RESUMEN
Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH-releasing hormone receptor. We evaluated the safety and tolerability and the GH-insulin-like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth velocity < 10th percentile for age, height < 10th percentile for age, and a maximum GH response of < or = 10 microg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day -1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x h/L (range, 1.3 to 35.6) for the GH area under the concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001), 12 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/L (range, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamoren mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.
Asunto(s)
Hormona del Crecimiento/efectos de los fármacos , Hormona del Crecimiento/deficiencia , Indoles/administración & dosificación , Indoles/farmacología , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Errores Innatos del Metabolismo/tratamiento farmacológico , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacología , Administración Oral , Niño , Método Doble Ciego , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Errores Innatos del Metabolismo/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate adult heights attained by patients with 21-hydroxylase deficiency and to perform a meta-analysis of height outcomes reported in this population. STUDY DESIGN: A retrospective chart review of our patients >5 years of age (n = 65) who were followed up from 1978 to 1998 for 21-hydroxylase deficiency was conducted. Final height (FH) SD scores and target height (TH) SD scores were determined. The impact of sex, time of diagnosis, and compliance was assessed. Meta-analysis of results from 18 studies was performed; TH was available for 204 of 561 patients. RESULTS: Mean FH SD score-TH SD score for our 65 patients was -1.03. For the meta-analysis, mean weighted FH SD score for all 561 patients was -1.37, whereas weighted mean FH SD score-TH SD score for the 204 patients for whom TH was available was -1.21. No difference in outcome was seen for males compared with females, although a statistically significant difference was seen for patients identified early versus late. CONCLUSIONS: Adult height in patients with 21-hydroxylase deficiency is often within 1 SD of TH. Early diagnosis and good compliance appear to improve the outcome. Rather than pursuing alternate therapies for congenital adrenal hyperplasia, efforts may instead be focused on early detection and improved compliance with traditional medical therapy.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Estatura , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/etiología , Hiperplasia Suprarrenal Congénita/psicología , Factores de Edad , Estatura/efectos de los fármacos , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Cooperación del Paciente/psicología , Cooperación del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Caracteres Sexuales , Factores de Tiempo , Resultado del TratamientoRESUMEN
Recent developments have increased our understanding of the molecular mechanisms that are responsible for several disorders of puberty. Specific gene mutations have been identified in three syndromes, one that is associated with delayed puberty (Kallmann syndrome) and two that are associated with precocious puberty (McCune-Albright syndrome and familial male precocious puberty). Mutations in the KAL gene have been shown to be responsible for cases of X-linked Kallmann syndrome. This gene encodes a protein that is believed to be involved in neural target recognition and protease inhibition. In McCune-Albright syndrome, heterozygous, postzygotic somatic mutations of the alpha-subunit of the stimulatory guanine nucleotide binding protein Gs have been shown to stimulate constitutive G protein activation and long-term cyclic adenosine monophosphate production. Similarly, familial male precocious puberty has been linked to gain-in-function mutations that result in increased levels of cyclic adenosine monophosphate; however, these mutations are found in the luteinizing hormone receptor gene itself. The clinical manifestations and the recent molecular advances in each of these three syndromes are explored.
Asunto(s)
Proteínas de la Matriz Extracelular , Mutación/genética , Pubertad Tardía/genética , Pubertad Precoz/genética , AMP Cíclico/genética , Femenino , Displasia Fibrosa Poliostótica/genética , Proteínas de Unión al GTP/genética , Genes/genética , Ligamiento Genético , Heterocigoto , Humanos , Síndrome de Kallmann/genética , Masculino , Proteínas del Tejido Nervioso/genética , Inhibidores de Proteasas , Receptores de HL/genética , Cromosoma XRESUMEN
Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Pubertad Precoz/tratamiento farmacológico , Absorciometría de Fotón/instrumentación , Absorciometría de Fotón/métodos , Absorciometría de Fotón/estadística & datos numéricos , Determinación de la Edad por el Esqueleto , Niño , Preescolar , Preparaciones de Acción Retardada , Femenino , Humanos , Leuprolida/administración & dosificación , Leuprolida/efectos adversos , Estudios Longitudinales , Pubertad Precoz/fisiopatología , Factores de TiempoRESUMEN
McCune-Albright syndrome (MCAS) is a sporadic disease classically including polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and other hyperfunctional endocrinopathies. An activating missense mutation in the gene for the alpha subunit of GS, the G protein that stimulates cyclic adenosine monophosphate formation, has been reported to be present in these patients. The mutation is found in variable abundance in different affected endocrine and nonendocrine tissues, consistent with the mosaic distribution of abnormal cells generated by a somatic cell mutation early in embryogenesis. We describe three patients with MCAS who had profound endocrine and nonendocrine disease and who died in childhood. Two of the patients were severely ill neonates whose complex symptoms did not immediately suggest MCAS. A mutation of residue Arg201 of GS alpha was found in affected tissues from all three children. A review of the literature and unpublished case histories emphasizes the existence of other patients with severe and unusual clinical manifestations. We conclude that the manifestations of MCAS are more extensive than is generally appreciated, and may include hepatobiliary disease, cardiac disease, other nonendocrine abnormalities, and sudden or premature death.
Asunto(s)
Arginina/genética , Displasia Fibrosa Poliostótica/genética , Proteínas de Unión al GTP/genética , Adolescente , Elementos sin Sentido (Genética) , AMP Cíclico/genética , Muerte Súbita/epidemiología , Enfermedades del Sistema Endocrino/genética , Femenino , Displasia Fibrosa Poliostótica/complicaciones , Humanos , Recién Nacido , Masculino , Mosaicismo , Mutación , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
Clitoral measurements were obtained in normal children; small increases in clitoral dimensions were associated with growth and puberty. Patients with androgen excess had major increases in clitoral size, clearly different from normal values.
Asunto(s)
Hiperplasia Suprarrenal Congénita/patología , Andrógenos/metabolismo , Clítoris/patología , Pubertad Precoz/patología , Aberraciones Cromosómicas Sexuales/patología , Adolescente , Corteza Suprarrenal/metabolismo , Niño , Preescolar , Clítoris/anatomía & histología , Femenino , Disgenesia Gonadal/patología , Humanos , Lactante , Valores de ReferenciaAsunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Pubertad Precoz/tratamiento farmacológico , Pamoato de Triptorelina/análogos & derivados , Estatura/efectos de los fármacos , Niño , Preparaciones de Acción Retardada , Femenino , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Masculino , Maduración Sexual/efectos de los fármacosRESUMEN
We investigated whether an increase in growth hormone secretion contributed to the growth spurt in children with precocious puberty by measuring the 24-hour profile of serum growth hormone in 51 patients with central precocious puberty. Girls with central precocious puberty had significantly greater mean 24-hour levels of growth hormone in comparison with normal prepubertal girls (5.1 +/- 0.5 SEM vs 3.4 +/- 0.3 ng/mL, P less than 0.005). Mean 24-hour growth hormone levels did not differ significantly between boys with central precocious puberty and normal prepubertal boys (4.4 +/- 1.2 vs 3.0 +/- 0.4 ng/mL). Serum somatomedin C levels were significantly correlated with mean 24-hour growth hormone levels in the girls only. Height age advancement (expressed as height age/chronologic age) was significantly correlated with mean 24-hour growth hormone levels in both boys and girls with central precocious puberty. We conclude that spontaneous 24-hour growth hormone secretion in girls with precocious puberty is greater than that of normal prepubertal girls and may mediate at least in part the increased growth rate in this disorder.
Asunto(s)
Hormona del Crecimiento/metabolismo , Pubertad Precoz/sangre , Estatura , Niño , Preescolar , Ritmo Circadiano , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/sangre , Masculino , Factores SexualesRESUMEN
Between 1979 and 1983, 129 children (95 girls) with precocious puberty were referred to the National Institutes of Health and received treatment for at least 6 months with the long-acting LHRH analogue D-Trp6-Pro9-NEt-LHRH. The majority (107 of 129) of the children had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis in association with hypothalamic hamartomas (24 of 107) or other central nervous system lesions (21 of 107), or idiopathic precocious puberty (62 of 107). Hypothalamic hamartomas or other central nervous system lesions were a frequent cause of central precocious puberty in girls (27 of 87), but idiopathic precocious puberty was still the most frequent diagnosis (63%). Idiopathic precocious puberty was uncommon in boys (6%). The patients with peripheral precocious puberty included six girls with McCune-Albright syndrome and six boys with familial male precocious puberty. These children had peripheral sex steroid secretion in the absence of hypothalamic-pituitary-gonadal axis maturation. The children with combined peripheral and central precocious puberty included nine children with congenital adrenal hyperplasia and one girl with a virilizing adrenal tumor. In the patients with central precocious puberty or combined peripheral and central precocious puberty, LHRHa therapy caused suppression of gonadotropin and sex steroid levels (P less than 0.001), stabilization or regression of secondary sexual characteristics, and decreases in growth rate and in the rate of bone age maturation (P less than 0.005). Patients with peripheral precocious puberty, however, had no significant change in gonadotropin or sex steroid levels, growth rate, or the rate of bone age maturation, and no improvement in secondary sexual characteristics. Thus, LHRHa is an effective treatment of central precocious puberty and combined peripheral and central precocious puberty, but is ineffective in the therapy of peripheral precocious puberty.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Pubertad Precoz/clasificación , Pubertad Precoz/tratamiento farmacológico , Pamoato de Triptorelina/análogos & derivados , Hiperplasia Suprarrenal Congénita/complicaciones , Niño , Preescolar , Preparaciones de Acción Retardada , Estradiol/sangre , Femenino , Displasia Fibrosa Poliostótica/complicaciones , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/uso terapéutico , Crecimiento , Hamartoma/complicaciones , Humanos , Neoplasias Hipotalámicas/complicaciones , Hormona Luteinizante/sangre , Masculino , National Institutes of Health (U.S.) , Pubertad Precoz/etiología , Caracteres Sexuales , Factores Sexuales , Testosterona/sangre , Estados UnidosRESUMEN
To assess the role of somatomedin-C as a possible mediator of the growth spurt in children with central precocious puberty, we compared Sm-C levels in 40 children with central precocious puberty, 87 age-matched normal children, and 110 normal pubertal controls. Somatomedin C levels were significantly elevated for age in the children with precocious puberty (P less than 0.01), and were similar to the levels observed during normal puberty. The patients with precocious puberty were given the luteinizing hormone releasing hormone analogue D-Trp6-Pro9-NEt-LHRH (LHRHa) for 6 months. Treatment caused a significant decrease in secondary sexual characteristics, growth rate, plasma gonadotropins, sex steroids (estradiol in the girls and testosterone in the boys), and Sm-C levels. Growth during LHRHa treatment returned to the age-appropriate rate, whereas plasma Sm-C levels, although lower than pretreatment levels, remained significantly elevated for age (P less than 0.002). In addition, growth rates before and during treatment did not correlate with the plasma somatomedin C levels, nor did the decreases in growth rate during LHRHa therapy correlate with the decreases in somatomedin C levels. Growth rates did correlate significantly, however, with plasma estradiol levels in the girls (P less than 0.0005) and with plasma testosterone levels in the boys (P less than 0.025). We conclude that the growth spurt in children with precocious puberty cannot be explained by the plasma level of somatomedin C.
Asunto(s)
Trastornos del Crecimiento/sangre , Pubertad Precoz/sangre , Somatomedinas/sangre , Niño , Preescolar , Estradiol/sangre , Femenino , Hormona Liberadora de Gonadotropina/uso terapéutico , Crecimiento/efectos de los fármacos , Trastornos del Crecimiento/etiología , Humanos , Lactante , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina , Masculino , Péptidos/sangre , Pubertad Precoz/complicaciones , Pubertad Precoz/tratamiento farmacológico , Caracteres Sexuales , Testosterona/sangreAsunto(s)
Neoplasias de las Glándulas Suprarrenales/complicaciones , Hormona Liberadora de Gonadotropina/análogos & derivados , Pubertad Precoz/tratamiento farmacológico , Pamoato de Triptorelina/análogos & derivados , Virilismo/etiología , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Preescolar , Femenino , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hormonas Hipofisarias/sangre , Pubertad Precoz/etiología , Virilismo/cirugíaAsunto(s)
Hipoparatiroidismo/complicaciones , Raquitismo/etiología , Calcio/uso terapéutico , Preescolar , Estudios de Seguimiento , Humanos , Hipocalcemia/tratamiento farmacológico , Hipoparatiroidismo/tratamiento farmacológico , Masculino , Osteólisis/fisiopatología , Fosfatos/sangre , Raquitismo/tratamiento farmacológico , Vitamina D/uso terapéuticoRESUMEN
We report a controlled standardized behavioral assessment of 33 girls with true precocious puberty using the Child Behavior Checklist. Although a majority of the girls were reported not to have behavior problems, many were reported to have a dysphoric adjustment to their condition. Twenty-seven percent of the girls with true precocious puberty scored greater than 2 SD above the mean on the Total Behavior Problem scale 10 times the expected prevalence rate. They also scored significantly higher (P less than 0.01) than matched controls on both the internalizing or "overcontrolled symptom" and externalizing or "undercontrolled symptom" scales. Forty-eight percent scored greater than 2 SD above the mean on the Social Withdrawal scale. The high prevalence of reported problem behaviors in this sample may be related directly or indirectly to the precocious maturation mediated by biologic, psychologic, social, and environmental variables. Although elevated levels of sex steroids may directly contribute to increased aggressive and hyperactive behaviors, they may also be modified by social and environmental factors.