RESUMO
OBJECTIVES: Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated. DESIGN AND PATIENT: The child exhibited prenatal and severe post-natal growth failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor. rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily by subcutaneous injection for periods of 2-2.5 days each. RESULTS: During rhIGF-I treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose to 60% greater than in the pre-treatment period. rhIGF-I injections produced only a modest decrease in indices of GH secretion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were not significantly reduced by IGF-I (mean of all values, 18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to the patient's fibroblasts was less than that bound by control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding by 260 000 fibroblasts from an age-matched control). However, the patient's fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a fashion similar to that of control fibroblasts. CONCLUSIONS: These studies show evidence in each of the indices examined of in vivo resistance to IGF-I and suggest that the growth retardation observed in such patients may be the direct result of the absence of one of the alleles encoding the type 1 IGF receptor.
Assuntos
Cromossomos Humanos Par 15 , Deleção de Genes , Transtornos do Crescimento/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Receptor IGF Tipo 1/genética , Cromossomos em Anel , Southern Blotting , Células Cultivadas , Pré-Escolar , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , RNA Mensageiro/análise , Receptor IGF Tipo 1/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêuticoRESUMO
OBJECTIVES: To measure the prevalence of behavioral and learning problems among children with short stature and to assess the effect of growth hormone (GH) treatment on such problems. STUDY DESIGN: A total of 195 children with short stature (age range 5 to 16 years, mean age 11.2 years) were tested for intelligence, academic achievement, social competence, and behavior problems before beginning GH therapy and yearly during 3 years of treatment. Children were classified as having growth hormone deficiency (GHD) when GH responses to provocative stimuli were <10 ng/mL (n = 109) and as having idiopathic short stature (ISS) when >10 ng/mL (n = 86). A normal-statured matched comparison group was tested at the baseline only. RESULTS: Seventy-two children in the GHD group and 59 children in the ISS group completed 3 years of GH therapy and psychometric testing. Mean IQs of the children with short stature were near average. IQs and achievement scores did not change with GH therapy. Child Behavior Checklist scores for total behavior problems were higher (P < .001) in the children with short stature than in the normal-statured children. After 3 years of GH therapy these scores were improved in patients with GHD (P < .001) and ISS (P < .003). Also, there was improvement in the scores of children in the GHD group in the internalizing subscales (withdrawn: P < .007; somatic complications, P < .001; anxious/depressed, P < .001) and on the 3 components of the ungrouped subscales (attention, social problems, and thought problems, each P = .001). Larger effects were observed in the GHD group than in the ISS group. CONCLUSIONS: Many referred children with short stature have problems in behavior, some of which ameliorate during treatment with GH.
Assuntos
Comportamento do Adolescente , Comportamento Infantil , Nanismo/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Logro , Adolescente , Análise de Variância , Ansiedade/psicologia , Atenção , Atitude , Estatura , Estudos de Casos e Controles , Criança , Transtornos do Comportamento Infantil/psicologia , Pré-Escolar , Depressão/psicologia , Nanismo/psicologia , Feminino , Seguimentos , Hormônio do Crescimento Humano/deficiência , Humanos , Inteligência , Relações Interpessoais , Masculino , Análise Multivariada , Ajustamento Social , Transtornos Somatoformes/psicologiaRESUMO
We studied the effects of 9 months of treatment with twice-daily subcutaneous injections of insulin-like growth factor I (IGF-I), 120 micrograms/kg per dose, in a 9.7-year-old child with growth hormone insensitivity syndrome, in whom short-term studies had suggested that IGF-I might promote linear growth. Height velocity increased from 6.5 cm/yr (+1.7 SD score) to 11.4 cm/yr (+8.8 SD score). Serum concentrations of IGF-I increased from pretreatment values of 9 +/- 2 micrograms/L to a peak of 347 +/- 26 micrograms/L after 2 hours. Serum concentrations of IGF-II were unchanged. Basal but not stimulated growth hormone concentrations were decreased. During the first 12 days of treatment, serum concentrations and the 24-hour urinary excretion of urea nitrogen were decreased by 28% and 10%, respectively (p < 0.05), there was a 2.4-fold increase in urinary excretion of calcium (p < 0.001), and creatinine clearance and urine volume increased by 22% and 55%, respectively (p < 0.02). The changes in serum levels of urea nitrogen and in urinary calcium and creatinine clearance were still evident at 10 weeks. Fasting and postprandial serum glucose concentrations remained normal. We conclude that IGF-I given as twice-daily subcutaneous injections is effective in stimulating statural growth without producing the hypoglycemia and hyperglycemia observed when IGF-I is infused continuously.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Fator de Crescimento Insulin-Like I/uso terapêutico , Glicemia/análise , Criança , Crescimento/efeitos dos fármacos , Transtornos do Crescimento/sangue , Transtornos do Crescimento/urina , Hormônio do Crescimento/sangue , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/farmacologia , Fator de Crescimento Insulin-Like II/análise , Masculino , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Ureia/sangue , Ureia/urinaRESUMO
Serum levels of somatomedin-C have been measured by a competitive membrane binding assay in normal individuals, in hypopituitary dwarfs, and in children with growth retardation from causes other than growth hormone deficiency. The mean level in untreated hypopituitary children is about 40% of that of age-matched normal children. Treatment of hypopituitary dwarfs with human growth hormone results in prompt increases in the serum concentration of somatomedin-C. Normalization of somatomedin is associated with the return of pituitary function in hospitalized psychosocial dwarfs. Supporting the possibility that somatomedin-C plays a pivotal role in skeletal growth is the finding that serum levels in hypopituitary children correlate with growth rate both on and off growth hormone therapy. In our hands, this assay has proved to be an efficient, reliable method for the diagnosis of growth hormone deficiency.
Assuntos
Transtornos do Crescimento/sangue , Hipopituitarismo/sangue , Somatomedinas/sangue , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Hormônio do Crescimento/deficiência , Humanos , MasculinoAssuntos
Cortisona/uso terapêutico , Nanismo Hipofisário/metabolismo , Glucose/metabolismo , Hormônio do Crescimento/uso terapêutico , Ilhotas Pancreáticas/metabolismo , Glicemia/análise , Criança , Cortisona/administração & dosagem , Cortisona/farmacologia , Sinergismo Farmacológico , Nanismo Hipofisário/sangue , Nanismo Hipofisário/complicações , Nanismo Hipofisário/tratamento farmacológico , Feminino , Teste de Tolerância a Glucose , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/farmacologia , Homeostase , Humanos , Hipoglicemia/etiologia , Insulina/sangue , Insulina/farmacologia , Leucina/farmacologia , Masculino , Gravidez , Tolbutamida/farmacologiaRESUMO
PIP: Medroxyprogesterone (MPA) is a progestin with no clinically detectable estrogenic and androgenic properties used in the treatment of sexual precocity. This report presents the results of administering large intramuscular doses of MPA (200 to 300 mg every 7 to 10 days for periods ranging from 5 to 40 months) in 3 girls and 1 boy with rapidly progressing idiopathic sexual precocity (e.g., breast enlargement, penile enlargement, pubic hair growth). Urinary steroids were measured by bioassay, standard modification of the double isotope derivative method, and other standard methods. The MPA regimen suppressed the signs and symptoms of precocious puberty. The 3 girls did not have further menstrual flow, breast tissue regressed, uterine size decreased, and vaginal cornification diminished, although not to prepubertal levels. A marked decrease in frequency of erections, no further penile enlargement, and only minimal progression of sexual hair were observed in the boy (the testis continued to enlarge, however). Excessive weight gain, rapid rate of linear growth and skeletal maturation were observed in the children during treatment, as was blood pressure elevation. The effectiveness of MPA appears to be mediated by the suppression of pituitary gonadotropin secretion. However, there was no consistent reduction of urinary gonadotropin levels, and suppression of gonadal stimulation was incomplete. Evidence of drug toxicity precludes further administration of high dosages of MPA even for research purposes.^ieng