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Biomedical subjects

L M Carlsson

Publications and source records attributed to L M Carlsson.

At least 55 records · Page 3Linked to original sources
PubMed1996

The obese growth hormone (GH)-deficient dwarf rat: body fat responses to patterned delivery of GH and insulin-like growth factor-I.

We describe a new animal model of obesity and GH deficiency and report the effects on body fat of administering (GH) and insulin-like growth factor (IGF-I) in the model. Female GH-deficient dwarf rats fed a high-fat diet became obese and insulin-resistant compared with chow-fed controls. They were treated with recombinant human GH (rhGH 100-500 micrograms/day, s.c. for 14 days) by daily injection or minipump infusion with or without rhIGF-I (200 micrograms/day, sc infusion). Injections of rhGH increased body weight; infusions of rhGH caused weight loss. RhIGF-I by itself, or rhIGF-I plus GH injections had little effect, whereas rhGH infusions plus rhIGF-I caused a weight loss equivalent to the weight gained during the high-fat feeding and a decrease in fat pad weight. For some responses (serum IGF-1 and GHBP), the obese rats were GH resistant. Fat was lost from the internal fat pads when obese rats were returned to a chow diet, and injections of rhGH surprisingly attenuated this loss of fat. In obese dwarf rats, the lipolytic effects of rhGH are dose-regime dependent. By itself IGF-I is not insulin-like, but in the presence of GH it has antiinsulin actions causing a powerful net lipolysis. If GH plus IGF-I have similar effects in humans they may be useful for reducing body fat.

Adipose Tissue↗
PubMed1996

The individual responsiveness to growth hormone (GH) treatment in GH-deficient adults is dependent on the level of GH-binding protein, body mass index, age, and gender.

The aim of the present trial was to study the individual responsiveness to GH treatment in terms of body composition and to search for possible predictors of the response in GH-deficient adults. Sixty-eight patients (44 men and 24 women) with a mean age of 44.3 (1.2) yr and verified GH deficiency participated in a 2-phase treatment trial with an initial randomized, double blind, placebo-controlled, 6-month period, followed by an open treatment period, thereby ensuring all patients 12 months of GH treatment. Recombinant human GH was administered sc daily at bedtime, with a target dose of 12 micrograms/kg x day. GHBP was measured by ligand-mediated immunofunctional assay, and serum insulin-like growth factor I (IGF-I) was determined by RIA after acid-ethanol extraction, using a truncated IGF-I analog as the radioligand. Lean body mass (LBM) and body fat (BF) were determined by dual energy x-ray absorptiometry, and total body water (TBW) was determined by bioelectrical impedance. During the placebo control period, serum IGF-I,LBM, and TBW increased (P < 0.001), whereas BF decreased (P < 0.001) and serum GHBP was unchanged in the group treated with GH compared with the patients treated with placebo. After 12 months of GH treatment, the individual changes in BF ranged from -12.5 to 4.3 kg and from -4.5 to 10.1 kg in LBM. Age (P < 0.05) and baseline GHBP level (P < 0.01) were inversely correlated with the increase in LBM. The GH-induced increment in IGF-I and TBW was greater in men than in women (P < 0.01), whereas the decreases in BF were similar in men and women. This trial demonstrates the variability in responsiveness to GH administration in GH-deficient adults. The best response to GH was obtained in younger patients with low GHBP levels. Furthermore, men responded better than women.

Absorptiometry, Photon↗
PubMed1996

22-kD growth hormone exclusion assay: a new approach to measurement of non-22-kD growth hormone isoforms in human blood.

Human growth hormone (GH) exists in a variety of isoforms. In the pituitary, the most abundant isoform is 22-kD GH (22 K GH), while other isoforms (non-22 K GH) are present in variable amounts. In human plasma, the GH heterogeneity contributes to the wide variability in GH levels measured by different immunoassays. The physiological role of the non-22 K GH isoforms is poorly understood, but they may represent a spectrum of agonists or antagonists of the GH receptor. It is possible that increased amounts of non-22 K GH isoforms in the circulation contribute to the growth failure observed in some short children and may be involved in the pathophysiology of acromegaly and other unrelated diseases. Currently, there is no method available to evaluate the ratio of non-22 K GH isoforms to total GH in large sets of serum samples. In this report, a novel assay procedure is described in which monomeric and dimeric isoforms of 22 K GH are removed from serum and non-22 K GH isoforms are quantitated. The 22 K GH exclusion assay (22 K GHEA) was established as a screening method to identify conditions in which the ratio of non-22 K GH isoforms to total GH in human blood is altered. A 22 K GH-specific monoclonal antibody (MCB) is used for binding to 22 K GH in serum. Magnetic beads coated with rat anti-mouse immunoglobulin G and a magnetic device are used to remove the 22K GH-MCB complexes from serum. The non-22 K GH isoforms are measured by a polyclonal antibody-based immunoradiometric assay (GH-IRMA). The assay procedure was optimized systematically by statistical experimental designs. In serum spiked with monomeric or dimeric 22 K GH, the 22 K GH extraction was efficient at GH levels up to 100 microg/l (range 96.3-100%). The intra- and interassay precision for non-22K GH levels of 3.9 microg/l were 2.6% and 8.7%, respectively, while for levels of 0.6 microg/l, which were very close to the detection limits of the assay, the coefficients were 17.0% and 21.6%, respectively. The percentage of non-22 K GH isoforms determined in serum samples from three different groups of subjects showed clearly distinctive values. The 22 K GHEA is a new method for evaluation of non-22 K GH isoforms in human blood under different physiological and pathophysiological conditions.

Adolescent↗
PubMed1995

Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group.

BACKGROUND: Short stature in children who are not deficient in growth hormone (GH) is probably caused by a variety of defects. Some children with idiopathic short stature have low serum concentrations of GH-binding protein, which is derived from the GH receptor. The possibility that low serum concentrations of GH-binding protein might indicate partial insensitivity to GH led us to investigate possible defects in the gene for the GH receptor in children with idiopathic short stature and low serum concentrations of GH-binding protein. METHODS: We studied 14 children with idiopathic short stature who were selected on the basis of normal GH secretion and low serum concentrations of GH-binding protein. Analysis of single-strand conformation polymorphisms and DNA sequencing were both used to identify mutations in the GH-receptor gene. RESULTS: Mutations in the region of the GH-receptor gene that codes for the extracellular domain of the receptor were found in 4 of the 14 children, but in none of 24 normal subjects. One of the four children with mutations was a compound heterozygote, with one mutation that reduced the affinity of the receptor for GH and a second mutation that may affect a function other than ligand binding. The remaining three children had single mutations in one allele of the gene. One mutation introduced a premature termination codon, and two caused substitutions of single amino acids in a structurally conserved domain of the receptor. CONCLUSIONS: Some children with idiopathic short stature may have partial insensitivity to GH due to mutations in the GH-receptor gene.

Adolescent↗
PubMed1995

Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia.

Extracellular superoxide dismutase (EC-SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) is a secreted Cu- and Zn-containing tetrameric glycoprotein, the bulk of which is bound to heparan sulfate proteoglycans in the interstitium of tissues. To test the function of EC-SOD in vivo, mice carrying a targeted disruption of the EC-SOD gene were generated. The EC-SOD null mutant mice develop normally and remain healthy until at least 14 months of age. No compensatory induction of other SOD isoenzymes or other antioxidant enzymes was observed. When stressed by exposure to > 99% oxygen, the EC-SOD null mutant mice display a considerable reduction in survival time compared to wild-type mice and an earlier onset of severe lung edema. These findings suggest that while under normal physiological conditions other antioxidant systems may substitute for the loss of EC-SOD; when the animal is stressed these systems are unable to provide adequate protection.

Animals↗
PubMed1995

Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. The National Cooperative Growth Study.

OBJECTIVE: To determine whether some patients with idiopathic short stature have partial resistance to growth hormone (GH). Patients with idiopathic short stature have decreased serum levels of the GH receptor-related GH-binding protein (GHBP), and low GHBP levels are associated with complete GH insensitivity (Laron) syndrome. We hypothesized that patients with idiopathic short stature and low GHBP levels may also have a degree of GH insensitivity. DESIGN: Retrospective analysis of patients in a multicenter study. SETTING: Ninety-six National Cooperative Growth Study centers in the United States and Canada. SUBJECTS: Five hundred eleven patients with idiopathic short stature who were treated with GH. All patients had a baseline height standard deviation score of less than -2 and a maximum stimulated GH level greater than 10 micrograms/L. Of these, 101 (20%) had a baseline GHBP standard deviation score of -2 or less. RESULTS: The patients with low GHBP levels, in comparison with those with normal GHBP levels, had a lower mean extracted standard deviation score for insulin-like growth factor I (-3.3 +/- 1.1 vs -2.5 +/- 1.4; p < 0.0001) but mean 12-hour GH values (2.8 +/- 1.1 vs 2.3 +/- 1.1 micrograms/L; p <0.0001). The differences between groups were statistically significant after control for age and weight-for-height standard deviation score. Among prepubertal patients, there was no significant difference between the low and normal GHBP groups in mean pretreatment or first-year growth rate (p = 0.74, 0.61 respectively) with comparable doses of GH. CONCLUSIONS: Patients with idiopathic short stature and low GHBP levels, compared with those with normal GHBP levels, had significantly lower standardized levels of insulin-like growth factor I, and higher mean 12-hour GH levels, which suggest partial GH insensitivity. There was no significant correlation of GHBP levels with the growth response to exogenous GH.

Body Height↗
PubMed1995

Expression of exon 3-retaining and exon 3-excluding isoforms of the human growth hormone-receptor is regulated in an interindividual, rather than a tissue-specific, manner.

GH has multiple effects on growth and metabolism, and these functions are mediated through binding to specific cell surface receptors. The human GH receptor (GHR) exists in two known isoforms; in one form exon 3 is present (GHR3+), and in the other, exon 3 is absent (GHR3-). Recent reports have suggested that the expression of the two isoforms is tissue specific and/or developmentally regulated. We used a reverse transcription-polymerase chain reaction assay to study the expression pattern of the two isoforms in a variety of tissues from normal subjects and patients with acromegaly. In skeletal muscle from both normal subjects and patients with acromegaly, the GHR3+ transcript was expressed, either alone or together with the shorter (GHR3-) transcript. When multiple tissues from six subjects were tested, the expression of the two isoforms varied among subjects, whereas different tissues from the same subject showed the same expression pattern. These results indicate that the expression of the GHR isoforms is not tissue specific. Instead, the expression of the GHR isoforms appears to be specific for each individual, suggesting that it is under the control of factors that affect all tissues in the body.

Adipose Tissue↗
PubMed1995

Acute and chronic effects of subcutaneous growth hormone (GH) injections on plasma levels of GH binding protein in short children.

A ligand-mediated immunofunctional assay was used to measure levels of GH binding protein (GHBP) in plasma from children on GH treatment. Blood was drawn at the time of sc injection of GH and thereafter every 2 h for 16 or 24 h in the acute group. The samples were analyzed for GHBP and GH. To study changes in GHBP levels after onset of GH treatment, samples were taken at the start and after 10, 30, and 90 days of treatment (short-term group) and at the start and after 1 and 2 yr of treatment (long-term group). All children in the short-term and long-term groups were prepubertal throughout the study. For the study of short-term and long-term effects of GH treatment, the children were divided into two groups according to the maximal GH response (GHmax) in an arginine-insulin tolerance test and, if available, the maximum peak on 24-h secretion. Children with a GHmax below 20 mU/L(10 micrograms/L) were classified as GH deficient (GHD), and children with a GHmax above 20 mU/L were classified as children of short stature (SS). In the acute group, GH was injected either at 1800 h (n = 73) or at 1000 h (n = 12). In the group given GH at 1800 h there was a decrease in GHBP levels, with the lowest values occurring after 8-10 h, i.e. between 0200 and 0400 h. We have previously reported that there was no correlation between endogenous GH peaks and changes in GHBP levels, but there was a small but significant diurnal variation in GHBP levels (coefficient of variation of about 10%), with a nadir between 0000 and 0400 h. In the group given GH at 1000 h, GHBP levels decreased to a minimum at 10 h after injection (at 2000 h, P < 0.01), with a further decrease at 16 h after injection (P < 0.05), corresponding to the nadir seen in normal children. The mean GHBP levels fell to 71.2% of the baseline value after 90 days in children with GHD (P = 0.004), but was unchanged in children with SS (P = 0.92). In children with GHD, the GHBP levels were unchanged at 1 yr (100.5% +/- 10.7) and 2 yr (97.1% +/- 6.6) after start of treatment. In children with SS, there was no significant increase after 1 yr (125.6% +/- 10.9, P = 0.16) and 2 yr (120.3% +/- 6.4, P = 0.17).(ABSTRACT TRUNCATED AT 400 WORDS)

Body Height↗
PubMed1994

Growth hormone-binding protein levels: studies of children with short stature.

A high-affinity growth hormone-binding protein (GHBP) in serum is derived from the extracellular domain of the GH receptor. In an attempt to investigate the differences in GHBP levels in various conditions of poor growth, we measured GHBP levels by two methods--an Ultrogel chromatographic technique and a ligand-mediated immunofunctional assay (LIFA). The following three groups of children were studied: Turner's syndrome (n = 7), idiopathic and/or familial short stature ([ISS] n = 15), and organic or idiopathic hypopituitarism (n = 19). All groups were similar in age (Turner's syndrome, 10.1 +/- 0.9 years; ISS, 10.0 +/- 0.7; hypopituitarism, 11.5 +/- 1.0) and height SEM score (Turner's syndrome, -2.9 +/- 0.3; ISS, -3.0 +/- 0.4; hypopituitarism, -2.3 +/- 0.4). Their values were compared with those values of GHBP in healthy controls of similar age. Immunofunctional assay values for GHBP were as follows: Turner's syndrome, 235.4 +/- 26.0 pmol/L; ISS, 122.4 +/- 11.0; and hypopituitarism, 157.1 +/- 23.0. These results were significantly different in subjects with ISS and hypopituitarism as compared with a group of healthy controls between the ages of 9 and 12 years (N = 255; GHBP = 287.9 +/- 10.9 pMol/L; P < .001 compared with both ISS and hypopituitarism). Similar changes were found using Ultrogel chromatography. This difference in GHBP levels is still significant even when more stringent criteria are applied to define hypopituitarism (ie, peak GH responses to stimuli < 6.0 ng/mL, instead of < or = 10 ng/mL originally).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-I in adolescents with insulin-dependent diabetes mellitus.

OBJECTIVE: It has been proposed that the dissociation between growth hormone secretion and insulin-like growth factor-I (IGF-I) concentrations in insulin-dependent diabetes mellitus arises because of partial resistance at the GH receptor. In order to explore this hypothesis further we have examined the relations between IGF-I, GH-binding protein (GHBP), and GH secretion in normal subjects and patients with diabetes during puberty. DESIGN AND SUBJECTS: Blood samples for the estimation of IGF-I and GHBP levels were obtained from 104 patients with diabetes and 89 puberty matched controls. Thirty-four of the controls and 42 of the patients with diabetes also underwent an overnight GH secretory profile with measurements of GH every 15-20 minutes between 2000 and 0800 h. RESULTS: In multivariate analysis using sex, puberty stage, and presence or absence of diabetes as dependent variables, diabetes was associated with increased GH levels (F = 23.04, P < 0.001), reduced IGF-I (F = 10.89, P < 0.001), and reduced GHBP levels (F = 31.36, P < 0.001). A negative relation between GH and GHBP levels (r = -0.44, P < 0.01) was found in normal subjects but this was absent in those with diabetes. Both GHBP and IGF-I levels in the diabetic subjects were correlated with total insulin dose (r = 0.4, P < 0.001, and r = 0.46, P < 0.001, respectively). Yet there was no direct correlation between GHBP and IGF-I concentrations. The variation in IGF-I levels was also related to glycosylated haemoglobin levels in the diabetics (r = -0.27, P = 0.01). In a stepwise multiple regression analysis insulin dose contributed 23%, HbA1 4.4% and C-peptide levels 3.7% to the variation in IGF-I levels. CONCLUSIONS: In adolescents with insulin dependent diabetes mellitus, the elevated GH concentrations are associated with low circulating IGF-I and GHBP concentrations and the normal reciprocal relation between GHBP and GH is no longer evident. Although IGF-I and GHBP are both related to insulin dose, there is no direct correlation between these variables. This may indicate that GHBP reflects GH receptor numbers but not necessarily post receptor events, and the weak positive correlation between GH and IGF-I indicates that increased growth hormone secretion may compensate for reduced receptor numbers.

Adolescent↗
PubMed1994

Reduced concentration of serum growth hormone-binding protein in children with idiopathic short stature. National Cooperative Growth Study.

One possible explanation for the growth failure in children with idiopathic short stature (ISS) is reduced peripheral responsiveness to GH. In Laron syndrome, growth retardation is caused by GH resistance due to GH receptor (GH-R) defects, which are associated in most cases with absent or low serum concentrations of the GH-R-related GH-binding protein (GHBP). We tested the hypothesis that some children with ISS have reduced serum concentrations of GHBP and that this may reflect decreased sensitivity to GH. A ligand-mediated immunofunctional assay was used to measure biochemically active GHBP in serum from 1549 children, including 773 controls, 573 with ISS, 107 with GH deficiency (GHD), and 96 with Turner syndrome (TS). Ages ranged from 1-17 yr. Serum GHBP concentrations in children with GHD, ISS, and TS were converted to SD scores and compared to controls by analysis of variance. In male and female ISS subjects, approximately 90% had GHBP concentrations below the age- and sex-adjusted mean for controls, and 20% had GHBP concentrations below the normal range. The mean serum GHBP SD score was lower in both males and females with GHD (-0.6) or ISS (-1.2) than in controls (both P < 0.005). The mean for ISS males was significantly lower than that for GHD males (P < 0.0001). The mean GHBP SD score for girls with TS (-0.3) did not differ significantly from that of the control females. The decreased levels of serum GHBP in some children with idiopathic short stature suggest that these children could have a defect at the level of the GH-R.

Adolescent↗
PubMed1993

Analysis of 24-hour plasma profiles of growth hormone (GH)-binding protein, GH/GH-binding protein-complex, and GH in healthy children.

Human blood contains a high affinity GH binding protein (GHBP) which corresponds to the extracellular domain of he GH-receptor. It has been suggested that GHBP can modify the biological actions of GH, and alter the distribution of GH in the body. To study the hormonal regulation of growth, it is therefore necessary to measure GHBP as well as GH. We recently developed a ligand-mediated immunofunctional assay (LIFA) which allows separate quantitation of total GHBP (free and GH-bound) and the complex formed by GH and GHBP (GH/GHBP-complex) in human blood. We have now used the ligand-mediated immunofunctional assay to measure GHBP levels in plasma profiles from healthy children. GH was measured by immunoradiometric assay. Fifteen 24-h plasma profiles from 12 healthy children (3 girls and 9 boys) of different ages (6-15 yr), heights (-2.5 to +3.0 SD scores) and pubertal stages (1-4) were examined. Blood was withdrawn continuously for 24 h and collected in 20-min fractions. Time series for GH, GHBP, and GH/GHBP-complex were analyzed by cross-correlation and Fourier analysis. GH was secreted in a pulsatile fashion in all subjects. The concentration of the GH/GHBP-complex varied during the sampling period, and the changes correlated significantly with the GH pulses with correlation coefficients reaching maximum at zero time lag. In contrast, the changes in the total GHBP concentration were minor (coefficients of variation approximately 10%), and not correlated to GH pulses. Fourier analysis showed similar spectral power patterns for GH and GH/GHBP-complex, suggesting a diurnal rhythm (12- to 24-h periods) as well as components of higher frequencies (around 4-h periods). Although there were only subtle fluctuations in the total GHBP concentration, Fourier transformation revealed a diurnal rhythm with nadir during the night, while components of higher frequencies were much less abundant. We conclude that variations in total GHBP as measured by LIFA during a 24-h sampling period are small and that the concentration can be estimated from a single random blood sample.

Adolescent↗
PubMed1993

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. I. Serum growth hormone-binding protein.

Previous studies have provided compelling evidence that GH secretion increases transiently during midpuberty in normally growing children. Although it is likely that the increase in GH production serves a primary role in generating the pubertal growth spurt, such a conclusion necessarily assumes that other essential "down-stream" components of the GH axis responsible for mediating the effects of GH remain unchanged. To investigate this concept, we assessed longitudinally another important component of the endogenous GH axis, the serum GH-binding protein (GHBP)/receptor system, in a cohort of 11 normal boys as they matured through normal puberty. At 4-month intervals over 4.0-5.1 yr, 24-h serum GH concentration profiles and serum GHBP activity were evaluated. Serum GHBP levels varied over a more than 12-fold range (40-504 pmol/L) among all subjects. However, the values for individual subjects consistently varied within more narrow limits. The coefficient of variation for values from all subjects was 51% compared to the mean intrasubject coefficient of variation of only 30% (P < 0.05). Although the highest GHBP level (all subjects) was 12.6-fold greater than the lowest, the mean intrasubject range was only 3.1 +/- 0.5-fold (P < 0.05). The overall mean serum GHBP level correlated directly with the overall mean body mass index (r = 0.69; P = 0.018), but correlated inversely with the mean 24-h GH concentration (r = -0.61; P < 0.05). There was no significant increase in the GHBP level during puberty. However, because mean 24-h GH concentrations did increase during midpuberty, the data suggest that an increase in the relative amounts of free vs. bound GH develops during the period of the pubertal growth spurt. These data indicate that serum GHBP levels are regulated in individual children within much more narrow limits than those present in the larger population and do not undergo the dramatic changes during puberty typical of GH secretion and linear growth velocity. As a consequence, alterations may develop in the relative amounts of free vs. bound GH present in serum during the midpubertal years compared to those present during either the prepubertal or postpubertal periods. The majority of the known age-related increase in serum GHBP levels probably occurs before the period of active pubertal development. These findings strengthen further the concept that the midpubertal changes in GH secretion serve a primary role in generating the growth spurt.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Determination by Skeleton↗
PubMed1992

The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins.

We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low weight patients with anorexia nervosa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding.

Adult↗
PubMed1992

Growth hormone (GH)-binding protein in normal and GH-deficient dwarf rats.

There are GH-binding proteins (GHBPs) present in the blood of many species, and these correspond to the extracellular GH-binding domain of the GH receptor. In the rat, GHBP arises by alternative splicing of the GH receptor mRNA, but little is known of the physiological role of circulating GHBP, or its relationship with episodic GH secretion. We have developed a sensitive radioimmunoassay based on recombinant GHBP, and have measured rat GHBP levels in small samples of plasma from normal and GH-deficient dwarf rats. In normal adult rats, GHBP levels were two- to threefold higher in females than in males (16.6 +/- 0.8 vs 6.4 +/- 0.4 micrograms/l, P < 0.001), but this sex difference was not seen in dwarf rats. A continuous infusion of human GH in dwarf males raised plasma GHBP to 23.5 +/- 3.5 micrograms/l compared with 6.7 +/- 0.5 micrograms/l in sham-infused animals, whereas suppression of GH by continuous infusion of a long-acting somatostatin analogue in female dwarf rats had no effect on GHBP. In anaesthetized rats, large changes in plasma GH caused by i.v. administration of rat GH, somatostatin or GH-releasing factor did not affect GHBP acutely. Both GH and GHBP were also measured in serial blood samples from conscious normal and dwarf rats. A sexually dimorphic GH secretory pattern was observed in both strains. Males showed peaks and troughs of GH every 3 h varying over a 100-fold range, whereas females exhibited more continuous GH secretion. Despite the large fluctuations in endogenous GH, GHBP levels remained relatively constant in individual normal or dwarf males, as well as in females of both strains, and there was no significant correlation between GH and GHBP either in individual rats or as a group. Our results suggest that GHBP is GH-dependent in the longer term, and that the higher GHBP levels in female rats require their continuous GH secretory pattern. However, plasma GHBP levels remain stable and are not affected by acute changes in endogenous or exogenous GH.

Animals↗
PubMed1991

Ligand-mediated immunofunctional assay for quantitation of growth hormone-binding protein in human blood.

Human serum contains a high affinity GH-binding protein (GHBP) whose amino-terminal sequence is identical to the extracellular domain of the GH receptor. Current methods that measure GHBP are laborious, require size or charcoal separation of the GH/GHBP complex, and may be influenced by ambient GH concentrations. We have developed a novel assay method that allows quantitation of the total amount of functional GHBP in serum or plasma. The assay can also be used to measure the concentration of the circulating GH/GHBP complex. An anti-GHBP monoclonal antibody, which recognizes both free GHBP and GH-bound GHBP, is used to capture the GHBP on a microtiter plate. Recombinant human GH is added to saturate all binding sites, and an anti-GH antibody conjugated with horseradish peroxidase is used to detect the amount of GH (endogenous and exogenous) bound to the GHBP. The same procedure, but without incubation with GH, allows measurement of the endogenous GH/GHBP complex. The assay is sensitive (detection range, 31-2000 pmol/L), with average inter- and intraassay precisions of 11.3% and 7.3%, respectively. Measurements in random blood samples from 16 healthy adults showed that all subjects had clearly detectable GHBP concentrations (range, 65.8-305.6 pmol/L). In contrast, GHBP levels were undetectable in samples from 2 patients with Laron-type dwarfism. We believe that this ligand-mediated immunofunctional assay, which combines the simplicity and specificity of an enzyme-linked immunosorbent assay with the ability to detect only biochemically active binding protein, will be useful for studies of the role of the GHBP in health and disease.

Antibodies, Heterophile↗
PubMed1991

Evidence for the role of the secretory pattern of growth hormone in the regulation of serum concentrations of cholesterol and apolipoprotein E in rats.

Adult male Sprague-Dawley rats were hypophysectomized and connected to an automatic i.v. infusion system. The same daily dose of human GH (hGH) was given either as eight daily pulses (3-h intervals) to mimic the male specific secretory pattern of GH or as a continuous infusion of GH, to mimic the female secretory pattern. Hypophysectomized rats received i.v. replacement therapy with L-thyroxine and cortisol. The rats were treated for 5 days. The serum cholesterol concentration was higher when hGH was given continuously than when hGH was given as eight daily pulses. The concentration of high-density lipoprotein (HDL)-cholesterol was not influenced by intermittent GH treatment, but increased when hGH was given as a continuous infusion. The serum concentration of apolipoprotein (Apo) E increased following treatment with a continuous infusion of hGH, whereas eight daily pulses of hGH had no effect. The serum concentration of ApoA-I was unaffected by hGH treatment. The serum concentration of ApoB decreased to the same degree whether hGH was given as a continuous infusion or as eight daily pulses. The serum concentration of triglycerides was not affected by hGH treatment. These results indicate that the higher serum HDL-cholesterol and serum ApoE concentrations of female rats may be due to their more continuous secretion of GH. In contrast, the effects of GH on the serum concentration of ApoB, which is not sexually differentiated, may be independent of the mode of GH secretion.

Animals↗