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YUKIHIRO HASEGAWA, TOMONOBU HASEGAWA, MAKOTO ANZO, TAIJI ASO, YUTAKA T ...
1996 Volume 43 Issue Suppl Pages
S1-S4
Published: 1996
Released on J-STAGE: November 25, 2006
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ALAN D. ROGOL
1996 Volume 43 Issue Suppl Pages
S5-S11
Published: 1996
Released on J-STAGE: November 25, 2006
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At puberty there occur marked increases in gonadotropin, gonadal steroid and GH secretion. An important physiological synergism exists between the gonadal and somatotropic axes to permit the growth spurt and adolescent development; however, epiphyseal maturation is also accelerated leading to cessation of long-bone growth. GH deficiency may be absolute, but often is not and the diagnosis may be complicated by a constellation of physical and hormonal findings that are along a spectrum from low normal GH sufficiency to absent GH secretion. Growth hormone therapy not only accelerates the growth velocity, but also promotes the redistribution of adipose tissue stores to more peripheral sites. Given the remarkable physiological alterations in the activities of the GH and gonadotropin gonadal axes during adolescence in normal children, how should the therapeutic plan for the treatment of prepubertal GH deficiency be altered at puberty? Evidence for efficacy has been reported for each of the following for the treatment of GH deficiency at adolescence: 1) GH alone at the usual dosage (approximately 0.3mg•kg
-1•day
-1); 2) Double or triple the amount of GH to mimic the finding of increased GH release at puberty. 3) GH at the usual or moderately increased dose and gonadotropin releasing hormone agonist analog to halt pubertal development. The latter two plans are at present hypotheses that must withstand the rigor of proper controlled trials. The end point is more than merely adult height, because of the significant psychological and skeletal system dysregulation that accompany decrements in the gonadal steroid hormones during adolescence.
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TOSHIAKI TANAKA, MARI SATOH, ITSURO HIBI
1996 Volume 43 Issue Suppl Pages
S13-S17
Published: 1996
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It has been reported that the final height in short children is strongly related to the height at the onset of pubertal development, and pubertal heiht gain in GH-treated children is not exceed the gain in normal children. Therefore, it is now the consensus that insufficient height at the onset of puberty leads to short final height. We have already demonstrated that the final height in GH-deficient children with spontaneous puberty with gonadal suppression therapy by medroxyprogesterone or cyproterone acetate was significantly taller than GHD with spontaneous puberty without gonadal suppression therapy. In this study, we treated short boys who started puberty at height shorter than 130cm with combined GH and LHRH analog. Final height was predicted by the height SD score for bone age. Although pubertal growth spurt was not recognized in short children on combination treatment, bone age maturation over 11.5years decelerated significantly to the rate of one year in three or four years. Even during this slow bone maturation period, growth velocity remained at 4cm/year due to GH treatment. Therefore, height SDS for bone age was improved in combination with the elongation of treatment period by the slow bone maturation. Some investigators recommend not to delay induction if puberty much beyond the normal age to avoid psychological problems and ennuchoid proportion in these children. When we explained to our Japanese patients the chance of increasing the final height with gonadal suppression treatment and the risk of delaying the pubertal development, almost all children preferred taller final height to pubertal development and they did not experience much psychological trouble. The differences in social and cultural circumstances do, however, influence patients' preferences.
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KENJI FUJIEDA, KUNIHIKO HANEW, TAKEKI HIRANO, YUTAKA IGARASHI, YOSHIKA ...
1996 Volume 43 Issue Suppl Pages
S19-S25
Published: 1996
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Growth response to GH therapy in prepubertal patients with idiopathic GH deficiency (GHD) was analyzed in terms of the chronological age at the start of GH treatment and the GH secretory capacity, by using the large database provided by the International Cooperative Growth Study (ICGS) Japan. 1192 patients, aged from 3 to 10years were divided into three groups with the following maximum GH values in GH stimulation tests: Group A: both _??_5ng/m
l, group B: both 5-10ng/m
l, group C: one >10ng/m
l. Analysis of age-related growth response using with delta height SDS (Δ height SDS) as a response variable revealed that the group A patients responded better to GH, while there was no differences between the other groups. Simple and multiple regression anlysis showed that IGF-I and chronological age (CA) negatively correlated with growth response, and target height SDS- height SDS positively correlated. These three most important predictors accounted for 49% of the variation in the growth response in group A, whereas six variables such as CA, frequency of GH injection, % overweight, GH dose, target height - height SDS, and pretreatment height velocity SDS accounted for only 28% of those in groups of B and C. These results lead us to conclude that growth response to GH is related to the degree of GH impairment with its cut-off level of 5ng/m
l. From these findings it might be suggested that treatment regimen should be tailored to individual requirements according to the degree of GHD.
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YUTAKA TAKAHASHI, HIDESUKE KAJI, YASUHIKO OKIMURA, KATSUMI GOJI, HIROM ...
1996 Volume 43 Issue Suppl Pages
S27-S32
Published: 1996
Released on J-STAGE: November 25, 2006
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The molecular basis of biologically inactive GH remained unclear until recently. We have very recently reported a child with short stature and a mutant GH caused by a single missense mutation in the GH-1 gene, which itself cannot transduce the GH-signal to the cells but can blunt the action of wild-type GH by virtue of its greater affinity for the GH binding protein (GHBP)/GH receptor. Briefly the clinical features of the patient are: At the age of 4.9years his height was 81.7cm (-6.1 SD) and bone age was 2years. The patient's serum insulin-like growth factor-1(IGF-1) concentration was 34ng/m
l. The basal serum GH concentration ranged from 7.0 to 14.0ng/m
l and peak concentrations after insulin hypoglycemia, arginine and L-dopa were 38.0, 15.0 and 35.0ng/m
l, respectively. A heterozygous single base substitution was identified in the GH-1 gene of the proband, predicted to convert codon 77 from arginine to cysteine. Isoelectric focusing revealed the presence of an abnormal GH peak in addition to a normal GH peak. The affinity of expressed mutant GH to GHBP was approximately 6times higher than that of wild-type GH. The mutant GH not only failed to stimulate tyrosine phosphorylation by itself, but it also inhibited the activity of wild-type GH when added simultaneously even in a one tenth dose of wild-type GH. The child whom we reported is therefore the first case of short stature caused by mutant GH with an antagonistic effect.
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TAKASHI KADOWAKI, KAZUYUKI TOBE, RITSUKO HONDA-YAMAMOTO, HIROYUKI TAME ...
1996 Volume 43 Issue Suppl Pages
S33-S41
Published: 1996
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Insulin and insulin-like growth factor-1(IGF-1) are two structurally related hormones which produce similar biological activities such as metabolic and growth promoting actions. Their receptors, insulin and IGF-1 receptors, also share similarities in both structure and functions such as tyrosine- specific protein kinase. We identified insulin receptor substrate-1 (IRS-1) as a common substrate for insulin and IGF-1 receptor tyrosine kinases. We generated IRS-1 knockout mice and showed that IRS-1plays a physiological role in signal transduction and biological actions of insulin and IGF-1. We also identified pp190 (IRS-2) as an alternative substrate for IRS-1.
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CHERYL A. CONOVER
1996 Volume 43 Issue Suppl Pages
S43-S48
Published: 1996
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The insulin-like growth factors (IGFs) are potent anabolic agents, structurally related to insulin, that can influence growth processes in virtually every system of the body. Unlike insulin, these peptides associate with distinct binding proteins present in serum and other biological fluids as well as in medium conditioned by cultured cells. The IGFs are pleiotropic in activity and near ubiquitous in distribution, making the IGF binding proteins (IGFBPs) integral components of IGF physiology that define and coordinate IGF and insulin action at the level of the target cell. Thus, to fully understand and, ultimately, manipulate IGF-directed growth, it is critical to take into account the IGFBPs. Six distinct IGFBPs have been cloned and characterized, and they are postulated to serve specific, but as yet poorly defined, functional roles. Expression of these multiple IGFBP species is under developmental, hormonal, and nutritional control. In addition, IGFBPs can undergo a variety of posttranslational modifications that can have profound effects on IGFBP structure/function, and, hence, IGF action. The significance of IGFBP glycosylation, phosphorylation, proteolysis, and cell-membrane and extracellular matrix association as components of IGF physiology has only begun to be appreciated. In each case identified so far the modified IGFBP acts dramatically different from native or recombinant IGFBP in solution. In this presentation, I will briefly review the IGF/IGFBP system and use data from in vitro models to illustrate the potential power of posttranslational regulation of IGFBP in cellular response to IGFs.
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CHARLES T. ROBERTS
1996 Volume 43 Issue Suppl Pages
S49-S55
Published: 1996
Released on J-STAGE: November 25, 2006
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The insulin-like growth factors (IGFs) control many aspects of growth, development and differentiation, and aberrant IGF action is implicated in a number of pathological states. Most of the actions of both IGF-I and IGF-II are mediated by their activation of the IGF-I receptor, a transmembrane tyrosine kinase that is structurally and functionally related to the insulin receptor. Control of the IGF-I receptor number at the cell surface is an important level at which IGF action can be regulated. Cell- surface receptor number, in turn, is principally determined by the level of expression of the IGF-I receptor gene. An important transcriptional regulatory factor that appears to be responsible for controlling IGF-I receptor gene expression is the product of the WT1 Wilms tumor suppressor gene. This latter protein functions by binding to specific sequences in the IGF-I receptor promoter and repressing transcription. During normal renal development, increased expression of the WT1 gene leads to repression of IGF-I receptor gene expression, allowing differentiation of the metanephrogenic blastema into renal epithelium. Persistent receptor expression due to mutational loss of WT1 function may contribute to the etiology of Wilms tumor. Decreased WT1 expression and subsequent up- regulation of the IGF-I receptor has also been implicated in non-malignant proliferative disorders such as benign prostatic hyperplasia.
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KEN KYHO, ANTHONY J O'SULLIVAN, DAVID M HOFFMAN
1996 Volume 43 Issue Suppl Pages
S57-S63
Published: 1996
Released on J-STAGE: November 25, 2006
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GH continues to be produced after the cessation of childhood growth and is the most abundant pituitary hormone in the adult pituitary. There is strong evidence that GH continues to exert significant biological effects on body metabolism in adult humans. The actions of GH may be direct or indirectly mediated by IGF-1. The direct actions of GH impart major effects on glucose, lipid and sodium homeostasis. GH administration causes hyperinsulinaemia and impairs the ability of insulin tosuppress hepatic glucose production and to stimulate glucose uptake and oxidation. GH enhances fat utilisation by stimulating lipolysis and fat oxidation. The significance of these effects is reflected in the finding of increased adiposity in GH deficiency (GHD) and reduced fat mass in acromegaly. GH causes sodium retention which occurs in part through activation of the renin-angiotensin system. Extracellular water volume is diminished in GHD and increased in relation to the extent of GH excess in acromegaly. Lean body mass is reduced in GHD and restored by GH treatment. The anabolic actions of GH are mediated by IGF-1. Studies of whole body protein metabolism show that this occurs through the stimulation of protein synthesis, reduction in protein oxidation but not inhibition of protein breakdown. GH plays an important role in the regulation of substrate metabolism and body composition in man.
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CHRISTIN CARTER-SU, ANTHONY PJ KING, LAWRENCE S. ARGETSINGER, LISA S. ...
1996 Volume 43 Issue Suppl Pages
S65-S70
Published: 1996
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GH has long been known as a regulator of body growth and metabolism, yet its mechanism of action at the cellular level has been elusive. We have recently shown that GH promotes the rapid association of GH receptor with the tyrosine kinase JAK2, activates JAK2, and promotes the tyrosyl phosphorylation of both JAK2 and GH receptor. This suggests that the initial signalling event in GH action is the activation of JAK2 which in turn phosphorylates tyrosines within JAK2 and GH receptor. We have identified a number of proteins that appear to bind to these phosphotyrosines in GH receptor/ JAK2 complexes. These proteins in turn become phosphorylated on tyrosines, resulting in their activation. These proteins include: 1) the signal transducers and activators of transcriptions (Stats) 1, 3 and 5 which have been implicated as regulators of transcription of a variety of genes; 2) the insulin receptor substrates (IRS) 1 and 2, which are believed to mediate some of the metabolic effects of GH; and 3) Shc proteins which lie upstream of Ras and the mitogen activator kinases (MAP) designated ERKs 1 and 2, proteins implicated in the regulation of cellular growth and/or differentiation. These various proteins work in concert with each other and with other signalling molecules to elicit the diverse effects of GH. Other hormones and growth factors also activate JAK kinases. Specificity in signalling was investigated by determining whether signalling pathways for particular ligands may be selectively inhibited by hormones or growth factors. Glucocorticoids were found to selectively decrease binding and cellular signalling in response to GH. This decrease appeared to be due to a decrease in the number of GH receptors in the plasma membrane. Using truncated and mutated GHR, two regions of the GH receptor were identified required for the inhibitory effect of glucocorticoids. Interestingly, they appeared to differ from the region required for GH-induced internalization. Hence, a large amount of insight into signalling by GH has been obtained during the 3years since JAK2 was identified as a signalling molecule for GH and other ligands that bind to members of the cytokine receptor family. This new insight, and the insight that will continue to be gained in the next few years should enable the design of new and better therapeutic uses of GH and the other ligands that bind to JAK kinase-linked receptors.
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Correlation with IGF-I and IGF Binding Protein-3
AKIRA SHIMATSU, YOSHIO NAKAMURA, CHIHIRO IHARA, HARUO MIZUTA, HIROYUKI ...
1996 Volume 43 Issue Suppl Pages
S71-S73
Published: 1996
Released on J-STAGE: November 25, 2006
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TOMONOBU HASEGAWA, YUKIHIRO HASEGAWA, MAKOTO TAKADA, YUTAKA TSUCHIYA, ...
1996 Volume 43 Issue Suppl Pages
S75-S76
Published: 1996
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HIROYUKI YAMAMOTO, LIAM J. MURPHY, YUZURU KATO
1996 Volume 43 Issue Suppl Pages
S77-S80
Published: 1996
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KUNIHIKO HANEW, AKI TANAKA, AKIRA SUGAWARA, KEIICHI ITOI, KEISHI ABE
1996 Volume 43 Issue Suppl Pages
S81-S83
Published: 1996
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MOTOAKI SHIRATSUCHI, TAIICHIRO OKAJIMA, KAORU INOUE, TOMOKO TAKAHASHI, ...
1996 Volume 43 Issue Suppl Pages
S85-S87
Published: 1996
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LIU YAN-JUN, TOSHIO TSUSHIMA, NORITAKA ONODA, SATOMI MINEI, MAYUMI SAN ...
1996 Volume 43 Issue Suppl Pages
S89-S91
Published: 1996
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TOMOKO MATSUMOTO, SHUNICHI YAMASHITA, R.G. ROSENFELD
1996 Volume 43 Issue Suppl Pages
S93-S95
Published: 1996
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OSAMU ISOZAKI, TOSHIO TSUSHIMA, EIJI OHMURA, NORITAKA ONODA, HIROSHI D ...
1996 Volume 43 Issue Suppl Pages
S97-S98
Published: 1996
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AKIHIRO IKEDA, KYU-TAE CHANG, TAKAHIRO NAKANO, SHIGEMI MATSUYAMA, MASU ...
1996 Volume 43 Issue Suppl Pages
S99-S101
Published: 1996
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MICHITOSHI SEKINE, HTTOSHI SEKI, YOUICHI HARA, HIROSHI NOGUCHI
1996 Volume 43 Issue Suppl Pages
S103-S105
Published: 1996
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TAKASHI IIZUKA, YOSHIHIKO KURAMOTO, MASAO OMURA, TETSUO NISHIKAWA
1996 Volume 43 Issue Suppl Pages
S107-S110
Published: 1996
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YOH MIYASHITA, SYOICHIRO HASHIGUCHI, MITUYA TOTUKA, YOSHIAKI ITOH, JIN ...
1996 Volume 43 Issue Suppl Pages
S111-S113
Published: 1996
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TOMOYO OHYAMA, MAKOTO SATO, YOSHINARU WADA, JIRO TAKAHARA
1996 Volume 43 Issue Suppl Pages
S115-S117
Published: 1996
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TAKAHIKO FUJIKAWA, HIDEO YOSHIZATO, HIDEAKI SOYA, KUNIO NAKASHIMA
1996 Volume 43 Issue Suppl Pages
S119-S122
Published: 1996
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NOBUHIRO MIKI, MASAMI ONO, YOJI MURATA, HIROSHI DEMURA
1996 Volume 43 Issue Suppl Pages
S123-S125
Published: 1996
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TAKASHI SAKURAI, SOICHI KODAMA, RIE URATA, MIKIO KOMATSU
1996 Volume 43 Issue Suppl Pages
S127-S128
Published: 1996
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Growth Hormone (GH) Therapy and the Size of Syrinx on Serial MR Images
SATOSHI TAKAKUWA, AKWA ASAI, NOBORU IGARASHI
1996 Volume 43 Issue Suppl Pages
S129-S130
Published: 1996
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JUNTA TAKAMATSU, MITSURU ITO, YURIKO YAMANO, TOSHITSUGU FUKAO, SADAKI ...
1996 Volume 43 Issue Suppl Pages
S131-S133
Published: 1996
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TOSHIAKI TANAKA, KAZUE TAKANO, KUNIHIKO HANEW, YOSHIKAZU NISHI, KENJI ...
1996 Volume 43 Issue Suppl Pages
S135-S136
Published: 1996
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SATOSHI MATSUO, YOKO TOKUNAGA, ZENRO KIZAKI, FUMIO INOUE, AKIHIKO KINU ...
1996 Volume 43 Issue Suppl Pages
S137-S139
Published: 1996
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JUNKO ENOMOTO, YOSHIO MURAKAMI, KUNIO KOSHIMURA, YUZURU KATO
1996 Volume 43 Issue Suppl Pages
S141-S143
Published: 1996
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YUKO NAKAYAMA, OSAMU ARISAKA, ATSUTO HOSAKA, SACHI FUJIWARA, KEIJIRO Y ...
1996 Volume 43 Issue Suppl Pages
S145-S146
Published: 1996
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