, multicenter trial of deflazacort versus methylprednisone in 27 prepubertal patients with kidney transplantation. Methylprednisone (0.20+/-0.03) was replaced by deflazacort (13 patients, 0.30+/-0.03 mg/kg per day). After 12 months, creatinine clearance decreased significantly only during methylprednisone therapy. Growth velocity increased only in patients treated with deflazacort from 3.3+/-0.6 to 5.6+/-0.5 cm/year. Serum levels of several components of the insulin-like growth factor axis did not change. Weight/height ratio was increased in methylprednisone-treated patients (P<0.05) and decreased in deflazacort-treated patients (P<0.005). Lean body mass increased in both groups (P<0.005). Fat body mass and serum leptin increased only in methylprednisone-treated patients (P<0.025). Total cholesterol and low-density lipoprotein-cholesterol increased in methylprednisone-treated patients by 9.9% (P<0.05) and 12.5% (P<0.025). High-density lipoprotein-cholesterol increased by 21% (P<0.005) and apolipoprotein B decreased by 11% (P<0.005) in deflazacort-treated patients. Total skeleton and lumbar spine bone mineral density decreased in both groups, but at 1 year methylprednisone-treated patients had lost 50% more bone. Bone mineral content decreased only in methylprednisone-treated patients (P<0.01). Our data suggest that substituting deflazacort for maintenance methylprednisone might prevent height loss, excessive bone loss, and fat accumulation; and leads to an improvement in the lipoproteins of these children.
Assuntos
Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim , Lipídeos/sangue , Prednisona/análogos & derivados , Prednisona/uso terapêutico , Pregnenodionas/uso terapêutico , Criança , Feminino , Crescimento/efeitos dos fármacos , Substâncias de Crescimento/sangue , Humanos , Leptina/sangue , Período Pós-OperatórioRESUMO
RET proto-oncogene mutation results in a dominant autosomic inherited syndrome (MEN 2) presenting three distinct subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). Detection of RET proto-oncogene mutation is a predictor before clinical or biochemical evidence of the disease is present and leads to preventive thyroid removal since there is no effective treatment for metastases. The aim of the present study was to characterize mutations in the RET proto-oncogene in affected patients and to identify potential carriers in their families. Two families with FMTC (5 and 6 members), 4 with MEN 2A (5, 5, 4 and 3 members) and 2 with MEN 2B (5 and 1 members), were studied. DNA was obtained from blood samples in all patients and from thyroid or from pheonochromocytoma tissues in patients submitted to surgery. PCR amplification was performed using specific primers for exons 10, 11 and 16, followed by direct sequencing. Mutations at codon 634 in exon 11 were found in 16 subjects with FMTC and MEN 2A: TGC --> CGC (cysteine to arginine) in 9 cases, TGC --> TAC (cysteine to tyrosine) in 3, and TGC --> TTC (cysteine to phenilalanine) in 4. A unique mutation of codon 918 in exon 16, ATG --> ACG (methionine to threonine), was found in both MEN 2B affected patients. The mutations detected in DNA from peripheral blood were the same as those present in DNA extracted from tumor material. RET mutations were detected in all affected patients, confirming the diagnosis, and in 10 members of their families. In five of the carriers total thyroidectomy was performed. Anatomopathological study showed C-cells hyperplasia or in-situ microcarcinoma in two children (9 and 12 y) with no clinical signs of diseases and medullary thyroid carcinoma in three adults, who were previously unaware of the presence of thyroid nodules. The early detection of RET mutation followed by total thyroidectomy may prevent the development of the disease, specially in affected families, and avoid the fatal outcome of delayed medullary thyroid carcinoma diagnosis.
Assuntos
Carcinoma Medular/diagnóstico , Proteínas de Drosophila , Neoplasia Endócrina Múltipla/diagnóstico , Mutação/genética , Feocromocitoma/diagnóstico , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/diagnóstico , Adulto , Carcinoma Medular/genética , Criança , DNA de Neoplasias/sangue , Feminino , Humanos , Masculino , Neoplasia Endócrina Múltipla/genética , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2b/diagnóstico , Neoplasia Endócrina Múltipla Tipo 2b/genética , Linhagem , Feocromocitoma/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide/genética , Fatores de TempoRESUMO
OBJECTIVE: The aim of this study was to evaluate the possibility of persistence of autonomous ovarian activity in girls with McCune-Albright syndrome (MAS) after withdrawal of medroxyprogesterone therapy administered for precocious puberty. DESIGN, SETTING, AND PARTICIPANTS: Five girls with MAS were followed-up 1.2 to 8.5 years after the end of treatment. The girls underwent luteinizing hormone-releasing hormone (LH-RH) tests, estradiol (E2) basal measurement, and pelvic ultrasound two times in the follow-up period. RESULTS: Menses resumed in four of five girls, 1.4 +/- 0.9 years after the end of treatment, at chronologic age of 11.3 +/- 1.3 years. Cycles for all girls were irregular. Three patients presented inadequate E2 levels (from 56 to 320 pg/mL) associated with low or absent gonadotropin response to LH-RH tests. The pelvic ultrasound showed ovarian cysts at the time of the study. CONCLUSION: These hormonal and ultrasonographic findings provide evidence of persistence of autonomous ovarian activity in some young women with MAS.
Assuntos
Displasia Fibrosa Poliostótica/fisiopatologia , Medroxiprogesterona/uso terapêutico , Ovário/fisiopatologia , Congêneres da Progesterona/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/fisiopatologia , Criança , Estradiol/sangue , Feminino , Displasia Fibrosa Poliostótica/sangue , Displasia Fibrosa Poliostótica/complicações , Hormônio Foliculoestimulante/sangue , Seguimentos , Humanos , Hormônio Luteinizante/sangue , Ovário/diagnóstico por imagem , Puberdade Precoce/sangue , Puberdade Precoce/complicações , UltrassonografiaRESUMO
The existence of homologous anti-human growth hormone (anti-hGH) and heterologous anti-bovine growth hormone (anti-bGH) humoral immune responses in hypopituitary patients under hGH therapy has been reported previously. In order to study the influence of the hormone source, both responses were compared by radiobinding assays performed with [125I]hGH or [125I]bGH as tracers. Fifty-seven hypopituitary patients treated with extractive hGH, recombinant methionyl hGH or authentic recombinant hGH were studied. A very low incidence of heterologous antibodies was found in patients under recombinant hGH therapy, contrary to the high incidence observed in patients treated with extractive hGH preparations. In addition, immunochemical studies performed with a synthetic peptide (hGH 44-128) indicated that this peptide exhibited, in the anti-bGH/[125]bGH radioimmunoassay system, higher reactivity than the native hGH, suggesting that such a fragment resembled an altered conformation of the hormone. The high heterologous response elicited only by the extractive hGH along with the behaviour of the hGH 44-128 fragment supports the fact that the extraction and purification procedures in extractive preparations may alter slightly the structure of the hGH molecule and trigger a heterologous immune response.
Assuntos
Hormônio do Crescimento/imunologia , Adolescente , Animais , Anticorpos/análise , Formação de Anticorpos , Especificidade de Anticorpos , Bovinos , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento/análogos & derivados , Hormônio do Crescimento/uso terapêutico , Hormônios/uso terapêutico , Hormônio do Crescimento Humano , Humanos , Hipopituitarismo/tratamento farmacológico , Imunoquímica/métodos , Lactente , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Especificidade da EspécieRESUMO
We measured serum sex hormone-binding globulin (SHBG), total testosterone (T), non-SHBG-bound T, albumin-bound T, free T, and SHBG-bound T in 19 prepubertal boys with hypopituitarism. Serum SHBG decreased with age with a slope similar to that in 91 normal prepubertal boys at higher level, and therefore, it reached similar values at a later age. Serum SHBG was significantly higher in hypopituitary prepubertal boys [mean, 123 +/- 12 (+/- SE) nmol/L] than in normal prepubertal boys (76 +/- 4; P less than 0.001) despite the fact that their mean age was also higher (10.0 +/- 4 vs. 7.1 +/- 4.1 yr; P less than 0.001). In 4 boys with isolated hypogonadotropic hypogonadism (Kallman's syndrome), aged 15.6 +/- 1.5 yr, serum SHBG was 21 +/- 14 nmol/L, a value below the 95% confidence limit of the regression line in GH-deficient boys. The affinity constants of association of the SHBG-DHT complex were similar in hypopituitary and normal boys. Eleven of the 19 hypopituitary boys (mean chronological age, 8.3 +/- 2.5 yr; mean bone age, 4.1 +/- 2.1 yr) were treated with recombinant hGH (0.5 U/kg BW.week) for 1 yr. Their mean serum SHBG level before treatment was 154 +/- 14 nmol/L, and it decreased gradually to 106 +/- 5 nmol/L (P less than 0.01) after 12 months of treatment. The tendency toward normalization of serum SHBG during treatment suggested that GH deficiency was responsible for the high serum SHBG levels. Serum SHBG correlated negatively with age in both treated hypopituitary and normal boys, but the slope of the regression line was significantly steeper in treated hypopituitary boys (P less than 0.01). On the other hand, the mean serum non-SHBG-bound T level was 0.10 +/- 0.02 (+/- SE) nmol/L in hypopituitary boys, significantly lower than that in normal boys (0.21 +/- 0.02 nmol/L; P less than 0.02). Since serum total T concentrations were similar in the two groups, the higher serum SHBG concentration resulted in lower serum bioavailable T levels in the hypopituitary boys. These changes might explain the poor response to T treatment reported in GH-deficient patients. The lower serum non-SHBG-bound T concentrations in the GH-deficient boys suggest there may be delayed exposure of central nervous system structures to increased levels of sex hormones, which, in turn, may slow body maturation. This mechanism might play a role in the delay of puberty that occurs in patients with isolated GH deficiency.