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.

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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.

Abstract. Recombinant IGF-I was administered as an iv bolus of 75 μg/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 < 0.001), more prolonged in the patients; b. in both groups, a dramatic rise in plasma hGH (p<0.01) which peaked at 60-90 min; in the patients this occurred after an initial immediate fall in plasma hGH (p<0.01); c. a progressive decrease of plasma GHRH and TSH (p<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.

Measurement of GH-binding protein activity and IGF-I was carried out in the sera of 13 patients with Laron type dwarfism, a syndrome caused by a lack of GH receptors which leads to impairment of IGF-I generation, and those of 16 of their close relatives. GH binding protein activity was measured by incubating 125I-hGH with 100 \ g=m\ l serum in the presence and in the absence of excess unlabelled hGH, followed by separation of specifically bound 125I-hGH binding protein complexes from free 125I-hGH by gel filtration. The results are expressed as percent specific binding relative to an adult reference serum. IGF-I was determined by RIA after acid extraction on octadecylsilane silica columns. All Laron type dwarfism patients had no, or only negligible GH binding protein activity, which supports the evidence that serum GH binding protein corresponds to the extracellular domain of the membranal GH receptor. Eight of the 16 relatives had serum GH binding protein activity more than 2 sd below the mean for age, a finding considered to denote heterozygocity for their molecular defect disease. The significant correlation (p < 0.001) between serum GH binding protein activity and IGF-I levels supports this conclusion. The ability to define heterozygotes of Laron type dwarfism will be helpful in genetic counselling. Laron type dwarfism (LTD) is a syndrome clinically undistinguished from isolated growth hormone deficiency (1). The basic defect has been found to be a lack of GH receptors (2) which leads to an in¬ ability to generate IGF-I (3). It is a hereditary dis¬ ease trasmitted in a recessive fashion (4) and fami¬ lial transmission has been proven by following the distribution of patients in families and within consanguinous clans (5,6). However, the identification of the heterozygous carriers of this molecular defeet (GH receptor gene deletion or abnormal gene) has not been possible until now.The recent finding that the circulating GH bind¬ ing protein (GHBP) is identical with the extracellu¬ lar hormone binding domain of the membranal GH receptor (7) has stimulated studies to measure the circulating GH receptor activity in LTD pa¬ tients. As expected from the above, Daughaday & Trivedi (8) found 3 patients, and Baumann et al. (9) found 1 patient with no serum GHBP activity.We herewith report the serum GHBP activity of 13 LTD patients and, for the first time, that in 16 of their close relatives. Subjects and MethodsWe studied 13 LTD patients of a large cohort followed in our clinic and 16 of their close family members (parents, siblings, offspring and chifdren of siblings) who agreed to be tested. Blood was drawn after overnight fasting, the sera separated after 2 h, and stored in glass tubes at -18°C until assayed. Serum GHBP activity was measured by a modification (fO) of the method of Herington et at. (11). 125I-biosynthetic hGH (88 nCi/ng) (Nordisk Gentofte A/S, Denmark) was purified weekly on an Ultrogel ACA.,,, column (0.9 X 24 cm) eluted with 0.025 mol/1 Tris HC1 containing 0.02 mol/1 CaCl2, 0.1% BSA (RIA grade, Si...