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Biomedical subjects

B Klinger

Publications and source records attributed to B Klinger.

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

Laron syndrome: clinical features, molecular pathology and treatment.

Primary growth hormone (GH) insensitivity (Laron syndrome) is a hereditary disease due to polymorphic defects in the GH receptor, or in the postreceptor mechanisms, leading to an inability to generate IGF-1. The clinical features and biochemical profiles are indistinguishable from isolated GH deficiency. A diagnostic feature is the lack of rise of serum IGF-1 in response to GH. In most patients growth hormone binding protein is low. Treatment of children with Laron syndrome by biosynthetic IGF-1 accelerates linear growth velocity and head circumference, reduces body fat, and stimulates kidney function.

Adolescent↗
PubMed1994

Serum growth hormone-binding protein (GHBP) activity is decreased by administration of insulin-like growth factor I in three Laron syndrome siblings with normal GHBP.

Three Laron Syndrome (LS) siblings with a post growth hormone (GH) receptor defect for insulin-like growth factor-I (IGF-I) synthesis were found to have serum GH-binding protein (GHBP) levels normal for age. Treatment with recombinant IGF-I (150 micrograms/kg/day) decreased serum GHBP activity to 62% of the basal value (P < 0.001) in two of the sibs in 1 week and in the third sib after 3 months of therapy. Scatchard analysis of the binding of [125I]human GH (hGH) to GHBP in patients' sera before and during therapy revealed affinity constants Ka = 1.55-1.80 x 10(9) M-1, similar to that of sera from healthy subjects. Variations in binding are due to changes in the binding capacity. IGF-I may be a regulatory factor for serum GHBP activity in man.

Carrier Proteins↗
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

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↗
PubMed1993

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↗
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

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↗
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

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↗
PubMed1992

Effect of insulin-like growth factor I on the thyroid axis in patients with Laron-type dwarfism and healthy subjects.

We have evaluated the effect of exogenous administration of IGF-I on the thyroid axis in four separate studies: (1) iv bolus injection; (2) single sc injection; (3) seven days' sc treatment, and (4) four months' treatment. Thirteen patients with Laron-type dwarfism (LTD) participated in the investigations. In studies 1 and 2, 10 healthy subjects were also included. Before and during long-term treatment (study 4) six LTD patients underwent a TRH test. IGF-I was administered in a dose of 75 micrograms.kg-1 iv or 120-150 micrograms.kg-1 sc. Single injections of IGF-I caused significant decreases of serum TSH in LTD patients (iv: 1.7 +/- 0.2 to 1.1 +/- 0.1 mU/l; sc: from 2.1 +/- 0.4 to 1.1 +/- 0.2; p < 0.0005). In controls the decrease was for iv from 1.2 +/- 0.2 to 0.8 +/- 0.2 mU/l (p < 0.02) and for sc from 2.0 +/- 0.5 to 0.8 +/- 0.2 mU/l (p < 0.05). Long-term administration of IGF-I induces a transitory decrease of both serum TSH and fT4, followed by a spontaneous rise to pretreatment or even higher values. No changes in T3 were observed. TSH stimulation by TRH was significantly augmented after four months of IGF-I treatment (p < 0.005). The effects of IGF-I can be explained by an early stimulation of somatostatin release causing a decrease in TSH and followed by the development of compensatory mechanisms. All changes were within the normal ranges, not causing abnormal thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Biochemical and hormonal changes induced by one week of administration of rIGF-I to patients with Laron type dwarfism.

OBJECTIVE: The purpose of this investigation was to evaluate the effectiveness of short-term administration of recombinant biosynthetic IGF-I on patients with an hereditary inability to generate this hormone. DESIGN AND PATIENTS: Ten patients with Laron type dwarfism (LTD) (4 males, six females) aged 3 1/2 to 37 3/4 years were submitted to seven daily s.c. injections of recombinant IGF-I in doses of 120 or 150 micrograms/kg/day. MEASUREMENTS: Blood samples were drawn before, after three and seven injections, and one week after stopping the trial. RESULTS: The main biochemical and hormonal changes registered were (mean +/- SD): a marked rise in serum type III procollagen (PIIINP) from 4.2 +/- 0.9 to 7.3 +/- 2 micrograms/l (P less than 0.0003) and decrease in the following blood components: plasma hGH from 32.51 +/- 43.77 to 4.02 +/- 2.48 mU/l (P less than 0.001), serum cholesterol from 5.9 +/- 1 to 5.7 +/- 0.8 mmol/l (P less than 0.04), serum SGOT from 28.9 +/- 11.6 to 15.5 +/- 7.6 U/l (P less than 0.01) and serum LDH from 286 +/- 88 to 222 +/- 37 U/l (P less than 0.0005). The response of plasma insulin was variable, decreasing in seven of ten and increasing in three. Some of these effects were transitory, and were found after 3 days therapy but afterwards decreased (insulin, cholesterol and liver tests), others persisted throughout the whole treatment period (hGH, PIINP). CONCLUSIONS: IGF-I mimics the biochemical and hormonal changes described after administration of hGH. The administration of IGF-I in patients with Laron type dwarfism is devoid of side-effects and warrants assessment in long-term studies.

Adolescent↗
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↗