GH secretion is regulated by hypothalamic somatostatin and GH-releasing factor. It has been postulated that GH feeds back on the hypothalamus and regulates its own secretion. We focused our attention on the action of GH in the hypothalamus in relation to GH secretion. Adult male rats were used throughout the studies, and the observation was made in conscious rats. Systemic administration of human GH induced c-fos gene expression, a marker of neuronal activity, in the hypothalamic arcuate nucleus (ARC) and the periventricular nucleus (PeV) in hypophysectomized male rats. The major cells in which c-fos gene expression was induced were neuropeptide Y (NPY) neurons in the ARC and somatostatin neurons in the PeV. GH receptor mRNA was demonstrated to be present in these neurons by in situ hybridization. The injection of a small dose of rat GH into the ARC or PeV inhibited GH secretion, whereas microinjection of IGF-I into these nuclei did not. Intracerebroventricular injection of NPY suppressed GH secretion, and this effect was abolished by anterolateral deafferentation of the medial basal hypothalamus (MBH), a procedure which disrupts the somatostatinergic input to the MBH. Taken together, these findings suggest that GH acts on NPY neurons in the ARC and somatostatin neurons in the PeV through GH receptor, and the activation of these neurons augments somatostatin release and inhibits GH secretion.

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GH binding to its receptor, which belongs to the cytokine receptor superfamily, activates Janus kinase (JAK) 2 tyrosine kinase, thereby activating a number of intracellular key proteins such as STAT (signal transducers and activators of transcription) proteins and mitogen-activated protein (MAP) kinases, which finally lead to GH's biological actions including gene expression. In contrast to receptor tyrosine kinases, the signalling pathways leading to MAP kinase activation by GH are poorly understood but appear to involve Grb2 and Shc. We now show that GH stimulated tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and its association with Grb2, and concomitantly stimulated MAP kinase activity in liver, a major target tissue. Expression of EGFR and its mutants into CHO-GH receptor (GHR) cells revealed that GH-induced full activation of MAP kinase and c-fos expression required tyrosine phosphorylation sites of EGFR but not its intrinsic tyrosine kinase activity. Moreover, by also using dominant negative JAK2 and in vitro kinase assay, we demonstrated that tyrosine 1068 of EGFR was evidently one of the major phosphorylation and Grb2 binding sites stimulated by GH via JAK2. These data suggest that the role of EGFR in GH signalling is to be phosphorylated by JAK2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression. This novel cross talk pathway may provide the first example of the hormone and cytokine receptor superfamily transducing signals via associated nonreceptor tyrosine kinase by phosphorylating growth factor receptor and utilizing it as a docking protein independent of its receptor tyrosine kinase activity.

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GH and its related peptide PRL are known to stimulate proliferation and insulin biosynthesis in pancreatic β-cells, and assumed to be involved in their functional maturation. We investigated signal transduction of GH and PRL in insulin-secreting cells using the differentiated rat insulinoma cell line, INS-1. In these cells, both hormones stimulated proliferation and DNA synthesis, increased viability, cellular metabolism and insulin content. GH induced cytosolic Ca²⁺ ([Ca²⁺]_i) rises, which appear to be due to Ca²⁺-influx through voltage-gated Ca²⁺-channels. GH also promoted tyrosine phosphorylation of several proteins in INS-1 cells, one of which was identified as JAK2 tyrosine kinase. Moreover, GH caused changes in DNA binding of nuclear proteins to some interferon-γ-activated sites. Verapamil inhibited neither DNA synthesis nor JAK2 phosphorylation stimulated by GH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect. Involvement of cAMP is also suggested because Rp-cAMPS, a competitive inhibitor of protein kinase A, abolished both [Ca²⁺]_i rises and DNA synthesis stimulated by GH. The effects of GH and PRL on [Ca²⁺]_i, JAK2 phosphorylation and DNA binding of the STATs were virtually identical in INS-1 cells. Since both hormones failed to activate MAP kinase in these cells, it is strongly suggested that activation of the JAK-STAT pathway is the major signalling event for the mitogenic effects of GH and PRL in β-cells. It remains to be clarified whether the [Ca²⁺]_i rise mediates other effects of these hormones.

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Recombinant human GH is now widely used for the treatment of short stature in diseases other than growth hormone deficiency. GH treatment increases bone mineral density in growth hormone deficiency, but a study using conventional method for the calculation of volumetric bone mineral density suggested that this effect was mainly due to the increase in bone size. A more accurate method for the evaluation of volumetric bone mineral density is needed. The effect of GH on mineral metabolism is another point of interest. GH administration induced dramatic changes in serum levels of mineral regulating hormones such as PTH and active vitamin D metabolites. These changes may provide us with new methods for the treatment of metabolic bone disorders.

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Serum insulin-like growth factor II (IGF-II) was characterized by radioimmunoassay and Western immunoblot in 44 patients with non-islet cell tumor hypoglycemia (NICTH). 31 of 44 patients with NICTH had big IGF-II in sera. When the presence of IGF-II in tumors from 20 patients was investigated, IGF-II in tumors was detected in 18 patients and these patients had big IGF-II in sera. In two patients whose tumors did not contain IGF-II, big IGF-II in sera was not detected. In six patients with IGF-II in tumors, hypoglycemia disappeared and the big IGF-II decreased after successful removal of the tumors. These data indicate that the big IGF-II could be related to hypoglycemia, and that the increased serum big IGF-II suggests IGF-II-producing NICTH. Serum IGF-II levels in 31 patients with big IGF-II were greater than those in 13 patients without it (Mean±SEM: 723±54 vs. 326±31ng/ml), but the elevated IGF-II levels were found in only 13 patients. Serum IGF-I levels were low in all patients with NICTH. In the 13 patients without big IGF-II, serum IGF-II levels were lower than those in the patients with big IGF-II, and serum IGF-I levels were also low. Serum IGF-II/IGF-I ratios in the patients with big IGF-II were elevated and greater than those in the patients without big IGF-II (35.0±2.2 vs. 11.5 ±2.4). The present data indicate that IGF-II-producing tumors are not rare in NICTH, and serum big IGF-II and IGF-II/IGF-I ratio are useful for screening patients with IGF-II-producing NICTH.

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To study the acute and long-term effect of GH on its down-stream axis, we measured serum GH-binding protein (GHBP) by ligand-mediated immunofunctional assay. Diurnal changes in serum GHBP were determined by every 20-min sampling for 24h in four normal short children. There weresmall or negligible fluctuations in serum GHBP levels, and no correlation with GH pulses was observed. The short-term effect of GH on GHBP levels was assessed in eight GH-deficient children by daily administration of GH (0.1U/kg) for 10 days. Serum GHBP levels did not significantly change, but IGF-I levels increased significantly. We also studied the long-term effect of GH administration on GHBP levels in seventeen patients with GH deficiency over six months. In twelve out of 17 patients, serum GHBP levels showed an increase when compared to the levels before treatment. In these patients, BMI was not largely changed during treatment, while it tended to decrease in patients whose GHBP levels did not increase. In conclusion, endogenous pulsatile GH secretion and short-term exogenous GH administration had no effect on serum GHBP levels. On the other hand, long-term GH administration increased GHBP levels in 70% of patients with GH deficiency. Changes in BMI may partly be attributed to this change. The direct long-term regulatory effect of GH on GHBP should be further studied.

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There is some evidence that insulin-like growth factors (IGFs) and/or IGF binding proteins (IGFBPs) (IGF-IGFBP axis) may be involved in glucose metabolism. The purpose of this study was to investigate the relationship between the IGF-IGFBP axis and diabetic control in subjects with insulindependent diabetes mellitus (IDDM). Thirty-nine subjects with IDDM without major complications (age: 5.8-30.3 years, 13 males and 26 females) participated in this study. In all subjects, the free form of IGF-I (free IGF-I), the total IGF-I (total IGF-I: free plus complexed form of IGF-I) and IGFBP-3 in serum or plasma were measured. The Z-scores of free ICE-I, total IGF-I, and IGFBP-3 were calculated. In 18 young adults with IDDM (age 18.0-30.3 years, 5 males and 13 females), IGFBP-1 in serum was also measured. In all subjects, the diabetic control parameters such as blood glucose (BS) (momentary control), 1, 5-anhydro-D-glucitol (1, 5 AG) (Ultrashort-term), fuructosamine (short term), and glycosylated hemoglobin (HbA1) (long-term) were measured. None of the Z scores for free IGF-I, total IGF-I or IGFBP-3 had a significant correlation with BS. In young adults, IGFBP-I was correlated with BS (r=0.57, P<0.005). None of the Z scores for free IGF-I, total IGF-I or IGFBP-3 had a significant correlation with 1, 5 AG, fructosamine or HbA1. In young adults, IGFBP-1 did not correlate with 1, 5 AG, fructosamine or HbA1. These data suggested that the IGF-IGFBP axis did not reflect diabetic control in subjects with IDDM under treatment.

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13, 707 longitudinal records of individuals (6, 749 boys and 6, 958 girls) from 6 years to 17 years were fitted by means of a smoothing cubic spline function and the factors influencing the change in height SDS during puberty were analysed. Children are divided into subgroups with 0.2 SD intervals according to height SDS at 6 years. Shorter children in subgroups at 6 years tend to increase their final height SDS by entering puberty later and making their height at onset of pubertal growth spurt (PGS) relatively taller. On the other hand taller children in subgroups at 6 years tend to decrease their final height SDS by entering puberty early and make height at PGS relatively shorter. The percentage distribution of a final height SDS against subgroups at 6 years also shows this tendency. This figure is useful in predicting the probability of final height SDS in the clinical field of growth disorders.

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An 8-yr-old boy with autoimmune chronic active hepatitis (AiCAH) was treated with steroid hormones. Liver function improved with this treatment, but the patient's growth was severely disturbed. At the age of 10y, GH treatment was added to the steroid therapy because of his short stature (height: -2.5SD), but in the following 12 months, he only grew 2cm. Oral administration of zinc (5mg/kg/day) was also added to the patient's therapy, but his height has not improved in the 12 months of this combined therapy.

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Thanatophoric dysplasia (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, relative macrocephaly, platyspondyly and reduced thoracic cavity. It has recently been reported that TD is caused by mutations in the FGFR3 gene. In the present study, we report a missense mutation in the FGFR3 gene in a Japanese patient with TD. The patient was noticed to have typical features of TD type 1(TD1) at birth. The genomic DNAs of the patient and his parents were isolated from whole blood. DNA fragments of the FGFR3 gene were amplified by polymerase chain reaction, and directly sequenced. The patient was revealed to be heterozygous for a missense mutation G370C, changing codon 370 (GGC) encoding Gly to TGC encoding Cys, but his parents did not have the G370C mutation. The G370C mutation introduces an unpaired cysteine residue in the extracellular domain of FGFR3, which may result in formation of an intermolecular disulfide bond between two mutant FGFR3 monomers and their constitutive activation. In conclusion, we have identified the G370C mutation in the FGFR3 gene in a Japanese TD1 patient.

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The clinical triad of Septo-optic dysplasia (SOD) comprises the absence of the septum pellucidum, congenital optic nerve dysplasia, and multiple endocrine defects. An incomplete form of SOD has been recognized, with two of the three elements. We present two cases of SOD in incomplete form.

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