RESUMEN
CONTEXT: Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial. OBJECTIVE: To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI. DESIGN: Prospective study. METHODS: Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11-26), time post TBI: 9 (7-11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups. RESULTS: No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol <500 nmol/L in 2/25. Mean spontaneous GH secretion was <3.1 µg/L in 16/22 but peak GH was low only in 1/22 profiles. One patient had abnormal spontaneous and stimulated GH secretion and hypogonadism. Fatigue and depression scores were higher in TBI patients (P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants. CONCLUSIONS: Fatigue and depression were common 8-10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.
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Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/psicología , Fatiga/sangre , Fatiga/psicología , Hormona de Crecimiento Humana/sangre , Calidad de Vida/psicología , Adolescente , Adulto , Lesiones Traumáticas del Encéfalo/epidemiología , Niño , Depresión/sangre , Depresión/epidemiología , Depresión/psicología , Fatiga/epidemiología , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: Bone marrow transplantation with total body irradiation (BMT/TBI) has adverse effects on growth, growth hormone status and adiposity. We investigated the GH-IGF-I axis in relation to adiposity. DESIGN: Cross-sectional case control study. PATIENTS: BMT/TBI survivors (n = 22) and short stature control participants (n = 19), all GH-naïve or off GH treatment >3 months. MEASUREMENTS: Auxology, DEXA scans and GH-IGF-I axis investigation: (i) 12-h overnight GH profiles; (ii) insulin tolerance test (ITT); and (iii) IGF-I generation test. ANALYSIS: auto-deconvolution of GH profile data and comparison of quantitative parameters using ANOVA. RESULTS: Eighty-two percent of BMT/TBI survivors had growth hormone deficiency (GHD) using ITT. GH profile area-under-the-curve (GH-AUC) was reduced in BMT/TBI survivors vs short stature control participants [geometric mean (range) 209 (21-825) vs 428 (64-1400) mcg/l/12 h, respectively, P = 0·007]. GHD was more marked in those who had additional cranial irradiation (CRT) [ITT peak 1·4 (0·2-3·0) vs TBI only 4·1 (1·1-14·8) mcg/l, P = 0·036]. GHD was more marked at the end of growth in BMT/TBI survivors vs short stature control participants (GH-AUC 551 (64-2474) vs 1369 (192-4197) mcg/l/12 h, respectively, P = 0·011) and more prevalent (9/11 vs 1/9, respectively, P = 0·005). GH profile data were consistent with ITT results in 80% of participants. IGF-I generation tests were normal. BMT/TBI survivors still demonstrated lower GH levels after adjustment for adiposity (fat-adjusted mean difference for GH-AUC 90·9 mcg/l/12 h, P = 0·025). CONCLUSIONS: GHD was more prevalent in BMT/TBI survivors than expected for the CRT dose in TBI, worsened with time and persisted into adulthood. GHD could not be explained by adiposity. There was no evidence of GH neurosecretory dysfunction or resistance after BMT/TBI.
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Adiposidad/fisiología , Trasplante de Médula Ósea , Hormona de Crecimiento Humana/sangre , Irradiación Corporal Total/efectos adversos , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
AIMS: To investigate whether changes in glucose concentrations during an OGTT in obese children reflect the presence of peripheral insulin resistance and/or cardiovascular risk factors more closely than single measurements of fasting plasma glucose (FPG). METHODS: One hundred and twenty-two obese children attending our Paediatric Obesity Service underwent formal OGTTs, following the measurement of blood pressure and fasting levels of insulin, glucose and lipid profiles in the majority. Fasting insulin was used as a surrogate measure of insulin sensitivity. Three different child-specific definitions for metabolic syndrome were used to identify clustering of cardiovascular risk factors in 65 of these children. RESULTS: In the whole group, 10.7% had IGT but changes in glucose during the OGTT were not influenced by age, sex, pubertal status or raw (or age- and sex-adjusted) body mass index (BMI). During the OGTT, FPG, glucose at 60 min and area under the glucose curve correlated highly with fasting insulin. Children with metabolic syndrome (defined using any of three definitions) had comparable FPG levels to those without metabolic syndrome, but they demonstrated significantly elevated glucose levels at 60 min. On sub-group analysis, obese children with normal carbohydrate metabolism were significantly more likely to have a 1 h glucose level > or = 7.8 mmol/l if they had metabolic syndrome (P = 0.026). CONCLUSIONS: These data suggest that an elevated 1 h post-load glucose measurement is seen in obese children who have a coexistent clustering of cardiovascular risk factors.
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Glucemia/metabolismo , Prueba de Tolerancia a la Glucosa , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Adolescente , Adulto , Niño , Preescolar , Métodos Epidemiológicos , Femenino , Humanos , Masculino , Síndrome Metabólico/sangreRESUMEN
AIM: To identify clinical features which predict those most at risk of co-morbidities within an obesity clinic. METHODS: Children attending an obesity clinic had fasting glucose, insulin, and lipids measured prior to a standard oral glucose tolerance test (OGTT). History and examination established birth weight, family history of type 2 diabetes/obesity, pubertal status, and presence of acanthosis nigricans. Central and total fat mass was estimated by bio-impedance. RESULTS: Of the 126 children evaluated, 10.3% (n = 13) had impaired glucose tolerance (IGT); the majority (n = 11) of these would not have been identified on fasting glucose alone. Those with IGT were more likely to have a parental history of type 2 diabetes (relative risk 3.5). IGT was not associated with acanthosis nigricans. Twenty five per cent (n = 19) of those evaluated (n = 75) had evidence of the "metabolic syndrome" (MS). HDL cholesterol and triglyceride levels were related to insulin sensitivity (HOMA-R); HDL cholesterol was also related to birth weight SDS. We observed a trend for those with MS to have a lower birth weight SDS. The severity of obesity did not influence the likelihood of IGT or MS. CONCLUSIONS: Significant numbers of obese children have associated co-morbidities. Analysis of fasting blood glucose samples alone is not satisfactory to adequately evaluate glucose homoeostasis. The overall level of obesity does not predict co-morbidities. Special attention should be given to those with parental diabetes and a history of low birth weight who are more likely to have IGT and abnormal lipid profiles respectively.
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Síndrome Metabólico/etiología , Obesidad/complicaciones , Adolescente , Peso al Nacer , Glucemia/metabolismo , Índice de Masa Corporal , Niño , Preescolar , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/genética , Ayuno/sangre , Femenino , Intolerancia a la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Lactante , Recién Nacido , Insulina/sangre , Masculino , Síndrome Metabólico/sangre , Obesidad/sangre , Servicio Ambulatorio en Hospital , Triglicéridos/sangreRESUMEN
OBJECTIVE: To determine the levels and patterns of physical activity in a sample of obese (> or =99th percentile body mass index (BMI)) and nonobese (<99th percentile BMI) children. DESIGN: Cross-sectional study. SETTING: Children were recruited from schools in Bristol and from the childhood obesity clinic, Bristol Royal Hospital for Children. Children were instructed in the use of the accelerometer either while at school or in the clinic, and wore the instrument while carrying out their normal daily activities for 7 days. PARTICIPANTS: A total of 133 children (mean age 10.5+/-0.8 y). In all 11 (16.9%) of the 65 girls and 14 (20.6%) of the 68 boys were classified as obese (above the 99th percentile for BMI and corresponding to projected adult BMI of 30). MAIN OUTCOME MEASURES: Objectively measured physical activity volume, intensity and pattern. RESULTS: Obese children were significantly less physically active overall than their nonobese counterparts (31,844+/-13,200 vs 41,844+/-10,430 counts/h; 95% confidence interval 4407 to 15592; P=0.001). Similarly the obese children spent less time in physical activity of moderate or greater intensity than the nonobese children (9.9+/-3.9 vs 12.9+/-4.2 min/h; 95% confidence interval 1.15 to 4.80; P=0.002). Hourly patterns of activity indicated a tendency in obese children to be less active than nonobese children at times when activity was more likely to be determined by free choice, particularly outside of school time. CONCLUSIONS: Obese children demonstrated patterns of physical activity that may have contributed to and are likely to sustain their obesity. Minute-by-minute accelerometry is a valuable tool to investigate physical activity patterns in obese children. It can identify periods when intervention to increase activity may be most appropriate and provide an evidence base for specific exercise prescription in primary and secondary care.
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Obesidad/fisiopatología , Esfuerzo Físico/fisiología , Índice de Masa Corporal , Niño , Conducta Infantil , Conducta de Elección , Ritmo Circadiano/fisiología , Estudios Transversales , Femenino , Humanos , Masculino , Monitoreo Ambulatorio/instrumentación , Monitoreo Ambulatorio/métodos , Factores SexualesAsunto(s)
Insuficiencia Suprarrenal/inducido químicamente , Androstadienos/efectos adversos , Antiinflamatorios/efectos adversos , Asma/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Enfermedad Aguda , Administración por Inhalación , Administración Tópica , Niño , Preescolar , Esquema de Medicación , Fluticasona , Glucocorticoides , HumanosRESUMEN
X linked adrenoleucodystrophy (X-ALD) is considered to be a rare cause of Addison's disease, although several small series suggest a high incidence in young Addisonian males. A survey in the south west of England identified 12 male patients diagnosed with Addison's disease in the period 1987-99. In 10 of these (83%) X-ALD was the underlying cause; the other two were of autoimmune aetiology. Five boys had developed Addison's disease subsequent to the diagnosis of X-ALD. Of the remaining five, in three boys the diagnosis of X-ALD was considerably delayed (by six months to two years from that of Addison's disease) and in two it was only made as a result of this survey. We also identified a patient who presented with Addison's disease at the age of 5 years but was only diagnosed as having X-ALD at the age of 34 years; in the interim his diagnosis of adrenomyeloneuropathy had been missed. Our experience highlights the absolute necessity of measuring very long chain fatty acids in all males with idiopathic Addison's disease.
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Enfermedad de Addison/etiología , Adrenoleucodistrofia/diagnóstico , Adolescente , Adrenoleucodistrofia/complicaciones , Adulto , Edad de Inicio , Niño , Preescolar , Cosintropina , Humanos , MasculinoRESUMEN
We report four white adolescents aged 13 to 15 years (three females, one male) from the south and west region of England who presented with type 2 diabetes mellitus associated with significant obesity (body mass index more than +3SDS) in the past two years. Although these are the first reported obese, white cases from the UK to present with diabetes, we believe this clinical scenario will become more prevalent given the epidemic of childhood obesity in this country.
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Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2/complicaciones , Obesidad , Adolescente , Biguanidas/uso terapéutico , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , MasculinoRESUMEN
To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40 microg/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg x h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg x night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean +/- SEM:IGF-I, 401 +/- 22 ng/ml; placebo, 256 +/- 20 ng/ml (P = 0.0002); IGF-I, 0.108 +/- 0.006; placebo, 0.074 +/- 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 +/- 0.03; placebo, 0.23 +/- 0.03 U/kg x min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r = -0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 +/- 1.5; placebo, 12.2 +/- 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 +/- 6.8; placebo, 82.2 +/- 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Insulina/uso terapéutico , Adolescente , Adulto , Niño , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Hemoglobina Glucada/análisis , Humanos , Inyecciones Subcutáneas , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Placebos , Radioinmunoensayo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Análisis de Regresión , Factores de TiempoRESUMEN
AIMS: To investigate pancreatic function in children attending an obesity clinic. METHODS: Thirty six children (of which 34 were white) with severe obesity of prepubertal onset (body mass index more than +2 SDS) were reviewed clinically and dysmorphologically, with assessment of pancreatic function. RESULTS: Eight had dysmorphic features and 13 had learning difficulties. Four of 17 prepubertal children had hyperinsulinaemia and seven had hyperproinsulinaemia. All 19 pubertal children had hyperinsulinaemia, 14 had hyperproinsulinaemia, and one had type II diabetes. CONCLUSIONS: Metabolic abnormalities predictive of type II diabetes occur in severely obese white children.
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Obesidad Mórbida/metabolismo , Páncreas/metabolismo , Adolescente , Índice de Masa Corporal , Niño , Preescolar , Diabetes Mellitus/etiología , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/etiología , Femenino , Humanos , Hiperinsulinismo/etiología , Masculino , Obesidad , Obesidad Mórbida/complicaciones , Pruebas de Función Pancreática , Valor Predictivo de las Pruebas , Pubertad Precoz/etiología , Pubertad Precoz/metabolismo , Factores de RiesgoRESUMEN
Growth hormone hypersecretion is extremely rare in childhood. We report a girl with neurofibromatosis type 1, an extensive optic nerve glioma and growth hormone hypersecretion. She was treated with chemotherapy to prevent further extension of her sight-threatening tumour. Three years after chemotherapy her growth hormone hypersecretion has resolved although she has gone on to develop precocious puberty.
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Glioma/complicaciones , Hormona de Crecimiento Humana/metabolismo , Neurofibromatosis 1/complicaciones , Neoplasias del Nervio Óptico/metabolismo , Determinación de la Edad por el Esqueleto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estatura , Preescolar , Dactinomicina/uso terapéutico , Femenino , Glioma/tratamiento farmacológico , Glioma/metabolismo , Prueba de Tolerancia a la Glucosa , Hormona de Crecimiento Humana/orina , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Imagen por Resonancia Magnética , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/fisiopatología , Neoplasias del Nervio Óptico/complicaciones , Neoplasias del Nervio Óptico/tratamiento farmacológico , Prolactina/orina , Pubertad Precoz/etiología , Vincristina/uso terapéutico , Aumento de PesoRESUMEN
OBJECTIVE: To examine counterregulatory responses during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 29 prepubertal patients with type 1 diabetes underwent two overnight profiles. Data were analyzed from 16 children (median [range] 8.7 [5.9-12.9] years of age) with a night of hypoglycemia and a nonhypoglycemic night. Children hypoglycemic (< 3.5 mmol/l) on night 1 were given 25% extra carbohydrate as uncooked cornstarch with their usual evening snack on night 2 to avoid hypoglycemia. Glucose, growth hormone, and cortisol were measured every 15 min, catecholamines every 30 min, and glucagon, pancreatic polypeptide, insulin, and ketones every 60 min. A group of 15 healthy control subjects, aged 9.5 (5.6-12.1) years, underwent one overnight profile. RESULTS: Median duration of hypoglycemia was 225 (30-630) min, and glucose nadir was 2.0 (1.2-3.3) mmol/l. Insulin levels were not different on the two nights (P = 0.9, analysis of variance), but children with diabetes had higher insulin levels than normal control subjects between 2300 and 0300, maximal at 0200 (mean +/- SEM 57.4 +/- 5.7 vs. 31.6 +/- 5.0 pmol/l, P = 0.002). Peak epinephrine was higher on the night of hypoglycemia (0.98 [0.52-2.09] nmol/l) versus nonhypoglycemia (0.32 [0.21-0.62] nmol/l), P = 0.001, but norepinephrine (1.29 [1.07-2.64] vs. 1.26 [1.04-1.88] nmol/l, P = 0.5), glucagon (93 [64.2-125.6] vs. 100.5 [54.6-158] ng/l, P = 0.6), pancreatic polypeptide (410.2 [191-643.2] vs. 270.8 [158.2-777.8] ng/l, P = 0.5), and cortisol (513 [300-679] vs. 475 [235-739] nmol/l, P = 0.6) were not different. Glucose threshold for epinephrine release was very low, 1.9 +/- 0.2 mmol/l. There was a short-lived rise in growth hormone from 75-105 min after onset of hypoglycemia, maximal at 90 min (7.8 +/- 1.2 vs. 3.5 +/- 0.9 ng/ml, P = 0.02). CONCLUSIONS: The prolonged nature of nocturnal hypoglycemic episodes may be explained in part by defective counterregulation. The risk of nocturnal hypoglycemia needs to be reduced before intensification of insulin therapy can be contemplated in this age-group.
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Glucemia/metabolismo , Ritmo Circadiano , Diabetes Mellitus Tipo 1/fisiopatología , Hormonas/sangre , Hipoglucemia/fisiopatología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Epinefrina/sangre , Glucagón/sangre , Hemoglobina Glucada/análisis , Hormona de Crecimiento Humana/sangre , Humanos , Hidrocortisona/sangre , Hipoglucemia/sangre , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Insulina/sangre , Cuerpos Cetónicos/sangre , Norepinefrina/sangre , Polipéptido Pancreático/sangre , Pubertad , Valores de ReferenciaRESUMEN
To investigate whether recombinant human insulin-like growth factor-I (rhIGF-I) has direct effects on the insulin requirement to maintain euglycemia independent of the growth hormone (GH) level, nine subjects with insulin-dependent diabetes mellitus ([IDDM] seven females; median (range) age, duration of diabetes, and hemoglobin A1C [HbA1C], 16.9 (12.5 to 21.9) years, 11.8 (4.6 to 16.8) years, and 9.8% (7.9% to 14.1%), respectively) underwent two euglycemic studies (6:00 PM to 8:00 AM) after double-blind subcutaneous administration of rhIGF-I/placebo (40 microg/kg). Octreotide infusion (300 ng/kg/h) suppressed endogenous GH, and three identical discrete GH pulses were infused on both nights. Variable-rate insulin infusion maintained euglycemia. Samples were taken every 15 minutes (glucose and GH), 30 minutes (insulin and intermediate metabolites), and 60 minutes (IGF-I and nonesterified fatty acids [NEFA]). Variables were analyzed during the steady-state period of euglycemia (4:00 to 8:00 AM). Data are expressed as the mean +/- SEM. The insulin infusion rate and free-insulin level were both significantly reduced after rhIGF-I administration (0.13 +/- 0.03 v placebo 0.23 +/- 0.05 mU/kg/min, P = .04, and 8.4 +/- 1.3 v placebo 12.1 +/- 1.4 mU/L, P = .03, respectively). GH pulse-related changes in the insulin requirement observed after placebo were not present after rhIGF-I. Glucagon levels were equally suppressed on both nights. Insulin clearance was not altered after rhIGF-I administration. NEFA and ketone levels also were not different on the 2 nights. In conclusion, in adolescents and young adults with diabetes, rhIGF-I administration directly affected insulin requirements independent of GH levels, but had no effect on fatty acid or ketone levels. This difference is related to the abolition of changes in the insulin requirement after GH pulses, and would suggest a complex interaction between GH and IGF-I on insulin action.
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Diabetes Mellitus Tipo 1/sangre , Hormona de Crecimiento Humana/sangre , Factor I del Crecimiento Similar a la Insulina/farmacología , Insulina/administración & dosificación , Adolescente , Adulto , Glucemia/análisis , Niño , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Método Doble Ciego , Ácidos Grasos no Esterificados/sangre , Femenino , Glucagón/sangre , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/genética , Cetonas/sangre , Masculino , Octreótido/administración & dosificación , Octreótido/farmacología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacologíaRESUMEN
OBJECTIVE: To investigate the effect of low dose oxandrolone and testosterone on the pituitary-testicular and GH-IGF-I axes. DESIGN: Prospective double-blind placebo-controlled trial. PATIENTS: Sixteen boys with constitutional delay of growth and puberty (CDGP) with testicular volumes 4-6 ml were randomized to 3 months treatment: Group 1 (n = 5), daily placebo: Group 2 (n = 5), 2.5 mg oxandrolone daily or Group 3 (n = 6), 50 mg testosterone monthly intramuscular injections with assessment (growth, pubertal development and overnight hormone profiles) at 0, 3, 6 and 12 months. MAIN OUTCOME MEASURES: LH and GH profiles (15-minute samples) were analysed by peak detection (Pulsar), Fourier transformation and autocorrelation. Testosterone levels were measured hourly and insulin, SHBG, IGF-I, and IGFBP-3 levels at 0800 h. Statistical analysis was by multivariate analysis of variance for repeated measures. RESULTS: LH and testosterone parameters increased significantly with time in all 16 (LH AUC, P < 0.001; peak amplitude, P = 0.02; number of peaks, P = 0.02; testosterone AUC, P = 0.02; morning testosterone, P = 0.002). In Group 2, however, LH and testosterone parameters decreased at 3 months followed by a rebound increase at 6 and 12 months. SHBG levels were markedly reduced at 3 months (P = 0.006) and a wider range of dominant GH frequencies was present although GH AUC was not increased until 6 months, with an increase in GH pulse frequency but not amplitude. IGF-I levels were increased at both 3 and 12 months. In Group 3, pituitary-testicular suppression was not apparent, but GH levels increased with an increase in GH amplitude at 3 and 12 months. CONCLUSION: Oxandrolone transiently suppressed the pituitary-testicular axis and altered GH pulsatility. Testosterone increased GH via amplitude modulation.
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Anabolizantes/administración & dosificación , Trastornos del Crecimiento/tratamiento farmacológico , Oxandrolona/administración & dosificación , Pubertad Tardía/tratamiento farmacológico , Testosterona/uso terapéutico , Adolescente , Anabolizantes/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Hormona del Crecimiento/metabolismo , Humanos , Hormona Luteinizante/metabolismo , Masculino , Oxandrolona/uso terapéutico , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Estudios Prospectivos , Tasa de Secreción/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
Insulin-dependent diabetes mellitus (IDDM) during adolescence is associated with complex derangements of the growth hormone (GH)/insulin-like growth factor (IGF) axis. Despite GH hypersecretion, IGF-I levels and IGF bioactivity are reduced. The diabetogenic effects of GH are well established, and GH hypersecretion has been implicated in the deterioration in glycemic control during adolescence and in the development of microangiopathy. Insulin deficiency or reduced portal delivery of insulin plays a central role in the development of these abnormalities, and although continuous subcutaneous insulin delivery may improve plasma IGF-I levels, it does not necessarily suppress GH levels. Recombinant IGF-I has been proposed as an adjunct to conventional insulin therapy, as restoring circulating IGF-I levels might lead to GH suppression. Placebo-controlled studies have shown a consistent reduction in GH secretion and related improvements in insulin sensitivity following a single subcutaneous IGF-I injection (40 micrograms/kg). Repeated daily subcutaneous IGF-I administration for 1 month resulted in a sustained increase in IGF-I levels, as well as a reduction in GH secretion and insulin requirements. There was no increase in hypoglycemia or other adverse effects. Recombinant IGF-I used in conjunction with insulin may therefore provide an additional approach to the management of IDDM during adolescence, allowing correction of abnormalities in the GH/IGF axis and leading to improved control and, hence, reduced risk of long-term complications. However, this hypothesis needs to be rigorously tested in long-term placebo-controlled studies.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Somatomedinas/metabolismo , Adolescente , Diabetes Mellitus Tipo 1/fisiopatología , Hormona del Crecimiento/metabolismo , Humanos , Insulina/uso terapéutico , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangreRESUMEN
Early pubertal boys (testicular volume, 4-6 mL) with constitutionally delayed growth and puberty were randomized to 3 months of treatment after a baseline 12-h overnight hormone profile: group 1 (n = 5), daily placebo; group 2 (n = 5), 2.5 mg oxandrolone daily; or group 3 (n = 6), 50-mg testosterone monthly im injections. LH and GH profiles (15-min samples) were analyzed by peak detection (Pulsar), Fourier transformation, and autocorrelation. FSH and testosterone levels were measured hourly, and insulin, sex hormone-binding globulin, insulin-like growth factor-I, and insulin-like growth factor-binding protein-3 levels were determined at 0800 h. Multiple regression was used to analyze the response to treatment (growth) with respect to baseline features. Endocrine variability was marked. Profiles ranged from unreactive to well established LH pulsatility and adult testosterone levels. The areas under the curve (AUC) for LH, FSH, and testosterone ranged 10-fold (4.4-46.3 IU/L.h), 8-fold (7.9-63.4 IU/L.h), and 45-fold (3.6-161.7 nmol/L.h), respectively. The growth response was individually varied, but significantly increased 0-6 months in the active treatment groups. Age, testicular volume, and LH AUC interacted significantly (r2 = 0.95; P < 0.05). Allowance for these produced a highly significant treatment effect (P = 0.006). Age, testicular volume, LH AUC, and testosterone AUC, but not treatment, significantly increased growth by 0-12 months (r2 = 0.88; P < 0.05). We demonstrate a spectrum of activation of the reproductive axis despite tight clinical staging. This, and not GH status at treatment commencement, influenced the growth response.
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Oxandrolona/uso terapéutico , Hipófisis/fisiopatología , Pubertad Tardía/tratamiento farmacológico , Pubertad/fisiología , Testículo/fisiopatología , Testosterona/uso terapéutico , Adolescente , Estatura , Hormona Folículo Estimulante/sangre , Análisis de Fourier , Hormona del Crecimiento/sangre , Humanos , Hormona Luteinizante/sangre , Masculino , Periodicidad , Placebos , Estudios Prospectivos , Pubertad Tardía/patología , Pubertad Tardía/fisiopatología , Análisis de Regresión , Testículo/patología , Testosterona/sangreRESUMEN
OBJECTIVE: We investigated the effect of low dose cranial irradiation (18-24 Gy) on spontaneous ACTH and cortisol secretion in children. DESIGN: We analysed 24-hour plasma ACTH and cortisol profiles sampled at 20-minute intervals. PATIENTS: Twenty long-term survivors of acute lymphoblastic leukaemia were studied and results compared with those in 14 normal children. MEASUREMENTS: ACTH and cortisol profiles were analysed by Fourier transformation and spectral analysis of stationarized data, autocorrelation and coherency analysis. RESULTS: The normal circadian rhythms of ACTH and cortisol were preserved in the children after cranial irradiation. The median 0900 h and midnight values were 1.50(0.8-6.4)pmol/l and 1.0(0.6-3.7)pmol/l respectively for ACTH and 282(48-1913)nmol/l and 57.5(44-637)nmol/l respectively for cortisol, and were not significantly different from those in the normal group. Fourier transformation revealed dominant periodicities for ACTH at 0.7-1.1 h, equivalent to 22-34 ACTH secretory bursts per 24 hours, and for cortisol at 0.7-1.1 h and 2-4.8 h. Similar results were found in the normal group. Coherency analysis indicated a significant shared periodicity of 0.7-1.2 h in nine children, corresponding to 20-34 related secretory bursts in 24 hours for ACTH and cortisol. After pooling the coherency spectra in the cranially irradiated group, comparison with the pooled data from the normal group revealed no significant difference between the two groups in the relationship between the two hormones. CONCLUSION: No significant disruption of spontaneous ACTH or cortisol secretion, either in the amount or pattern of hormones secreted, was found in children after low dose cranial irradiation (18-24 Gy).
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Irradiación Craneana/efectos adversos , Hidrocortisona/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Adolescente , Hormona Adrenocorticotrópica/sangre , Niño , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Dosificación Radioterapéutica , Tasa de Secreción/efectos de la radiaciónRESUMEN
GH deficiency, skeletal disproportion and early or precocious puberty may complicate irradiation to the head or axial skeleton in childhood. Certain cohorts of children are at particular risk, including those irradiated for brain tumours and various haematological malignancies. Both GH deficiency and impaired spinal growth may result in short stature, whereas the occurrence of early puberty in association with GH deficiency reduces the time available for GH therapy. The age of the child at irradiation is critical in that, in younger children, the central nervous system is more radiosensitive, the severity of the subsequent skeletal disproportion is greatest and the onset of puberty earliest. It is the very young craniospinally-irradiated child who is most at risk of extreme short stature.
Asunto(s)
Trastornos del Crecimiento/etiología , Crecimiento/efectos de la radiación , Radioterapia/efectos adversos , Factores de Edad , Niño , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/deficiencia , Hormona del Crecimiento/uso terapéutico , Humanos , Pubertad Precoz/etiologíaRESUMEN
Urinary growth hormone (uGH) excretion and serum growth hormone concentrations have been compared in three groups of children. Group 1 consisted of 21 children who had had cranial irradiation as part of their treatment for acute lymphoblastic leukaemia; group 2, 18 normal children; and group 3, 12 boys with constitutional delay in growth and puberty who were in early puberty. Children in groups 1 and 2 each had a 24 hour serum growth hormone profile (sampling every 20 minutes) and concurrent urine collection. The 12 boys in group 3 had a total of 21 profiles (sampling every 15 minutes for 12 hours) and concurrent urine collections. In the prepubertal children (n = 17), in both groups 1 and 2, there was a significant correlation between mean serum growth hormone and total uGHng/g creatinine. There were also significant correlations between total uGHng/g creatinine and both peak serum growth hormone and mean amplitude of the pulses in the growth hormone profile. In the pubertal children (n = 22), in groups 1 and 2, whether combined or in separate groups, there was no significant correlation between total uGHng/g creatinine and mean serum growth hormone, peak serum growth hormone, or mean amplitude of the pulses in the growth hormone profile. In group 3 there were significant correlations between total uGHng/g creatinine and both the mean serum growth hormone and mean amplitude of the pulses in the profile. Therefore uGH estimations appear to correlate well with serum growth hormone profiles in children who are prepubertal or in early puberty, but not in those further advanced in pubertal development. These results may reflect a variation in the renal handling of growth hormone during pubertal development. uGH estimation may be an unreliable screening investigation for growth hormone sufficiency in mid to late puberty.
Asunto(s)
Hormona del Crecimiento/sangre , Hormona del Crecimiento/orina , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Pubertad/metabolismo , Adolescente , Factores de Edad , Niño , Irradiación Craneana , Creatinina/orina , Femenino , Trastornos del Crecimiento/metabolismo , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Urea/orinaRESUMEN
OBJECTIVE: We aimed to investigate the effect of low dose (1800 cGy) prophylactic cranial irradiation on physiological growth hormone secretion. DESIGN: We performed an analysis of 24-hour serum GH profiles using 20-minute sampling. PATIENTS: Forty-four children were studied, of whom 21 were long-term survivors of acute lymphoblastic leukaemia and 23 were normal children. They were further subdivided into prepubertal, pubertal and post-pubertal groups. MEASUREMENTS: GH profiles were analysed by autocorrelation, Fourier transformation and spectral analysis of stationarized data, and peak detection using the Pulsar peak detection program. RESULTS In the normal children, there was a significant increase in the median (range) area under the curve (AUC) of the GH profile between the prepubertal and pubertal groups (62 (11-124) and 137 (142-158) IU/I/h respectively, (P less than 0.01)). There was also a change in the spectral analysis through puberty. The dominant frequencies were spread widely in the prepubertal and post-pubertal groups but sharply focused in the pubertal group. In the cranially irradiated children there was no significant increase in AUC between the prepubertal (62(13-110) IU/I/h) and pubertal groups (92 (14-163) IU/I/h). The wide range of dominant frequencies persisted in the pubertal cranially irradiated group due to the presence of additional high frequency pulses. The impression of a disturbance of the periodicity of GH secretion in the cranially irradiated pubertal group was further supported by the finding that the autocorrelation function in this group alone was not significantly different from that which would arise from random data. CONCLUSIONS: A novel form of GH insufficiency has been observed after low dose irradiation in childhood in which an abnormality of periodicity and a quantitative reduction in GH secretion appears restricted to puberty.