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The characteristics of the human serum growth hormone-binding protein (GHBP) were compared with those of a water-soluble GH-binding site prepared by incubating cultured IM-9 lymphocytes in assay buffer with 25 mmol/l iodoacetamide. High-performance liquid chromatography gel filtration of the water-soluble GH-binding site incubated with 125I-labeled human GH ([125I]hGH) revealed a large peak of bound [125I]hGH eluting at the same position as the peak of [125I]hGH bound to the GHBP in serum. The estimated M(r) of the peak was 120,000, presumably representing one [125I]hGH bound to two binding sites. The binding specificities of the serum GHBP, the water-soluble GH-binding site and the GH receptor on IM-9 lymphocytes were identical. The binding affinities for 22,000 hGH and for 20,000 hGH of the serum GHBP were similar to the binding affinity of the water-soluble GH-binding site but lower than those of the cellular GH receptor. These findings show that the characteristics of the serum GHBP are comparable to those of the water-soluble GH-binding site released from IM-9 cells and support the hypothesis that in man the serum GHBP is produced by proteolytic cleavage of the cellular GH receptor.

Objective: Since there appears to be a relationship between circulating oestrogens and growth hormone, we have investigated the effect of the oestrogen status of adult women on serum levels of GHBP and IGF-I., Design and Patients: The investigation was performed on serum samples of 14 spontaneously menstruating women, 10 women taking oral contraceptives containing 20-50 micrograms ethinyloestradiol, and 30 pregnant women at different stages of pregnancy., Measurements: Serum levels of GHBP were measured by HPLC gel filtration and IGF-I levels were measured by RIA after acid-ethanol extraction., Results: In the spontaneously menstruating women the mean +/- SD serum level of GHBP was 34.6 +/- 6.7% and of IGF-I 30 +/- 7 nmol/l. Serum GHBP levels were negatively (r = -0.67; P < 0.01) and IGF-I levels were positively related (r = 0.69; P < 0.01) to serum oestradiol concentrations. In the women taking oral contraceptives serum levels of GHBP were 47.0 +/- 7.4%. This was significantly (P < 0.001) higher than in spontaneously menstruating women. In contrast, IGF-I levels were not different from those obtained in spontaneously menstruating women. In the pregnant women, the mean +/- SD serum level of GHBP was not different from that observed in non-pregnant spontaneously menstruating women. Polynomial regression analysis, however, showed a significant (P = 0.01) second-order relationship between the duration of pregnancy and serum GHBP levels, with increasing levels during the first half of pregnancy and decreasing levels thereafter. Serum concentrations of IGF-I increased during the second half of pregnancy and were significantly (P < 0.005) elevated in the third trimester., Conclusions: In non-pregnant women the endogenous oestrogen status seems to modulate negatively GHBP levels and positively IGF-I levels, whereas oral oestrogen administration, in contrast, increases serum levels of GHBP without modification of IGF-I levels. During pregnancy serum GHBP levels increase slightly during the first half of pregnancy and decrease thereafter, whereas IGF-I concentrations increase during the second part of pregnancy. The oestrogen status of women has a complex effect on serum concentrations of GHBP and IGF-I and has therefore to be taken into account when evaluating serum levels of GHBP and IGF-I.

Serum levels of insulin-like growth factor I are reduced in patients with Type 1 (insulin-dependent) diabetes mellitus. To evaluate the role of the hepatic growth hormone receptor in the decreased serum concentrations of insulin-like growth factor I, serum levels of the high affinity growth hormone-binding protein, which is qualitatively and quantitatively related to the hepatic growth hormone receptor, and of insulin-like growth factor I were measured in 70 children and adolescents with Type 1 diabetes and 105 healthy control children. Analysis of variance revealed a significant negative effect of Type 1 diabetes on serum levels of the growth hormone-binding protein and of insulin-like growth factor I. In the diabetic patients, serum levels of the growth hormone-binding protein were positively related to body mass index and to insulin dose per kg body weight, and were not influenced by pubertal stage, gender, or plasma levels of haemoglobin A1c. Serum levels of insulin-like growth factor I increased during early puberty reaching peak levels at mid-puberty and decreasing thereafter. No relationship was found between serum levels of growth hormone-binding protein and of insulin-like growth factor I. Our data suggest that decreased liver somatogenic receptor levels, as reflected by the concentrations of circulating growth hormone-binding protein, play a minor role in the suppressed concentrations of circulating insulin-like growth factor I. Post-growth hormone receptor defects or changes in the insulin-like growth factor binding proteins probably contribute more to the lower serum levels of insulin-like growth factor I.

Serum levels of GH-binding protein (GH-BP) and insulin-like growth factor-I (IGF-I) were measured in 14 adolescent girls with Turner's syndrome (TS) before and during treatment with recombinant human GH (rhGH) and oral ethinyl estradiol (EE2). Before treatment, the mean +/- SE GH-BP level in TS patients was 33.2 +/- 2.0%; this was higher (P < 0.05) than that in bone age-matched (27.9 +/- 1.1%; n = 13) or chronological age-matched (28.1 +/- 0.8%; n = 17) control girls. The mean +/- SE IGF-I level in TS girls (283 +/- 26 micrograms/L) was comparable to that in bone age-matched controls (255 +/- 17 micrograms/L), but lower (P < 0.005) than that in chronological age-matched pubertal controls (568 +/- 35 micrograms/L). In 7 TS girls treated with daily sc injections of rhGH in a dose of 0.8 U/kg.week for 18 months, serum levels of IGF-I increased from 330 +/- 39 to 707 +/- 48 micrograms/L after 3 months of treatment and remained elevated for the entire observation period (P < 0.002). In contrast, GH-BP levels did not change significantly. In 7 other TS girls, puberty was induced after 2 yr of daily sc injections with rhGH (1 U/kg.week) by adding 100 ng/kg.day EE2, orally, during ongoing rhGH therapy. During 18 months of pubertal induction, serum GH-BP levels increased gradually from 31.4 +/- 2.7% at the start of EE2 treatment to a maximum of 49.2 +/- 0.8% after 1 yr (P < 0.001). Serum IGF-I levels, in contrast, did not change significantly. These results show that in adolescent TS patients 1) pretreatment serum GH-BP levels are higher than in bone age-matched or chronological age-matched control girls, and IGF-I levels are similar to those in bone age-matched but lower than those in chronological age-matched controls; 2) during rhGH treatment GH-BP levels do not change, whereas IGF-I levels increase significantly; and 3) oral EE2 treatment during ongoing rhGH treatment increases GH-BP levels markedly, but does not modify IGF-I levels.

Objective: The aim was to investigate the effect of pubertal development on serum levels of growth hormone binding protein (GHBP) and IGF-I, and to study the relationship between GHBP levels and height standard deviation score (SDS), nutritional state and IGF-I levels., Design and Patients: The investigation was performed on serum samples from 72 healthy adolescents of different pubertal stage. Results were compared to those obtained in 46 prepubertal children., Measurements: Serum levels of GHBP were measured by HPLC gel filtration and IGF-I levels were measured by RIA after acid-ethanol extraction., Results: No effect of pubertal stage on serum levels of GHBP was found. A positive relationship was found between serum levels of GHBP and height SDS (r = 0.38; P < 0.005) and weight expressed as percentage of median weight for height age (r = 0.46; P < 0.0005). Serum levels of IGF-I increased during puberty and were not correlated with height SDS or weight for height age. In pubertal subjects, no relationship existed between serum levels of GHBP and IGF-I. In prepubertal subjects, however, a significantly positive relationship between GHBP and IGF-I levels (r = 0.66; P < 0.0005) was found., Conclusions: Pubertal development does not seem to influence serum levels of GHBP. Height SDS and nutritional state are related to the concentration of GHBP. Before puberty, the level of GHBP is positively related to IGF-I levels; during puberty, however, the increase in serum IGF-I levels is not accompanied by changes in the amount of circulating GHBP.

Growth hormone-binding protein (GH-BP) levels were studied in cord serum of 69 human infants born after 24 to 41 wk of gestation and in serum of 14 infants aged 1 to 3 mo. GH-BP levels were measured by HPLC-gel filtration of serum incubated overnight with 125I-hGH. The radioactive elution profile revealed two small 125I-hGH peaks of high molecular weight and a large peak, corresponding to monomeric 125I-hGH. The first peak of high molecular weight was variable, showed some of the characteristics (high molecular weight, displaceability by a large excess of unlabeled hGH) of the described low affinity, high capacity GH-BP, and did not correlate with gestational age or birth weight (peak I-BP). The second peak was identified as 125I-hGH bound to the high affinity, low capacity GH-BP (peak II-BP). Mean +/- SD specific binding of 125I-hGH to this peak was significantly (p less than 0.0001) different between preterm infants (3.1 +/- 1.1%; n = 51), term infants at birth (4.2 +/ 1.1%; n = 18), and 1- to 3-mo-old infants (8.5 +/- 1.6%; n = 14). To evaluate the effect of intrauterine nutritional state, the ponderal index (weight/lengths) was calculated. Peak II-BP levels were lower (p less than 0.05) in infants with the ponderal index less than 2.35 (2.8 +/- 1.0%; n = 20) than in those with the ponderal index between 2.35 and 2.65 (3.4 +/- 1.2%; n = 29) or greater than 2.65 (3.8 +/- 1.2%; n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)

In most of the children with short stature, no organic basis can be found, which has led to the suggestion that some cases of growth failure may be due to an immunoreactive but bioinactive growth hormone (GH). In order to compare GH immunoreactivity and bioactivity (measured as receptor binding ability), a radioreceptor assay allowing the measurement of GH levels in human serum was developed using cultured human lymphocytes and 125I-labeled human GH purified by high-performance liquid chromatography. Serum samples were obtained after pharmacological stimulation with either insulin, glucagon or GRF from 19 healthy control subjects and 114 patients with various growth disturbances, aged 2.3-24.8 years. In general, there was a good correlation between the GH levels measured by the two methods, the RRA-GH levels being lower than the RIA-GH levels at all times irrespective of the stimulation test. In all the groups studied, most of the individual RRA/RIA ratios were within normal limits. It is concluded that the presence of an abnormal (bioinactive) GH molecule is extremely rare in patients with short stature.