Classification of growth hormone insensitivity syndrome.
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Antibodies↗
Biomedical subjects
Z Laron
Publications and source records attributed to Z Laron.
Disorders of growth hormone resistance in childhood.
This review describes the recent developments in the diagnosis and treatment of states of resistance to growth hormone based mainly on the studies performed on patients with an inborn molecular defect of the growth hormone receptor, ie, Laron syndrome. Use of the polymerase chain reaction technique has facilitated the study of the defect, which in the large majority of patients resides in the extracellular domain of the growth hormone receptor. This recessively transmitted hereditary disease, characterized clinically by dwarfism and obesity and biochemically by high levels of serum human growth hormone accompanied by low serum concentrations of insulin-like growth factor I, is diagnosed mainly in inbred societies of Asian Jews, Arabs, Iranians, Italians, and Spaniards or their descendants. Isolated mutations have been found in many countries all around the world. The recent biosynthesis of insulin-like growth factor I has enabled the successful treatment of these patients, accelerating their growth, reducing their obesity, and normalizing their metabolic abnormalities resultant from the insulin-like growth factor I deficiency. The Pygmies are an inbred population in Africa, Asia, and Oceania who seemingly also have a defect in the growth hormone receptor. Acquired states of growth hormone resistance are also discussed.
Drug Resistance↗
Modulation of IGF-I receptors by exogenous hGH treatment in constitutionally short children.
OBJECTIVE: To study the in-vivo regulation of IGF-I binding sites on erythrocytes (RBC) following administration of growth hormone (hGH) to constitutionally short children. Recently, owing to biosynthetic techniques, treatment with hGH has been administered not only to children with GH deficiency but also to children with constitutional growth delay and with familial short stature. PATIENTS AND DESIGN: Growth hormone (rhGH-Norditropin, Novo/Nordisk) was administered at a dose of 0.1 U/kg/day s.c. to 11 children with constitutional short stature. Before and at 1-2 months after initiation of treatment IGF-I binding sites and serum IGF-I were determined. Erythrocytes were separated from whole blood by centrifugation over Ficoll Hypaque and used to assess IGF-I binding sites. RESULTS: Serum IGF-I levels increased from 14.93 +/- 1.50 nmol/l (mean +/- SEM) to 30.29 +/- 2.32 nmol/l, with a mean difference of 15.36 +/- 2.21 (P = 0.00001). Concomitantly, the number of binding sites per cell decreased from 5.77 +/- 0.81 sites per cell (m +/- SEM) to 2.10 +/- 0.36, with a mean difference of -3.67 +/- 0.76 (P = 0.0003). The dissociation constant (Kd) also decreased from 0.47 +/- 0.16 nM (m +/- SEM) to 0.10 +/- 0.02 with a mean difference of -0.37 +/- 0.16 (P = 0.02), indicating an increase in the affinity of the receptors. CONCLUSION: Treatment of children with constitutional short stature with hGH raises the circulating IGF-I levels and down-regulates the IGF-I receptors. This study shows that IGF-I is capable of regulating its homologous receptor concentrations in vivo and it is suggested that the measurement of IGF-I binding sites on RBC may be used for the diagnosis of subtle states of resistance to IGF-I.
Child↗
Growth curves for Laron syndrome.
Growth curves for children with Laron syndrome were constructed on the basis of repeated measurements made throughout infancy, childhood, and puberty in 24 (10 boys, 14 girls) of the 41 patients with this syndrome investigated in our clinic. Growth retardation was already noted at birth, the birth length ranging from 42 to 46 cm in the 12/20 available measurements. The postnatal growth curves deviated sharply from the normal from infancy on. Both sexes showed no clear pubertal spurt. Girls completed their growth between the age of 16-19 years to a final mean (SD) height of 119 (8.5) cm whereas the boys continued growing beyond the age of 20 years, achieving a final height of 124 (8.5) cm. At all ages the upper to lower body segment ratio was more than 2 SD above the normal mean. These growth curves constitute a model not only for primary, hereditary insulin-like growth factor-I (IGF-I) deficiency (Laron syndrome) but also for untreated secondary IGF-I deficiencies such as growth hormone gene deletion and idiopathic congenital isolated growth hormone deficiency. They should also be useful in the follow up of children with Laron syndrome treated with biosynthetic recombinant IGF-I.
Age Factors↗
Body fat in Laron syndrome patients: effect of insulin-like growth factor I treatment.
Changes in body fat mass were studied in 25 untreated patients with Laron syndrome from childhood into adulthood. It was found that these patients, characterized by marked dwarfism, high plasma hGH and low serum insulin-like growth factor I (IGF-I), develop progressive and marked obesity and have a tendency for elevated serum cholesterol levels. Long-term treatment of 8 children and 5 adults with this syndrome with IGF-I (50-150 micrograms/kg/day s.c.) resulted in a significant decrease in subcutaneous fat in all patients and a lowering of the serum cholesterol and triglycerides, mainly in the adults. As in Laron syndrome the GH receptors are inactive, it is hypothesized that IGF-I exerts a direct effect on adipose tissue metabolism.
Adipose Tissue↗
Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats.
In the adult rat, expression of the liver GH receptor, insulin-like growth factor-I (IGF-I), and IGF-I-binding protein-3 (IGFBP-3) genes has been shown to be under GH control. Additionally, hypophysectomy and GH treatment have a differential effect on the relative abundance of liver IGF-I mRNA variants in adult rats. To further elucidate the time of appearance and the extent of GH control of liver GH receptor, IGF-I, and IGFBP-3 gene expression, we studied the effect of hypophysectomy and GH and IGF-I treatment in juvenile rats. Male Wistar rats were hypophysectomized (Hx) on postnatal day 26 and received twice daily sc injections of saline, recombinant human GH (2.5 U/kg.day), or recombinant human IGF-I (500 micrograms/kg.day) for 7 days. Sham-operated rats received the same treatment. Hx animals also received T4 (20 micrograms/kg.day). In Hx animals, there was a significant reduction in body weight (69.8 +/- 6.6 vs. 100.4 +/- 5.4 g; P < 0.001). GH, but not IGF-I, treatment increased body weight (79.6 +/- 9.6 g after GH vs. 69.8 +/- 6.6 g before GH; P < 0.05). GH treatment partially maintained liver, kidney, and lung weights in Hx animals and increased them in intact animals, whereas IGF-I treatment did so only in the lungs of intact and Hx animals. Serum GH and IGF-I levels were markedly reduced in Hx animals compared with those in intact controls, and GH treatment maintained, albeit partially, circulating IGF-I levels compared with those in saline-treated Hx animals. IGF-I mRNA levels were markedly reduced in Hx liver (25.0 +/- 5.4%; P < 0.001 compared with intact controls). GH treatment for 7 days increased IGF-I mRNA levels by 4.8-fold over the levels in 9-day Hx animals and increased IGF-I mRNA levels by 2.2-fold in control rats. Hypophysectomy decreased exon 2-containing transcripts by 7.0-fold and exon 1-containing transcripts by 4.1-fold. GH treatment, however, affected both exon 1- and exon 2-containing transcripts similarly. Hepatic IGFBP-3 mRNA levels were reduced in Hx (53.2 +/- 1.8%; P < 0.01 compared with intact controls) and IGF-treated Hx animals, but were not decreased in Hx GH-treated animals (100.6 +/- 9.5). No changes in GH receptor or GH-binding protein mRNA levels were caused by Hx, GH, or IGF-I treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Characterization of a noncontiguous gene deletion of the growth hormone receptor in Laron's syndrome.
Noncontiguous deletion of the GH receptor (GHR) gene has been described as a molecular defect causing Laron's syndrome (LS). The abnormal allele (GHR Del-3,5,6) lacks exons 3, 5, and 6. Exon 4 is retained on variant-sized restriction fragments. We studied DNA from 10 additional LS subjects of Jewish-oriental origin and found this allele in 3 samples. All subjects with this complex deletion allele were from Iran or Iraq and were not clinically distinguishable from other individuals with LS. Multiple restriction enzyme digests and Southern blotting with GHR exon 4-specific probes demonstrated that the allele retains genomic material for at least 9.8 kilobases 5' and 1.8 kilobases 3' to exon 4. Reverse transcription of mRNA, polymerase chain reaction amplification, and cDNA sequencing showed that exon 4 is syntenic and colinear with the other GHR exons. Normal splice sites were used, but the predicted protein was severely truncated due to a frameshift and a premature stop codon in exon 7. The premature stop codon terminated the protein after amino acid 53 and led to loss of the transmembrane and intracellular portions of the receptor. This mutant GHR gene results clinically in severe GH insensitivity.
Alleles↗
Long-term treatment of Laron type dwarfs with insulin-like growth factor-1 increases serum insulin-like growth factor-binding protein-3 in the absence of growth hormone activity.
Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-I) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-I may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.
Adolescent↗
Growth hormone-releasing activity of growth hormone-releasing peptide-1 (a synthetic heptapeptide) in children and adolescents.
The heptapeptide growth hormone-releasing peptide-1 (GHRP-1), one of a series of recently synthesized small growth hormone (GH)-releasing peptides, was administered as an iv bolus (1 microgram/kg) to 15 (six prepubertal, nine pubertal) short but healthy children and adolescents and to eight juvenile patients with pituitary insufficiency (four with isolated growth hormone deficiency, two with multiple pituitary hormone deficiencies, one with partial GH deficiency and one with GH-releasing hormone (GHRH) deficiency). Eleven out of 23 subjects also underwent an in GHRH (1-29) test (1 microgram/kg). All the healthy children responded with a progressive rise in plasma human GH (hGH) peaking at 15-30 min, with a significantly higher rise (p < 0.05) in the pubertal than prepubertal group. The hGH response to GHRH (1-29) in these children was similar or slightly higher. Six hypopituitary patients had no response to either GHRP-1 or GHRH; the patient with partial GH deficiency had a hGH peak of 6.5 micrograms/l (at 5 min) to GHRP-1 and 9.2 micrograms/l (at 15 min) to GHRH. One patient had no response of hGH to hypoglycemia, clonidine and GHRP-1, but the plasma hGH rose to 10 micrograms/l after GHRH. Following the GHRP-1 bolus there was a significant (p < 0.01) rise in plasma free thyroxine and a decrease of thyrotropin (p < 0.01), both in the limits of normal values. There was also a transitory rise of plasma cortisol (p < 0.05). Plasma prolactin, luteinizing hormone and follicle-stimulating hormone did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels.
We have analysed the expression of the IGF-I receptor gene in lymphocytes of patients with low levels of circulating IGF-I (four patients with isolated GH deficiency (IGHD) and one Laron-type dwarf (LTD)) in comparison with a control group exhibiting normal serum IGF-I levels and endocrine profiles. 125I-Labelled IGF-I binding assays were performed on erythrocytes to determine the number of IGF-I binding sites per cell and their dissociation constants. Erythrocytes from patients with IGHD or LTD contained significantly (P = 0.002) more receptors per cell (10.9 +/- 3.1 binding sites/cell), with a reduced affinity (Kd = 0.49 +/- 0.05 nM), than erythrocytes from controls (2.0 +/- 0.4 sites/cell; Kd = 0.14 nM). The levels of IGF-I receptor mRNA in circulating lymphocytes were determined by an RNA template-specific reverse transcription/polymerase chain reaction method. There was a statistically significant increase in IGF-I receptor mRNA levels in lymphocytes from patients with LTD or IGHD when compared with controls (3108.1 +/- 775.9 vs 576.0 +/- 465.7 arbitrary units, P = 0.006). The increased level of IGF-I binding due to increased IGF-I receptor gene expression may represent a compensatory up-regulation process activated in response to the low levels of IGF-I in the circulation of patients with LTD or IGHD.
Base Sequence↗
The early postnatal development of the murine mandibular condyle is regulated by endogenous insulin-like growth factor-I.
Skeletal growth during the early postnatal period is thought to be GH-independent, and is probably regulated by intrinsic growth factors. We studied the involvement of locally produced insulin like growth factor-I (IGF-I) in the growth of the neonatal mandibular condyle. Immunofluorescence studies revealed intense staining with antibodies to IGF-I in the mandibular condyle of 2-day-old ICR mice. We have also shown that these mandibular condyles contain specific high-affinity binding sites (Kd = 0.157 nmol/l) for IGF-I (427 fmol/mg). Autoradiographical studies of iodinated IGF-I revealed that the distribution of the receptors for IGF-I was parallel to that of IGF-I production, mainly in the younger zones of the condyle, namely the chondroprogenitor and the chondroblast cell layers. Immunoinhibition of IGF-I resulted in an almost complete inhibition (-91%) of thymidine incorporation into DNA, as well as in marked degenerative changes in the morphological appearance of the condyle. Our studies support the hypothesis that early postnatal growth is dependent on the paracrine activity of endogenous GH-independent IGF-I.
Animals↗
Somatomedin-1 (insulin-like growth factor-I) in clinical use. Facts and potential.
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Diabetes Mellitus↗
Laron syndrome due to a post-receptor defect: response to IGF-I treatment.
Three siblings with Laron syndrome (LS) and normal serum growth hormone binding protein (GHBP) are described. Basal serum levels of hGH were high and IGF-1 low, and in contradistinction to the classical form of the disease serum GHBP and IGFBP-3 were normal in these patients. After 7 days of human growth hormone administration serum IGFBP-3 levels as well as the number of red blood cell IGF receptor sites increased. After short- and long-term IGF-1 administration the IGF-1 receptor binding capacity as well as the number of IGF receptor sites decreased to levels found in control subjects. One year treatment with IGF-1 increased the growth velocity by 47-96% in the two older children. It is concluded that the findings described are compatible with a normal GH receptor and normal signal transmission for IGFBP-3 synthesis but a defect exists in the post-GH receptor mechanism for the generation of IGF-1. This is the first description of this type of defect leading to a variant of Laron syndrome.
Adult↗
Growth hormone response to TRH in families multiply affected with schizophrenia.
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Adult↗
Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism.
Patients with Laron-type dwarfism are clinically indistinguishable from those with isolated growth hormone (GH) deficiency, yet have high circulating GH concentrations associated with an inability to generate endogenous insulin-like growth factor I (IGF-I). Biosynthetic IGF-I was administered subcutaneously once daily for 3 to 10 months to 5 children with Laron-type dwarfism aged 3.3 to 14.5 years. There was a rapid stimulation of linear growth in body limbs, with a striking increase in head circumference, increased body weight, and a reduction in subcutaneous fat. Administration of IGF-I to patients with Laron-type dwarfism seems to have a beneficial effect on growth similar to that observed with long-term administration of GH in children with GH deficiency.
Adipose Tissue↗
Growth hormone therapy in normal short children induces a transitory decrease in plasma growth hormone releasing hormone levels and in human growth hormone responsiveness to exogenous growth hormone releasing hormone.
A three-month study of the effect of growth hormone (hGH) therapy (0.1 U/kg/day sc) on plasma levels of GH releasing hormone (GHRH), somatostatin and insulin-like growth factor I (IGF-I) and on the hGH responsiveness to exogenous GHRH was carried out in 32 prepubertal short-stature children with normal GH secretion. Blood samples were collected prior to initiation of therapy, and at 5, 30 and 90 days of onset of therapy, as well as 2 and 90 days after termination of therapy. The nonconventional hGH therapy induced an increase in serum IGF-I levels which lasted as long as therapy was continued. Plasma GHRH levels showed an early transitory decrease after five days of therapy, whereas plasma somatostatin levels were unaltered. A slight suppression in hGH responsiveness to exogenous GHRH was found at 2 but not at 90 days after termination of hGH therapy. It is concluded that nonconventional hGH treatment does not cause permanent changes in physiological hGH secretion.
Adolescent↗
Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients.
A single oral dose of 500 mg sodium valproate had no effect on prolactin, growth hormone and cortisol secretion in 10 migraine patients when compared with five healthy controls and four migraine patients receiving placebo. Basal values of prolactin (PRL), cortisol and growth hormone (GH) were within the normal range, though PRL basal levels were lower in three patients (21.5%) in the migraine group.
Adult↗