Serum GHBP Research Articles

Growth Hormone-Binding Protein in Patients with Anorexia Nervosa Determined in Two Assay Systems

To learn the mechanism of low plasma insulin-like growth factor-I (IGF-I) despite high growth hormone (GH) secretion in patients with anorexia nervosa, we assessed human serum GH-binding protein (BP) (GH-BP), which has been shown to be identical to the extracellular domain of GH receptor, and therefore might reflect peripheral GH receptor expression (i.e. there is a significant linear correlation between GH-BP and IGF-I at less than 2.0 U/ml in healthy children). The serum GH-BP level was determined by gel filtration and confirmed by immunoassay using GH receptor monoclonal antibody. Furthermore, we analyzed serum IGF-binding proteins (IGFBPs) by the affinity cross-linking method to determine the GH-IGF-I axis in this condition. Measurement of GH-BP by the two assays gave identical results, suggesting that serum GH-BP corresponds to the extracellular domain of GH receptor. The low GH-BP and high IGFBP levels in patients with anorexia nervosa shown in this study, which were normalized by an improved nutritional state, would indicate resistance to GH as well as to IGFs in this condition, in which the former is in part compensated by high GH levels while the latter is not.

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)

Ontogeny of messenger RNA for the rat growth hormone receptor and serum binding protein

Little is known of the regulation of gene expression for the family of growth hormone (GH) and prolactin (PRL) receptors (PRL-R). Furthermore, the rélationship between expression of the GH receptor (GHR) and its soluble truncated form (GH-binding protein, GHBP) is unclear. The actions of both GH and PRL are developmentally regulated and several studies have examined the ontogeny of these receptors by classical hormone-binding techniques. In the current study we have examined the expression of GHR/GHBP and PRL-R mRNA in the male rat over a broad developmental range —fetal through to 110 days of age. The GHR mRNA (4.5 kb) was barely detectable in fetal and early (< 20 days) postnatal livers, but was followed by a gradual increase up to 40 days of age by which time adult plateau levels were reached. In contrast, hepatic GHBP mRNA (1.2 kb) was clearly identifiable in the fetus and subsequently followed a similar pattern to the 4.5 kb GHR mRNA although there was a somewhat earlier rise. Hepatic membrane binding studies using 125I-bovine GH as ligand revealed no measurable binding activity at less than 20 days of age. Binding remained low thereafter. In contrast, the serum GHBP binding activity was detectable at 10 days of age and rose to adult levels by 50 days of age. These results indicate that mRNA species for GHR, GHBP, PRL-R and insulin-like growth factor I (IGF-I) are all developmentally regulated with the pattern for IGF-I correlating more closely with that of GHBP than GHR. The presence of the GHBP at the fetal stage may signify a role in fetal growth as well as in regulating the local actions of circulating GH, which is high in the fetus.

The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa

The endocrine abnormalities along the growth hormone (GH) axis in anorexia nervosa (AN) and in obesity include hypothalamic, pituitary, and peripheral elements. The present study was undertaken to evaluate the effects of these nutritional extremes on GH-binding protein (BP) levels and on insulin-like growth factor-I (IGF-I) receptors on red blood cells (RBC). Nine patients with AN and 20 obese subjects were compared with normal control children, adolescents, and adults. GH-BP was measured by a binding assay with dextran-coated charcoal separation. IGF-I binding was measured on enriched RBC. Serum GH-BP levels were markedly reduced in the AN patients, and highly increased in the obese. Scatchard analyses showed linear plots with unaltered binding affinities (Ka). The binding capacity (Bmax) was significantly lower than normal control in the AN patients and higher in the obese. GH-BP levels correlated positively with the body mass index (BMI). RBC [ 125I]IGF-I binding was significantly elevated in the AN patients and low in the obese. Scatchard analyses showed curvilinear plots. The high-affinity constants (Ka 1) were slightly, but significantly, higher in the AN patients and in the obese compared with control. The binding capacity of the first binder (Bmax 1) was lower in obesity than in AN or control. The low-affinity constants (Ka 2) were similar in the three groups, and its binding capacity (Bmax 2) was similar in the AN patients and the controls, but significantly lower in the obese. [ 125I]IGF-I binding correlated negatively and significantly with the BMI and with the GH-BP. AN, with low GH-BP and high IGF-I receptors, can, therefore, be viewed as a condition of GH resistance and IGF-I hypersensitivity. On the other hand, obesity, with high GH-BP and low IGF-I receptors, can be viewed as a condition with GH hypersensitivity and IGF-I resistance. Taken together, these results indicate positive correlation between BMI and GH responsiveness, and negative correlation between BMI and IGF-I responsiveness. The results of the present study show that these two phenomena correlate negatively with each other.

Growth Hormone-Binding Protein Activity Is Inversely Related to 24-Hour Growth Hormone Release in Normal Boys*

To investigate the physiological relationship between serum GH-binding proteins and 24-h GH release, we compared the 24-h GH pulse attributes in serum samples obtained at 20-min intervals to the serum GH-binding protein activity (GH-BP) from 38 normal boys between 7 5/12 and 18 4/12 yr of age. GH-BP was determined in a serum sample from each study (containing less than 1.0 micrograms/L GH) using a standardized GH-BP assay. GH-BP results are expressed as the percentage of [125I]human GH bound to the high affinity GH-BP complex (peak II) per 160 microL serum. There were significant inverse relationships between the high affinity (receptor-related) GH-BP and several characteristics of 24-h GH release. Specifically, GH-BP was significantly (P less than 0.005 for all), but negatively, correlated with mean 24-h GH concentration (r = -0.62), sum of the GH pulse amplitudes (r = -0.57), sum of the GH pulse areas (r = -0.55), interpulse mean GH concentration (r = -0.53), and number of GH pulses per 24 h (r = -0.53). In addition, GH-BP correlated positively with the mean time interval between pulses (r = 0.59). There was also a significant positive correlation (r = 0.75; P less than 0.001) between GH-BP and the subject's age-adjusted body mass index SD score (BMI-SDS). Each characteristic of 24-h GH release correlating inversely with GH-BP also correlated inversely with BMI-SDS (P less than 0.01 for all comparisons). GH-BP did not, however, correlate with plasma insulin-like growth factor-I levels, serum testosterone concentrations, or height SDS. Binding to the low affinity GH-BP (peak I) did not correlate significantly with any of the examined GH pulse attributes, BMI-SDS, or the degree of binding to the high affinity GH-BP (peak II). We conclude that an inverse relationship exists between the high affinity serum GH-BP and 24-h GH release in boys under normal physiological conditions. We speculate that abnormalities in this relationship probably also exist and may underlie some disorders of growth.

42 SERUM GROWTH HORMONE BINDING PROTEIN (GH-BP) IN PRE-PUBERTAL CHILDREN IS CORRELATED WITH HEIGHT

Recently serum GH-BP has been shown to have identical N-terminal amino acid sequence as the tissue hGH receptor. Serum hGH levels and the specific binding activity of GH-BP (expressed as % of GH-BP activity of an adult reference serum = RSGH-BP) were estimated in 25 prepubertal children (19 M, 6 F, aged 6-11 yrs). When the results were related to height, 3 groups could be distinguished. It is evident that GH-BP levels in children significantly correlated (r=0.83, p ≪ 0.001) with height SDS, but not with basal hGH levels or age. It is therefore possible that GH-BP presents a simple non-invasive tool to determine growth hormone activity.