To know the effect of the age factor on growth response to growth hormone (GH) therapy in patients less than three years of age with complete idiopathic growth hormone deficiency (GHD). One hundred thirty-seven prepubertal children with complete idiopathic GHD from the database of the International Growth Cooperative Study (ICGS) of Japan for more than two years were analyzed. The patients were divided into four groups according to age at the start of GH therapy; group 1, _??_three years, group 2, three to _??_six years, group 3, six to _??_nine years, group 4, >nine years. In group 1 the mean birth weight SDS of -0.17 was not the lowest. Patients in group 1 had the lowest HSDS (-4.53) at the start of the therapy (P<0.01). During two years of the treatment, the mean HSDS improved from -4.53 to -2.15 with an increase in mean SD score of 2.12 in group 1, but in group 4 it was only 0.92 (P<0.01). In group 1, the mean HSDS declined from -0.17 at birth to -4.53 progressively. Delta height SDS during the first year of treatment in Group 1 was 1.59 SD, which is the highest. The decrease in%overweight during the first year showed that in group 1, the reduction in adiposity was the greatest among the groups (P<0.05). Our data showed that in children with complete GHD less than three years of age, there was severe growth failure, and the onset was not in the prenatal period, but in the postnatal period. Early detection of GHD and therapy with GH is important because normalization of height may be achieved earlier than in older age groups.

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Ras is a low molecular weight (Mr 21, 000) GTP binding protein that plays an essential role in cell proliferation and differentiation. Mutations that result in constitutive activation of Ras are associated with several types of neoplastic tissue in mammals and expression of these alleles into cultured fibroblasts results in cellular transformation. Opposing the Ras activation pathway, the low molecular GTP binding protein Rap was originally observed to revert or suppress the transformed phenotype in Ki-Ras-transformed fibroblasts. This apparent antagonism between Ras and Rap function may reflect the ability of Rap and Ras to interact with the same downstream effectors, since these proteins share identical sequences within their respective effector domains. Although the precise molecular details remained to be established, there is a substantial similarity in the upstream signaling mechanisms that regulate both Ras and Rap activation. Ras GTP binding is stimulated upon the targeting of the Ras guanylnucleotide exchange factor SOS to the plasma membrane location of Ras. The carboxyl terminal domain of SOS contains a proline-rich regions that directs its association with the SH3 domains of the small adapter protein, Grb2. Similarly, the formation of active GTP-bound Rap results from the specific interaction with the Rap guanylnucleotide exchange factor C3G which specifically associates with the central SH3 domain of the small adapter protein, CrkII. Thus, efficient regulation of receptor tyrosine kinase downstream signaling events require the coordinate interplay of these two pathways.

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In order to identify the mutual interaction between GH and leptin, we studied the effect of GH on fatty Zucker rats. GH administration at a high dose (5.0IU/kg) reduced % body fat after 7 days. The leptin mRNA level in subcutaneous fat tissue was not changed but that in epididymal fat tissue was decreased by an even lower dose of GH (1.5IU/kg). IGF-I treatment (200μg/kg/day) did not change the % body fat or leptin mRNA level. These observations suggest that GH directly interacts with visceral fat and reduces fat mass and leptin expression. We also measured serum leptin levels in patients. The levels in patients with acromegaly were significantly lower than those in normal subjects with the same amount of body fat, but serum IGF-I and urinary C peptide excretion rates were higher in the acromegalic. These observations also suggests that GH directly interacts with adipose tissue and reduces leptin expression. Next we investigated the direct action of leptin on GH release from the pituitary. Leptin pretreatment of pituitary cells in culture or rats in a fasted or fed condition did not change GRH induced GH secretion. As indicated also by other recent studies, leptin may increase GRH or decrease somatostatin secretion by the hypothalamus. Thus GH interacts with fat tissues and leptin may be a good marker of the interaction.

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Distinct from other growth factor receptors, insulin and insulin-like growth factor-I (IGF-I) receptors phosphorylate endogenous substrates on tyrosine residues which in turn associate with the SH2 domain-containing proteins transducing signals to downstream pathways. Among the cellular substrates of insulin and IGF-I receptors, insulin receptor substrate (IRS)-1 has been shown to play an important role in mediating the actions of these hormones. Recently, several proteins with similar structures and different tissue distributions were cloned as IRS-2, -3 and -4. To study the roles of these IRSs in mediating insulin actions, we analyzed liver, muscle and adipocytes, the major targets of insulin actions, from IRS-1 null mice which we previously generated, and showed that: 1) insulin-stimulated activation of PI 3-kinase, mitogen-activated protein kinase and glucose transport were impaired in muscles from IRS-1 null mice which was in contrast to the grossly normal signaling and actions in livers from these mice; 2) the difference in the degree of insulin resistance in these two major insulin targets appeared to depend on the amount of tyrosine phosphorylation of IRS-2 compensating for IRS-1 deficiency; 3) insulin-induced activation of PI 3-kinase, glucose transport and GLUT4 translocation were impaired but not abolished in adipocytes from these mice in which IRS-3 was the major tyrosine- phosphorylated protein activating PI 3-kinase and at least partially mediating some residual insulin actions in the absence of IRS-1. These data suggest that the members of the IRS family redundantly regulate insulin actions in each target organ in a distinct fashion.

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Objective: It is important for GH-deficient children to treat abnormal body composition associated with a metabolic consequence, not only short stature. In this study we evaluated long-term effects of GH therapy on body composition in GH-deficient boys and girls. Subjects and Methods: Fortynine subjects with GH deficiency, 35 boys and 14 girls, 6 to 14 years of age, were studied. All the subjects were treated for three years with recombinant human GH at a weekly dosage of 0.5IU/kg by subcutaneous daily injection. Body composition was measured by bioelectrical impedance analysis (BIA 101), Spectrum II 287, RJL Systems, Detroit, Mich. Results: Body fat (%) decreased significantly during the first three months of GH treatment. These values were maintained low thereafter in boys, in contrast to those which continued to tend upward in girls from the second year of the treatment. Lean body mass (kg) increased significantly with increasing extracellular water (kg) and body cell mass (kg) in both sexes during GH treatment. Conclusion: Our data demonstrate that GH can reduce body fat mass in GH-deficient boys and girls. The gender difference in changes in body fat with age during the course of this study is compatible with that observed in normal children. The rapid increase in extracellular water and the gradual increase in body cell mass both contributed to the steady increase in LBM during GH treatment.

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We describe two short boys with normal GH responses to the stimuli in whom GH therapy was interrupted for 6 months. Their growth rates before and after the interruption, and after readministration of GH were evaluated. Height velocity (HV) in case 1 before and after the interruption was 6.6cm/y and 5.0cm/y, respectively. HV was not increased (5.0cm/y) by re-initiation of GH therapy despite the high serum IGF-1 level. Height velocity (HV) in case 2 before and after the interruption was 5.6cm/y and 3.6cm/y, respectively. HV was slightly increased to 4.1cm/y by readministration of GH, but it was far below the pretreatment value. Serum IGF-1 was increased by GH in this case as well. We conclude that re-acceleration of growth by re-administration of GH after interruption of therapy, as seen in classical GHD patients, may not be expected in normal short children.

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Recent studies revealed favorable para- and/or autocrine effects of IGF-1 in the pathogenesis 'of diabetic complications. On the other hand, hyperglycemia is a risk factor for the development of 'diabetic vascular complications. In this study we examined the effects of high glucose and/or IGF-1 on 'cell migration and angiogenesis (tubular formation) by using human endothelial cells (EC) in vitro. First 'we examined cell migration by the two-chamber method. Chronic treatment with a high concentration 'of D-glucose strongly stimulated the cell migration, which was mimicked by PMA, a protein kinase C (PKC) agonist. The cell migration was also induced by IGF-1. The glucose-induced cell migration was
blocked by PKC inhibitor, H7. IGF-1-induced cell migration was not blocked by PD98059, MAPK/ERK
kinase (MEK) inhibitor or wortmannin, a phosphatidylinositol (PI) 3-kinase inhibitor. Next we
examined the effects of high glucose and/or IGF-1 on the tubular formation of EC. The tubular
formation was induced only when the cells were exposed to a combination of high glucose and IGF-1.
The tubular formation was blocked by MEK inhibitor and PI 3-kinase inhibitor but not by PKC inhibitor.
These results indicate that hyperglycemia and IGF-1, respectively, stimulate the EC migration, and
tubular formation is induced by a combination of IGF-1 and hyperglycemia.

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Bioactivity of Insulin-like growth factors (IGEs) are positively or negatively regulated by IGF binding proteins (IGFBPs). Like IGFs, production of IGFBPs are influenced by a number of hormonal factors. We studied the effects of cytokines on production of IGFBPs in human fibroblasts in culture. Both IL-1β and TNF-α inhibited IGFBP-3 (42/38KDa species) production in a concentration dependent manner judged by Western ligand blot. Expression of IGFBP-3 mRNA was also decreased by these cytokines. Moreover, the treatment with IL-1β and TNF-α resulted in appearance of smaller mol weight (26KDa) immunoreactive IGFBP-3 fragment(s) which lacked the ability to bind ¹²⁵I-IGFs, indicating that these cytokines degrade IGFBP-3 via activation of proteases. Both IL-1β and TNF-α decreased production of IGFBP-4, whereas they increased that of IGFBP-6, IL-6 had little effect on production of IGFBPs. Likewise, interferon-γ failed to affect of production of IGFBPs except at high concentrations. The present data demonstrate that cytokines, especially IL-1β and TNF-α are potent regulators of IGFBPs production and degradation. These cytokines may alter tissue uptake of IGFs and help to counteract the catabolic state induced by them.

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High GH and low IGF-I are well known in IDDM patients. To delineate this altered GH-IGF-I axis in IDDM, we investigate the role of GH-binding protein (GHBP) in relation to the metabolic and nutritional states. Materials and Methods: Forty seven patients with IDDM, mean 13.7 years, were evaluated. Blood samples were obtained before insulin injection and breakfast to test for plasma glucose (PG), IGF-I, IGFBP-1, IGFBP-3, total and complex GHBP (tGHBP and cGHBP), and HbA_1C. Urine samples were collected in the morning for urinary GH (uGH). The difference between tGHBP and cGHBP is defined as fGHBP. The levels of PG and HbA_1C were not correlated with each level of tGHBP, cGHBP, fGHBP or uGH. The levels of tGHBP, cGHBP and fGHBP were not all correlated with uGH. Both the levels of IGF-I and body mass index (BMI) were positively correlated with (GHBP). The duration of IDDM was negatively correlated with tGHBP, cGHBP and fGHBP. Discussion: As the previous report of the relationship between GH binding reserve to GHBP and IGF-I or BMI in non-diabetic subjects, fGHBP again showed statistical links with these parameters in IDDM. We therefore suggest that GHBP, especially its free form, may reflect a malmetabolic state of IDDM liver, resulting in an altered GH-IGF-I axis.

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The “Tanner-Whitehouse 2” method is the most popular in evaluating skeletal maturation, but this method has some inherent weak points. We therefore developed the new system to automatically evaluate the skeletal maturation of Japanese children by means of a personal computer. The subjects of this study were 318 healthy Japanese boys and 199 girls ranging from 2 to 15 years of age. The bone age was calculated by multiple regression analysis with parameters for the epiphysis and metaphysis. Successful automatic evaluation was about 80-90% on each phalanx. There was a significant correlation between chronological age and the ratio of epiphyseal width to metaphyseal width. The system developed in this study was useful for evaluating the skeletal maturation.

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The present study has compared body height and weight of thyrotoxic female patients of childhood onset and adult onset. The body height of 141 out of 143 (99%) adult-onset thyrotoxic patients was within the range of mean±2SD for the age-matched general Japanese female population. On the other hand, in 42 patients with childhood-onset thyrotoxicosis, 6 (14%) had their height being greater than the mean+2SD of general population, and 34 (81%) were taller than the mean value. In 86 patients with siblings, 42 (49%) were at least 2cm taller than their sisters, and 26 (30%) were more than 2cm shorter than their sisters. The body weight of 27 out of 42 (68%) patients younger than 20 years was not decreased but was even greater than the mean value for the age-matched general population. The results indicate that excessive thyroid hormone in vivo enhances body height in humans. The increased body weight in some young patients suggests that enhanced dietary intake due to increased appetite in hyperthyroidism has overcome the energy loss with increased metabolism.

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We report an 11-year-old girl with growth failure caused by long-term administration of 13-cis-retinoic acid after bone marrow transplantation for neuroblastoma. Her growth velocity was 1-2 cm/year after 13-cis-retinoic acid administration. Her endocrinological findings were normal except for peak growth hormone levels of 6.4ng/ml (clonidine) and 9.7ng/ml (arginine). IGF-1 and IGFBP-3 were normal. It is not possible to conclude that her severe growth failure was caused by partial growth hormone deficiency, but premature epiphyseal closure was seen on radiographic examination. We concluded that the growth failure was caused by pediatric cancer therapy for the musculoskeletal system but not by endocrinological disturbance.

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