RESUMO
BACKGROUND AND PURPOSE: Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury. MATERIALS AND METHODS: Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods. RESULTS: In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region. CONCLUSIONS: NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.
Assuntos
Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Encéfalo/metabolismo , Cetoacidose Diabética/complicações , Espectroscopia de Ressonância Magnética , Adolescente , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Edema Encefálico/metabolismo , Criança , Colina/metabolismo , Transtornos da Consciência/diagnóstico , Transtornos da Consciência/etiologia , Transtornos da Consciência/metabolismo , Creatina/metabolismo , Cetoacidose Diabética/metabolismo , Escala de Coma de Glasgow , Humanos , PrótonsRESUMO
Insulin and the insulin-like growth factors (IGF-I, IGF-II) constitute a family of peptides capable of stimulating diverse cellular responses, including cell proliferation. In order to determine the effects of these peptides on malignant cells, we analyzed the expression and function of insulin, IGF-I, and IGF-II receptors on B-cell precursor acute lymphoblastic leukemia (BCP ALL) cell lines, utilizing competitive binding, affinity crosslinking, and cell proliferation assays. The BCP ALL cells bound to each peptide with mean specific binding for 125I-insulin, 125I-IGF-I, and 125I-IGF-II of 19.6%, 7.1%, and 4.3% of radioligand added, respectively. Competitive binding to intact cells demonstrated that 125I-IGF-I was displaced by IGF-I = IGF-II >> insulin, 125I-IGF-II was displaced by IGF-II > insulin = IGF-I, and 125I-insulin was displaced by insulin >> IGF-II > IGF-I. These data were remarkable for the potency of IGF-II displacement of 125I-IGF-I and 125I-insulin. Affinity crosslinking of radioligands to SUP-B2 cell membranes demonstrated the high affinity insulin and IGF-I (type 1 IGF) receptors. IGF binding proteins were also present in BCP ALL cell membrane preparations. In the cell proliferation studies, insulin stimulated a 50-130% increase in leukemic cell growth with a half-maximal concentration of 0.1-3.0 ng/ml in three BCP ALL cell lines. The proliferative response to insulin was blocked by the addition of an insulin receptor antibody. However, no response was observed with IGF-I, and IGF-II was only weakly mitogenic with a proliferative response noted at 100 ng/ml. Thus, while BCP ALL cells possess receptors for insulin and IGF-I, only the insulin receptor mediated a proliferative response.
Assuntos
Linfoma de Burkitt/patologia , Insulina/farmacologia , Divisão Celular/efeitos dos fármacos , Reagentes de Ligações Cruzadas , Humanos , Técnicas In Vitro , Insulina/metabolismo , Cariotipagem , Mitógenos/farmacologia , Receptor de Insulina/metabolismo , Receptores de Somatomedina/metabolismo , Proteínas Recombinantes/farmacologia , Somatomedinas/metabolismo , Células Tumorais CultivadasRESUMO
Normal adult human keratinocytes in monolayer culture and SCL-1, a skin-derived squamous-cell carcinoma cell line, were investigated for the expression of receptors for insulin-like growth factors (IGF) and insulin. As demonstrated by affinity crosslinking, radiolabeled IGF-1, IGF-2, and insulin bound specifically to both cell types. Each cell expressed type I IGF receptors, with affinity for IGF-1 greater than IGF-2 much greater than insulin. Insulin receptors, with highest affinity for insulin, were also present on both cells. However, keratinocytes and SCL-1 cells differed in 125I-IGF-2 binding. 125I-IGF-2-bound to both type I and type II IGF receptors in normal keratinocytes, but bound predominantly to membrane-associated IGF binding proteins in SCL-1. IGF-1 was slightly more potent than IGF-2 in stimulating growth of both keratinocytes and SCL-1 cells. In keratinocytes, concentrations of IGF-1 ranging from 5-100 ng/ml, and of IGF-2 from 50-100 ng/ml, resulted in a significant increase in cell number. At the maximum dose of 100 ng/ml, either IGF-1 or IGF-2 caused a 2.3-times increase in cell number. In SCL-1 cells, IGF-1 was more potent than IGF-2 or insulin at lower concentrations, but either IGF-1 or IGF-2 at the maximal concentration of 333 ng/ml stimulated a 4.7-times increase in thymidine incorporation. The stimulatory effect of insulin in SCL-1 was 10-50 times less potent than that of the IGF. The effect of either IGF on SCL-1 was completely inhibited by the type I IGF receptor antibody alpha IR-3, suggesting that both IGFs are mitogenic through the type I IGF receptor. Insulin action was partially blocked by alpha IR-3, suggesting that insulin can act through both the insulin and type I IGF receptors. It thus appears that IGF-1 and IGF-2 are mitogens for normal and transformed human keratinocytes and that their actions are primarily mediated through the type I IGF receptor, whereas insulin is a mitogen through both the IGF-1 receptor and the insulin receptor.
Assuntos
Divisão Celular/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Queratinócitos/citologia , Mitógenos , Carcinoma de Células Escamosas , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , Humanos , Insulina/farmacologia , Fator de Crescimento Insulin-Like II/metabolismo , Queratinócitos/efeitos dos fármacos , Cinética , Proteínas de Membrana/isolamento & purificação , Proteínas de Membrana/metabolismo , Receptor de Insulina/isolamento & purificação , Receptor de Insulina/metabolismo , Receptores de Superfície Celular/isolamento & purificação , Receptores de Superfície Celular/metabolismo , Receptores de Somatomedina , Proteínas Recombinantes/farmacologia , Neoplasias Cutâneas , Timidina/metabolismoRESUMO
Recent studies have provided a consensus that insulin-like growth factor-I (IGF-I) stimulates IGF-binding protein-3 (IGFBP-3) in vivo and in vitro. While it also appears well established that IGFBP-1 is inversely related to insulin concentrations, evidence regarding regulation of other IGFBP is inconclusive. Using immunoprecipitation and Western ligand blot, we have characterized the IGFBPs released into conditioned medium (CM) by cells from the adult human fibroblast cell line N3652 and the human epidermal squamous cell carcinoma line SCL-1. N3652 cells expressed IGFBP-3, IGFBP-2, a 24-kilodalton (kDa) IGFBP presumed to be IGFBP-4, and IGFBPs at 30 and 28 kDa. SCL-1 expressed IGFBP-3 and a putative IGFBP-4, with intermediate bands at 34 and 30 kDa. As determined by ligand blot of CM from confluent cells 72 h after the addition of peptides to serum-free medium, IGF-I and IGF-II potently stimulated IGFBP-3 in both cell lines, but otherwise IGFBP regulation in the two cells diverged. In N3652 cells, IGFBP-3 concentrations in CM increased to 700% and 800% of basal levels in the presence of IGF-I and IGF-II (at 100 ng/ml; n = 5 experiments), respectively. IGFBP-3 was not affected by insulin up to 10 micrograms/ml. In contrast, IGFBP-4 levels were diminished 54% and 73% by 100 ng/ml IGF-I and IGF-II, respectively, with no response to insulin. In SCL-1 cells, IGF-I and IGF-II were virtually identical in stimulating a mean 200% increase in IGFBP-3 (n = 5 experiments). Insulin was less potent, but caused a significant stimulation of IGFBP-3 levels. IGF-I, IGF-II, and insulin all stimulated an approximately 50% increase in IGFBP-4 concentrations. To test the hypothesis that IGF-induced alterations in IGFBP-3 and IGFBP-4 concentrations were regulated via the type 1 IGF receptor, we attempted to block IGFBP changes with type 1 IGF receptor antibody alpha IR-3 and to induce IGFBP changes with an IGF-II analog, [Leu27]IGF-II, with little affinity for the type 1 receptor. alpha IR-3 failed to block either the IGF-induced rise in IGFBP-3 in each cell line or the decline in IGFBP-4 in N3652 CM. [Leu27]IGF-II was as potent as IGF-II or IGF-I in inducing changes in IGFBP-3 and IGFBP-4 concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Proteínas de Transporte/metabolismo , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Receptores de Superfície Celular/metabolismo , Carcinoma de Células Escamosas , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Insulina/farmacologia , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Cinética , Receptores de Somatomedina , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Neoplasias CutâneasRESUMO
Deficits in bone mineral have been widely reported in Turner syndrome. The bone mineral status of 19 adolescents with Turner syndrome (16 receiving GH therapy) was evaluated by dual photon absorptiometry of the lumbar spine and whole body and compared with a normal female control group (n = 45) with the same mean age (14.3 yr). The conventional measurements of bone mass, bone mineral content (BMC = g), and bone mineral density (BMD = g/cm2), as well as bone mineral apparent density (BMAD = g/cm3), an expression of bone mineral adjusted for bone volume, were determined for both sites. Although mean BMC was decreased in Turner females, mean BMD and BMAD in the two groups were not significantly different. Analyzed in relation to chronologic age, bone age, height, and pubertal status, mean BMD and BMAD values in Turner subjects were equal to or greater than that of controls. BMD and BMAD were elevated in the Turner group vs. controls matched for height. In subjects with bone age less than or equal to 12.5 yr, mean spinal BMAD was unexpectedly greater in Turner patients compared with controls (0.148 +/- 0.011 vs. 0.134 +/- 0.013, P = 0.009). When data were analyzed by pubertal status, mean spinal BMD and BMAD in subjects with Tanner breast stages 1-2 were higher in the Turner group than in the controls (BMAD 0.146 +/- 0.011 vs. 0.132 +/- 0.015, P = 0.015). No differences were seen in mid- to late pubertal females. Bone mineral properties were additionally reassessed after a mean interval of 1.3 yr in 10 of the subjects with Turner syndrome. Percentage increases in mean follow-up spinal BMD and BMAD were greater in 5 subjects begun on estrogen replacement than in 5 untreated patients. We conclude that: 1) bone mineral values in adolescents with Turner syndrome on GH therapy are not abnormal, 2) lumbar bone mineral is greater in younger Turner adolescents matched with controls for bone age or pubertal status, a difference which could relate to GH therapy, and 3) estrogen therapy may augment bone mineral accretion in Turner syndrome, but early estrogen replacement cannot be justified on the basis of bone mineral status.
Assuntos
Densidade Óssea , Hormônio do Crescimento/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Absorciometria de Fóton , Adolescente , Criança , Feminino , Humanos , Valores de Referência , Coluna Vertebral/metabolismo , Síndrome de Turner/metabolismoRESUMO
OBJECTIVE: We compared a rapid, subcutaneous (SQ), single-sample gonadotropin-releasing hormone (GnRH) stimulation test with the standard multiple-sample, intravenous (IV) GnRH stimulation test used in the evaluation of central precocious puberty (CPP). METHODS: We evaluated 22 patients presenting with evidence of precocious puberty. GnRH (100 microg) was administered subcutaneously in the clinic setting with single serum luteinizing hormone (LH) measured 40 minutes after injection. A standard IV GnRH stimulation test was performed within 2 weeks, with serum LH obtained at 0, 20, 40, and 60 minutes. LH was assayed by immunochemiluminometric assay. RESULTS: The mean peak LH levels after IV and SQ testing were identical. A significant correlation (r = .88) was found between the LH determined by SQ stimulations and the peak LH determined by IV GnRH testing. CPP was diagnosed (LH, >/- 8 IU/L) by both SQ and IV testing in 7 of 22 patients and was excluded by both tests in 14 of 22 patients. A diagnostic discrepancy between peak IV and SQ results was seen in 1 patient. CONCLUSIONS: We conclude that mean GnRH-stimulated LH levels from rapid SQ and standard IV testing are indistinguishable and that individual LH levels by each method are strongly correlated. A rapid SQ GnRH test is a valid tool for laboratory confirmation of CPP.
Assuntos
Hormônio Liberador de Gonadotropina/administração & dosagem , Puberdade Precoce/diagnóstico , Determinação da Idade pelo Esqueleto , Criança , Estradiol/sangue , Estudos de Avaliação como Assunto , Seguimentos , Humanos , Imunoquímica , Injeções Intravenosas , Injeções Subcutâneas , Medições Luminescentes , Hormônio Luteinizante/sangue , Reprodutibilidade dos Testes , Maturidade Sexual , Fatores de TempoRESUMO
The quantification of messenger RNA is central in studies of gene expression. We describe a quantitative assay for specific mRNAs (QASM) that measures mRNAs for insulin-like growth factor-I, IGF binding proteins (IGFBPs) -2, -3, -4, and -5, and beta-actin. The assay utilizes reverse transcription and polymerase chain reaction, followed by an ELISA based DNA assay technique. The use of internal (competitive) quantification standards gave poorly linear results, while external standards gave linear and reproducible results. QASM results correlated with IGFBP protein concentrations in conditioned medium and with mRNA levels determined by Northern blotting. QASM was used to study IGFBP expression in human malignant melanoma cells. Messenger RNA for IGFBP-2, -3, and -5 were present, while IGF-I and IGFBP-4 mRNAs were not detected. IGFBP-2 and -3 expression was increased in a dose dependent manner by treatment with IGF-I. Protein concentrations in conditioned media paralleled mRNA levels. QASM is a sensitive, specific, and reproducible approach to determining mRNA levels.
Assuntos
Proteínas de Transporte/genética , Expressão Gênica , Fator de Crescimento Insulin-Like I/genética , Melanoma/metabolismo , RNA Mensageiro/análise , Actinas/genética , Sequência de Bases , Northern Blotting , Meios de Cultivo Condicionados , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , DNA Polimerase Dirigida por RNA , Células Tumorais CultivadasRESUMO
We report on a father and son with a previously undescribed skeletal abnormality and severe short stature. Antenatal sonographic evaluation of the propositus (son), obtained due to maternal pre-eclampsia, suggested an abnormal spine. At birth, no congenital anomalies were noted and transition to extra-uterine life was smooth. Radiographs performed five days after birth showed spina bifida, hemivertebrae in the mid-thoracic region, and widened lumbar interpedicular distances. MRI of the lower thoracic and lumbar vertebrae documented crescent-shaped appearance of the affected vertebrae and abnormally narrow A-P diameter of the vertebral bodies. Intervertebral discs were small, and the posterior elements, as well as the spinous processes of the affected vertebrae, were markedly hypoplastic. However, there was no narrowness of the spinal canal, and the limbs were unaffected. CT scan with three-dimensional reformatting of the thoracic and lumbar vertebrae documented unusual sagittal clefting of all of the vertebral bodies, which has previously been undescribed. The father had severe kyphoscoliosis and a height of 131.6 cm (-7.5 S.D.). Radiographically, he was found to have multiple segmentation anomalies and diminished A-P diameter of his affected vertebral bodies. The multiple vertebral anomalies are the probable cause for the father's severe kyphoscoliosis. The pattern of inheritance suggests that an autosomal dominant gene is responsible for this condition and that the father represents a de novo mutation. These radiographic abnormalities have not been described previously and represent a new form of vertebral spinal dysplasia.
Assuntos
Disostoses/genética , Coluna Vertebral/anormalidades , Adulto , Pré-Escolar , Genes Dominantes , Humanos , Cifose/genética , Masculino , Mutação , Escoliose/genéticaRESUMO
The insulin-like growth factors (IGF)-I and IGF-II are peptides with structural homology to insulin and potent mitogenic and anabolic actions in vitro and in vivo. IGF-I levels are growth hormone (GH)-dependent and vary strikingly with age. IGF-I levels are typically low in infancy and childhood, increase dramatically during puberty, and then gradually decline with advancing age. Whether age-associated changes in GH production or sex steroid secretion, or other unknown factors, cause diminished IGF production in the elderly remains to be determined. In the brain, IGF-II appears to be the most prevalent IGF, but a truncated form of IGF-I also has been recognized. IGF actions are mediated by binding to a family of receptors, which includes the insulin receptor, the structurally homologous type I IGF receptor, and the IGF-II/M-6P receptor, all of which are found in the central nervous system. Additionally, the IGFs bind with high affinity to a family of IGF-binding proteins (IGFBPs). Of the six known IGFBPs, IGFBP-2 appears to be the major one in the mammalian brain and is a major component of CSF. Immunoreactive IGFBP-2 has been identified in astrocytes, and its mRNA has been identified in fetal and adult brain and choroid plexus. The IGFBPs transport the IGFs in serum and other body fluids and appear to regulate IGF access to receptors. In vivo regulation of IGFBPs includes tissue-specific proteases, which cleave specific IGFBPs, altering their affinities for IGF peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Somatomedinas/fisiologia , Animais , Proteínas de Transporte/fisiologia , Linhagem Celular Transformada , Hormônio do Crescimento/fisiologia , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Receptores de Somatomedina/fisiologiaRESUMO
Recombinant human growth hormone (hGH) has been available for nearly a decade. Side effects are rare. Its efficacy in promoting growth acceleration has been widely confirmed in children with GH deficiency (GHD), Turner syndrome, idiopathic short stature, chronic renal failure, and a variety of other conditions. The dramatic increase in height velocity in the first year of therapy partially attenuates in subsequent years in all patient groups, and convincing final height data are only available in GHD and Turner syndrome. Pediatric endocrinologists continue to be troubled by definitions of GHD. Although profound GHD is relatively obvious, other patients with severe growth failure but borderline or normal endocrine testing also respond to hGH therapy. Thus many endocrinologists use auxologic criteria [e.g. low growth velocity, height < -3 standard deviation (SD), poor predicted adult height] as the de facto basis for therapy, leading to a blurred distinction between treatment of disease and enhancement of normal characteristics and, finally, raising questions about the ultimate benefit of hGH therapy. Brief clinical trials of hGH therapy in adults both with and without GHD have reported increased muscle mass, decreased fat, and improvement in quality of life. Internists may soon be faced with treatment decisions analogous to those confronting pediatricians, i.e. whether to use hGH to repair aspects of the normal aging process.
Assuntos
Hormônio do Crescimento/uso terapêutico , Seleção de Pacientes , Adulto , Estatura/efeitos dos fármacos , Criança , Cocarcinogênese , Uso de Medicamentos , Ética Médica , Feminino , Crescimento/efeitos dos fármacos , Hormônio do Crescimento/efeitos adversos , Hormônio do Crescimento/deficiência , Saúde , Humanos , Masculino , Proteínas Recombinantes , Alocação de Recursos , Medição de Risco , Síndrome de Turner/tratamento farmacológicoRESUMO
The production of insulin-like growth factors and insulin-like growth factor binding proteins by twelve human leukemic lymphoblast cell lines was evaluated by radioimmunoassay, affinity cross-linking, ligand blot, and immunoprecipitation of conditioned media. In all cell lines, detectable IGF-I and IGF-II levels were less than 0.1 micrograms/l and less than 0.3 micrograms/l, respectively. IGF binding proteins were identified in 6/12 of the lymphoblast cell lines studied. A pair of IGF binding proteins at 31 and 33 kD, immunoprecipitated with an antibody recognizing IGF binding protein 2 but not by an IGF binding protein 3 antibody, was produced by both T and B cells. A 24 kD IGF binding protein, presumably IGF binding protein 4, since it was not recognized by the antibodies for IGF binding proteins 1, 2, and 3, was produced by B cell precursor cells and faintly by one T cell line. These IGF binding proteins were not altered by deglycosylation. Neither IGF binding protein 1 nor IGF binding protein 3 was identified in any of the conditioned media. We speculate that local production of IGF binding proteins 2 and 4 regulates access of the IGFs to lymphoblasts and to hematopoietic precursors in general.
Assuntos
Linfócitos B/metabolismo , Proteínas de Transporte/biossíntese , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T/metabolismo , Linfócitos B/imunologia , Humanos , Imunofenotipagem , Técnicas de Imunoadsorção , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Linfócitos T/imunologia , Células Tumorais CultivadasRESUMO
The newborn whose genitalia are ambiguous presents a challenge to the pediatrician and the family. A clear understanding of the basis of sex differentiation and timely consultation with a pediatric endocrinologist is critical in the evaluation and determination of sex of rearing in a newborn who has ambiguous genitalia. Sex karyotype and a 17-OHP level may suffice in the initial evaluation of female pseudohermaphroditism because most patients will have virilizing CAH. If male pseudohermaphroditism is suspected on the basis of palpable gonads, we routinely obtain a karyotype, basal adrenal steroid levels, and levels of hCG-stimulated serum testosterone and DHT, then consider a testosterone treatment trial. Physicians who care for children who have ambiguous genitalia must appreciate the family's cultural, religious, and psychological needs and avoid determining sex of rearing before accurate diagnosis is reached.
Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Transtornos do Desenvolvimento Sexual/tratamento farmacológico , Transtornos do Desenvolvimento Sexual/genética , Feminino , Fludrocortisona/administração & dosagem , Fludrocortisona/uso terapêutico , Genitália/anormalidades , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/uso terapêutico , Masculino , Oxigenases de Função Mista/sangue , Cromossomo XRESUMO
OBJECTIVE: We assessed the utility of spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays in the evaluation and monitoring of precocious puberty. METHODS: We evaluated serum gonadotropin values from intravenous GnRH stimulation tests in 49 girls with clinical signs suggesting central precocious puberty (CPP). Because GnRH-stimulated LH has been considered the standard for diagnosing CPP, we used it as the basis for comparison with GnRH-stimulated FSH levels and spontaneous LH and FSH measured by immunochemiluminometric assay. RESULTS: Twenty-six patients had a peak serum LH value above the +2 SD threshold for normal prepubertal female subjects (LH > 5 IU/L). The GnRH-stimulated FSH values had a narrow range and did not discriminate patients with CPP. In contrast, elevations in spontaneous LH and FSH were found to be specific for CPP. Spontaneous LH levels correlated strongly with peak stimulated LH levels in subjects with precocious puberty (r = 0.79) or in control subjects (r = 0.93, both p (0.0001). Spontaneous LH levels in excess of 0.1 IU/L detected true puberty with 94% sensitivity and 88% specificity. Random LH levels in excess of 0.3 IU/L had 100% specificity for CPP. CONCLUSIONS: The GnRH-stimulated FSH levels do not adequately differentiate children with and without CPP and have limited utility in the evaluation of precocious puberty. Spontaneous FSH levels are elevated in CPP with fair sensitivity and marked specificity. Elevated random LH, measured by third-generation assay such as immunochemiluminometric assay, is strongly correlated with and highly predictive of elevated peak GnRH-stimulated LH, and is a useful screening tool for CPP.
Assuntos
Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Puberdade Precoce/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Ensaio Imunorradiométrico/estatística & dados numéricos , Leuprolida/uso terapêutico , Medições Luminescentes , Masculino , Puberdade Precoce/sangue , Puberdade Precoce/terapia , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To test the usefulness of estrogen priming to enhance the growth hormone (GH) response following stimulation with clonidine hydrochloride in short children. DESIGN: Randomized and patient series. SETTING: Pediatric endocrine clinic in a referral center. SUBJECTS: Seventy-three children (63% male) between 1.8 and 15.4 years of age (mean age, 8.8 years) with growth problems who underwent clonidine GH stimulation tests were randomly assigned to receive either estrogen pretreatment or no pretreatment. An additional 49 subjects, seen before or after the randomized study and who did not receive conjugated estrogen, are also described. SELECTION PROCEDURE: Consecutive sample. INTERVENTION: Estrogen pretreatment consisted of 2.5 mg of conjugated estrogen (Premarin) to be taken the evening before and the morning of the clonidine GH stimulation test. Growth hormone concentrations were determined before and 60 and 90 minutes after the subjects received oral clonidine hydrochloride (5 micrograms/kg) by a laboratory blinded to the subject's estrogen status. Growth hormone concentrations greater than 10 micrograms/L were considered normal. RESULTS: Eight of the 73 subjects failed both clonidine and arginine-insulin GH stimulation tests. We analyzed the GH data from the 65 GH-sufficient subjects to determine the effect of estrogen pretreatment on the specificity of the clonidine GH stimulation test. There were no statistically significant differences in the mean GH concentrations between the two groups at any time point during the test. CONCLUSIONS: Our data demonstrate that estrogen priming does not improve the diagnostic yield of clonidine GH stimulation tests.
Assuntos
Clonidina , Estrogênios Conjugados (USP) , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento/deficiência , Administração Oral , Adolescente , Arginina , California/epidemiologia , Criança , Pré-Escolar , Clonidina/administração & dosagem , Clonidina/farmacologia , Árvores de Decisões , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/farmacologia , Feminino , Transtornos do Crescimento/sangue , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento/sangue , Hormônio do Crescimento/efeitos dos fármacos , Hospitais Pediátricos , Humanos , Lactente , Insulina , Masculino , Estudos ProspectivosRESUMO
We report results from 2 years of therapy with the long-acting form of the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate, which was previously reported in short-term trials to be efficacious in the treatment of central precocious puberty. Thirteen girls and two boys, aged 1.9 to 9.7 years, who satisfied clinical criteria including GnRH-stimulated luteinizing hormone (LH) greater than 10 IU/L (mean radioimmunoassay LH, 29.1 +/- 5.54 IU/L), received depot leuprolide, 6 to 15 mg intramuscularly every 4 weeks. Estradiol (or testosterone), insulin-like growth factor I, and GnRH-stimulated gonadotropins were obtained at baseline, at 2 months, and at 6-month intervals with bone age determinations. Pubertal progression ceased in all patients, and menses did not occur. Mean increase in height during therapy was 5.77 +/- 2.0 cm/yr. Predicted adult height increased over baseline by 5.52 +/- 1.16 cm at 18 months. Mean estradiol values in the girls declined from 3.3 +/- 0.6 to 0.60 +/- 0.03 ng/dl, with no overlap of baseline and treatment values. The mean basal LH value was unchanged by therapy; mean basal and peak LH values for all follow-up GnRH stimulation tests were 4.05 +/- 0.57 and 4.95 +/- 0.70 IU/L, respectively. Basal and peak follicle-stimulating hormone (FSH) values were suppressed from 4.10 +/- 0.62 and 10.06 +/- 1.34 IU/L, respectively, to generally undetectable levels (< 1). Comparison with untreated control patients suggested that basal LH did not completely return to prepubertal levels, whereas FSH levels were suppressed below prepubertal levels. Estradiol, FSH, and LH levels reached their nadir by 2 months; in contrast, mean serum levels of insulin-like growth factor I progressively declined from +0.57 +/- 0.19 SD score to -0.06 +/- 0.22 SD score at 24 months. Two girls were withdrawn from the study because of reactions at injection sites, with apparent sterile abscess formation in one patient. This study provides evidence that (1) long-term treatment with depot leuprolide is characterized by immediate and sustained laboratory and clinical suppression, (2) GnRH-stimulated LH and random FSH and estradiol concentrations are useful laboratory measures of efficacy, and (3) the progressive increase in predicted adult height is temporally associated with decreased serum levels of insulin-like growth factor I and striking deceleration of bone age advancement.
Assuntos
Leuprolida/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Criança , Pré-Escolar , Preparações de Ação Retardada , Avaliação de Medicamentos , Feminino , Hormônio Foliculoestimulante/sangue , Hormônios Esteroides Gonadais/sangue , Crescimento/efeitos dos fármacos , Humanos , Injeções Intramusculares , Fator de Crescimento Insulin-Like I/análise , Leuprolida/administração & dosagem , Leuprolida/farmacologia , Hormônio Luteinizante/sangue , Masculino , Puberdade Precoce/sangue , Puberdade Precoce/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVE: We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents. METHODS: Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay. RESULTS: Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range. CONCLUSIONS: Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.
Assuntos
Hormônio Foliculoestimulante/sangue , Ensaio Imunorradiométrico/estatística & dados numéricos , Medições Luminescentes , Hormônio Luteinizante/sangue , Puberdade/sangue , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Fluorimunoensaio , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Ensaio Imunorradiométrico/métodos , Lactente , Recém-Nascido , Masculino , Puberdade/fisiologia , Puberdade Precoce/sangue , Puberdade Precoce/diagnóstico , Radioimunoensaio , Valores de Referência , Fatores SexuaisRESUMO
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.
Assuntos
Densidade Óssea/efeitos dos fármacos , Puberdade Precoce/tratamento farmacológico , Absorciometria de Fóton/instrumentação , Absorciometria de Fóton/métodos , Absorciometria de Fóton/estatística & dados numéricos , Determinação da Idade pelo Esqueleto , Criança , Pré-Escolar , Preparações de Ação Retardada , Feminino , Humanos , Leuprolida/administração & dosagem , Leuprolida/efeitos adversos , Estudos Longitudinais , Puberdade Precoce/fisiopatologia , Fatores de TempoRESUMO
Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.