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A Silbergeld

Publications and source records attributed to A Silbergeld.

At least 37 records · Page 2Linked to original sources
PubMed1994

GH and GHBP activity and not IGF-1 and its receptor activity express growth velocity reduction during treatment of central precocious puberty by a superactive GNRH analogue.

We studied six patients with central precocious puberty (CPP) (five girls and one boy, aged 9-14.4 years) before and after 5 and 12 months of treatment with GnRH-A (D-TRP-6-LHRH-depo, DECAPEPTYL Ferring, Sweden), and 14 age-matched prepubertal children serving as controls. GnRH suppressed gonadal sex hormone secretion and arrested the gonadarche development. Growth velocity decreased from 9.8 +/- 1.6 (mean +/- SD) to 4.6 +/- 1.0 cm/year after 1 year of treatment. Basal serum IGF-1 levels of the CPP patients were 35.4 +/- 2.8 nmol/l, which was significantly higher than that of the controls (18.8 +/- 1.9, P = 0.00007). After GnRH-A there was a slight but significant increase in serum IGF-1 levels from 35.4 +/- 2.8 (mean +/- SE) to 40.3 +/- 2.1 nmol/l after 5 months (mean difference of 4.9 +/- 1.7, P = 0.02), reversing to 35.6 +/- 2.8 nmol/l after 12 months. The number of high affinity IGF-1 binding sites on erythrocytes (RBC) in the controls was 3.3 +/- 0.3 sites/cell, similar to that found in the patients before treatment. Following therapy, the number of the binding sites decreased from 4.0 +/- 0.8 (mean +/- SE) to 2.5 +/- 0.6 sites/cell after 5 months (mean difference of -1.4 +/- 0.5, P = 0.01), to 2.7 +/- 0.7 sites/cell after 12 months. Basal levels of plasma GH in the CPP patients were 7.1 +/- 1.3 ng/ml, significantly higher than those of the controls (1.2 +/- 0.2, P = 0.00001). Treatment decreased plasma GH in patients from 7.1 +/- 1.3 to 1.3 +/- 0.3 ng/ml after 5 months (mean difference of -5.8 +/- 1.3, P = 0.003) and to 2.7 +/- 1.5 ng/ml after 12 months. The GH binding protein (GHBP) activity in the controls was 76.2 +/- 6.2% relative specific binding, similar to that of the patients before therapy. The mean basal GHBP activity of the patients increased from 75.5 +/- 7.3 to 101 +/- 6.4% (mean difference of 25.5 +/- 9.7, P = 0.01) after 5 months and to 90.1 +/- 5.6% after 12 months of treatment. In conclusion, plasma GH and its receptor activity are a better indicator of the GnRH-A effect on growth than IGF-1 and its receptor activity.

Adolescent↗
PubMed1993

Modulation of insulin like growth factor I (IGF-I) binding sites on erythrocytes by IGF-I treatment in patients with Laron syndrome (LS).

The in vivo regulation of IGF-I binding sites was evaluated using erythrocytes (RBC) from 8 patients with Laron syndrome (LS), before and after IGF-I treatment (120-150 micrograms/kg/day s.c.). Basal fasting IGF-I averaged 20.48 +/- 2.06 nmol/l (mean +/- S.E.M.) in the control group as compared to 4.72 +/- 0.84 nmol/l in the 8 LS patients (P = 0.0001). After 1 week of IGF-I treatment serum IGF-I levels increased to 6.53 +/- 1.58 nmol/l (a mean difference of 1.81 +/- 0.95, P = 0.05) and after 1 month of treatment to 14.37 +/- 4.56 nmol/l (a mean difference of 9.37 +/- 4.42, P = 0.03). Concomitantly, we found a significant decrease in the number of high affinity IGF-I binding sites, from 5.74 +/- 0.86 sites/cell (mean +/- S.E.M.) in the non-treated state to 2.29 +/- 0.64 sites/cell and 2.17 +/- 0.53 sites/cell after 1 week and 1 month of treatment, respectively (a mean difference of -3.44 +/- 0.94, P = 0.004 and -3.58 +/- 0.79, P = 0.002, respectively), values similar to those found in the control group. These data demonstrate that replacement treatment of LS patients with IGF-I down regulates its specific receptors. We propose IGF-I binding to RBC as a test to determine the responsiveness of patients considered for long term IGF-I treatment.

Adolescent↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1992

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↗
PubMed1992

IGF binding protein 3 in patients with Laron type dwarfism: effect of exogenous rIGF-I.

OBJECTIVE: The aim of the study was to investigate the serum levels of IGFBP-3, the major IGF-I binding protein, in patients with Laron type dwarfism (LTD) before and after IGF-I treatment. DESIGN AND PATIENTS: Eight Laron type dwarfism patients (four children and four adults) were treated for 7 days by one daily s.c. injection of biosynthetic IGF-I in doses of 120 or 150 micrograms/kg/day. MEASUREMENTS: Blood was sampled in the fasting state before and 1 and 7 days after the last injection. RESULTS: It was found that IGF-I administration significantly reduced plasma hGH levels with recovery after one week of no treatment. Serum IGFBP-3 was abnormally low (0.70 +/- 0.37 mg/l) and decreased significantly further during IGF-I treatment (to 0.48 +/- 0.28 mg/l) (P less than 0.065). CONCLUSIONS: The finding that serum IGFBP-3 is low in Laron type dwarfism, a disease due to molecular defects in the GH receptor, is compatible with the hypothesis that this IGF binding protein is GH-dependent. On the other hand the decrease during IGF-I administration and concomitant suppression of GH secretion may denote either that GH activity is not completely blocked in this syndrome or that there are additional mechanisms regulating IGFBP-3 synthesis.

Adolescent↗
PubMed1992

Serum prolactin in patients with Laron-type dwarfism: effect of insulin-like growth factor I.

Prolactin (PRL) secretion was studied in Laron-type dwarfism (LTD) patients (8 children and 9 adults) in basal condition, after acute insulin-like growth factor (IGF-I) or TRH injections and during 2 months of daily IGF-I treatment. Basal PRL was repeatedly higher (12.6 +/- 1.6 micrograms/l) than that in control subjects (7.6 +/- 1.2 micrograms/l, p < 0.05). Acute IGF-I injection caused an immediate slight decrease in serum PRL and growth hormone (GH), followed by a progressive rise to mean peak levels of 33.3 +/- 4.5 micrograms/l again parallel to serum hGH which rose to 86 +/- 20 micrograms/l--a response to the IGF-I-induced hypoglycemia. Intravenous TRH in LTD children induced a marked response in serum PRL, similar to that registered in estrogenized adult females. Serum PRL did not show consistent changes during chronic IGF-I treatment. It is suggested that the higher-than-normal PRL levels and release in LTD patients are due to a drift phenomenon of the mammosomatotropes which produce large amounts of hGH.

Adult↗
PubMed1992

The interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig.

We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH). Infant and pubertal male pigs (N = 5 per group) received either rpGH 0.15 mg/kg daily or diluent intramuscularly for 12 days. Somatic growth, serum IGF-I and GH BP and [125I]bovine GH (bGH) binding to MgCl2-treated hepatic membrane homogenates were examined. Marked age-related increases were seen in serum GH BP (p less than 0.001) and [125I]bGH binding to hepatic membranes (p less than 0.001). GH BP was increased in rpGH treated animals (p = 0.03), from 13.8 +/- 1.2 (mean +/- 1 x SEM) (controls) to 17.8 +/- 2.0% in infants, and from 35.2 +/- 2.6 (controls) to 41.8 +/- 3.4% in pubertal animals. [125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p less than 0.05), from 7.0 +/- 1.6 (controls) to 15.4 +/- 3.6% in infants and from 53.7 +/- 7.1 (controls) to 65.1 +/- 11.8% in pubertal animals. No significant interaction between age and treatment was seen. Overall, serum GH BP correlated significantly with [125I]bGH membrane capacity (r = 0.82, p less than 0.001), with a correlation of r = 0.83 in the infant animals but no significant correlation in the pubertal animals considered alone (r = 0.13). Serum IGF-I correlated significantly with serum GH BP (r = 0.93, p less than 0.001) and [125I]bGH membrane binding capacity (r = 0.91, p less than 0.001). These observations suggest that serum GH BP levels reflect major changes of hepatic GH receptor status.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Growth hormone and insulin-like growth factor regulate insulin-like growth factor-binding protein-1 in Laron type dwarfism, growth hormone deficiency and constitutional short stature.

Insulin-like growth factors (IGFs) mediate the effects of growth hormone (GH), and the insulin-like growth factor-binding proteins (IGFBPs) modulate the actions of IGFs in tissues. We studied the circulating levels of IGFBP-1 in 6 children and 9 adults with Laron type dwarfism (LTD), in 11 children and 21 adults with growth hormone deficiency (GHD), and in 8 children with constitutional short stature. Compared with the situation in healthy children, the basal serum IGFBP-1 concentration was 5.4-fold higher in LTD children, 4.1-fold higher in GHD children, and 3.8-fold higher in children with short stature (p < 0.02 vs controls in all groups). In adult patients with multiple pituitary hormone deficiency (MPHD), the IGFBP-1 concentration was 2-fold elevated, but it was normal in adult LTD patients. Intravenous (N = 10) or subcutaneous (N = 9) administration of IGF-I (75 micrograms.kg-1 and 150 micrograms.kg-1, respectively) in LTD children resulted in a rapid 50-60% fall in serum insulin (p < 0.02), a decline in blood glucose and a concomitant 40-60% rise of IGFBP-1 levels (p < 0.05). Treatment for seven days with IGF-I (150 micrograms.kg-1 x d-1) resulted in a decrease by 34% and 44% of serum IGFBP-1 level in two out of three children with LTD. After prolonged GH therapy, the IGFBP-1 level fell in GHD children by 29% (p < 0.05), in GHD adults by 52% (p < 0.02) and in children with constitutional short stature by 17% (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effect of octreotide on 24-hour growth hormone and prolactin secretory patterns in acromegalics.

Four adult patients with active acromegaly underwent studies of their 24-hour secretory pattern of hGH and Prl prior to and at the end of 3 months of treatment with the octreotide (somatostatin analog SMS 201-995) 100 micrograms s.c. every 8 h. Blood was withdrawn at 30-min intervals with the aid of a constant withdrawal pump. The best fit cosinor method was used to define the following rhythm parameters: mesor, amplitude, acrophase and periodicity. Prior to treatment, hGH secretion was increased in all patients. The mean 24-hour ranged from 9-47 ng/ml with amplitude 5.2-23 and observed maximal pulse 41-95 ng/ml. Computed rhythms were circadian in 3 patients and ultradian in 1; in 2 patients the acrophases were shifted to daytime. hPrl secretion was altered in 3 of the patients. Two had elevated mean 24-hour of 17.7 and 22.2 ng/ml, while computed rhythms showed semicircadian periodicity in 1 of them and circadian periodicity with a shift of acrophase to daytime in the other. The third patient who had normal hPrl levels, showed ultradian 8-hour periodicity. At the end of treatment there was a marked reduction in hGH secretion in 1 patient and a lesser reduction in the other 3. The rhythm was influenced by the masking effect of the drug, to yield an 8-hour period with acrophases related to injection clock time having equal amplitudes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1991

Erythrocytes from patients with low serum concentrations of IGF-I have an increase in receptor sites for IGF-I.

The binding characteristics of insulin-like growth factor I on erythrocytes were studied in 11 patients with long-term IGF-I deprivation and low serum IGF-I levels. Six patients had Laron type dwarfism and 5 idiopathic isolated growth hormone deficiency, with a mean (+/- SEM) serum IGF-I level of 6.01 +/- 1.01 nmol/l as compared with that in 25 normal controls of 26.35 +/- 2.73 nmol/l (p = 0.00001). The mean (+/- SEM) [125I]IGF-I specific binding at a concentration of 4 x 10(12) cell/l was 12.11 +/- 1.29% for the patient group compared with 8.75 +/- 0.62% for the controls (p = 0.005). Scatchard analysis showed a curvilinear plot. Using a non-linear curve fit, the mean (+/- SEM) number of high-affinity receptor sites per cell was found to be 7.34 +/- 1.80 in the IGF-I-deprived patients and 2.84 +/- 0.29 in the controls (p = 0.0005). The mean +/- SEM dissociation constant was found to be 0.33 +/- 0.10 nmol/l for the patients and 0.26 +/- 0.08 nmol/l for the controls (NS). This study has demonstrated that the low serum concentration of IGF-I in Laron type dwarfism and isolated growth hormone deficiency is associated with an increase in receptor sites for IGF-I on the erythrocytes. The application of this property as a diagnostic acid remains to be established.

Adolescent↗
PubMed1990

Elimination characteristics of intravenously administered rIGF-I in Laron-type dwarfs.

The distribution and elimination characteristics (Ke alpha, Ke beta, t1/2) of an intravenous bolus of biosynthetic IGF-I administered to 10 patients with Laron-type dwarfism (LTD, 3 children and 7 adults) and 6 healthy volunteers (3 children and 3 adults) are reported. The mean (+/- SD) endogenous level of IGF-I in the LTD patients was 5.24 +/- 2.77 nM/l and in the controls 27.2 +/- 9.4 nM/l. In the LTD patients the mean elimination constant (Ke beta) was 0.004 +/- 0.001 min-1 and t1/2 = 2.6 +/- 0.7 h, whereas in the controls, Ke beta was 0.003 +/- 0.009 min-1 and the t1/2 = 4.4 +/- 0.5 h (p less than 0.05). The more rapid elimination of injected IGF-I in the LTD patients is assumed to be due to the absence of the GH-dependent 150 kDa IGF-I binding protein.

Adolescent↗
PubMed1990

Intravenous administration of recombinant IGF-I lowers serum GHRH and TSH.

Recombinant IGF-I was administered as an iv bolus of 75 micrograms/kg to 10 patients with Laron type dwarfism (3 children aged 9, 11 and 12 years and 7 adults aged 30.6 +/- 3.5 years) and to 8 healthy subjects (mean age 19.9 +/- 12.1 years) and determinations of IGF-I, GHRH, hGH, TSH, and glucose were made before and at 2, 5, 15, 30, 60, 90, and 120 min. The following effects were observed: a. an immediate, marked and sustained drop in blood glucose (p less than 0.001), more prolonged in the patients; b. in both groups, a dramatic rise in plasma hGH (p less than 0.01) which peaked at 60-90 min; in the patients this occurred after an initial immediate fall in plasma hGH (p less than 0.01); c. a progressive decrease of plasma GHRH and TSH (p less than 0.05, 0.02) in both patients and healthy controls. An hypothesis is put forward that acute and time-limited release of somatostatin by IGF-I is the main cause of the hormonal changes registered. As the IGF-I bolus also suppressed circulating insulin levels, the hypoglycemia is considered to be a direct effect of IGF-I.

Adult↗
PubMed1989

Serum growth hormone binding protein activity in healthy neonates, children and young adults: correlation with age, height and weight.

Serum growth hormone binding protein (GHBP) activity was estimated in healthy neonates (n = 6), children and adolescents (n = 97) and young adults (n = 19). GHBP activity was measured by incubating 125I-hGH (human growth hormone) (approximately 25,000 c.p.m.) with serum (100 microliters) in the presence and in the absence of excess unlabelled hGH, followed by separation of specifically bound 125I-hGHBP complexes from free 125I-hGH by gel filtration on Ultrogel AcA44 minicolumns. The results are expressed as the percentage specific binding relative to an adult reference serum (%RSB), after correction for endogenous hGH of the unknown serum. The between-assay coefficients of variation for two sera of %RSB activity of 51.2 and 115.4% were 6.0 and 7.0% respectively. In neonates, low values of serum GHBP were found (%RSB = 27.1 +/- 5.0 SEM) followed by a major rise during the first 6 years of life to a mean value (%RSB = 68.3 +/- 4.1 SEM) which more than doubled that of neonates. Thereafter, values rose progressively throughout childhood and puberty to reach maximum values in young adults (%RSB = 95.0 +/- 3.1 SEM). A novel observation was that serum GHBP activity correlated significantly with height standard deviation score (SDS) (males: r = 0.77, P less than 0.001; females: r = 0.56, P = 0.01) and weight SDS (P less than 0.001) for both sexes before puberty. During puberty GHBP correlated only with weight SDS in males (r = 0.60, P less than 0.01). In all age groups studied, no correlation could be found between serum GHBP and height velocity.

Adolescent↗