Ragnar Bjarnason

Two weeks of daily injections and continuous infusion of recombinant human growth hormone (GH) in GH-deficient adults: 1. effects on insulin-like growth factor-I (IGF-I), GH and IGF binding proteins, and glucose homeostasis☆

Recombinant human growth hormone (GH) is routinely administered as daily subcutaneous injections to patients with GH deficiency (GHD). However, in the hypophysectomized rat, pulsatile and continuous infusion of GH has been shown to differ in terms of the magnitude of effect on longitudinal bone growth, serum insulin-like growth factor-I (IGF-I) concentrations, and hepatic metabolism. The aim of the present study was to compare the effects of daily injections and continuous infusion of GH in GHD adults on previously well-documented GH-dependent factors. Recombinant human GH (0.25 U/kg/wk) was administered to nine men with GHD for 14 days in two different ways, ie, as a daily subcutaneous injection at 8 PM and as a continuous subcutaneous infusion, with 1 month of washout between treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. An oral glucose tolerance test (OGTT) was performed on day 0 and day 14. Daily injections and continuous infusion of GH exerted similar effects in terms of body weight and body composition. The two modes of administration resulted in similar daily urinary GH excretion and similar serum GH concentrations in the morning. GH binding protein (GHBP) concentrations did not change significantly during the various treatment periods. Serum IGF-I and IGF-I binding protein (IGFBP)-3 concentrations increased to a greater degree during continuous infusion of GH versus daily injections. Serum IGFBP-I concentrations decreased to a similar degree during the two modes of administration. Serum concentrations of free triiodothyronine and total triiodothyronine (T3) increased and free thyroxine (T4) decreased to a similar degree, independent of the mode of administration. However, total T4 concentrations were unchanged during both modes of treatment. Serum thyrotropin (TSH) concentrations decreased during continuous infusion, and there was a similar nonsignificant decrease during daily injections of GH. Fasting free fatty acid (FFA) levels increased during treatment with only daily injection of GH, but there was no significant effect from continuous infusion. Results of measurements of fasting concentrations of blood glucose and oral glucose tolerance (OGT) indicated a more impaired glucose tolerance after daily injections of GH versus continuous infusion. In conclusion, continuous infusion and daily injections of GH have similar effects on the variables described, but the magnitude of the effects differs.

Standard and low‐dose IGF‐I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature

objective  Abnormalities in the GH–IGF‐I axis, consistent with GH insensitivity (GHI), have been reported in some patients with idiopathic short stature (ISS). The standard IGF‐I generation test (IGFGT) has not demonstrated mild GHI in subjects with ISS. The aim of this study was to investigate the GH–IGF‐I axis in ISS by performing standard and novel low‐dose IGFGTs together with determination of spontaneous GH secretion.

Currently used growth‐promoting treatment of children results in normal bone mass and density. A prospective trial of discontinuing growth hormone treatment in adolescents

BACKGROUND AND AIMS The need for continued GH replacement in patients with childhood‐onset GH deficiency (GHD) into adulthood has been recognized. The consequences of discontinuing GH treatment on bone mineralization in adolescent patients with GHD and short stature were examined over a period of 2 years.

Spontaneous growth hormone secretory characteristics in children with partial growth hormone insensitivity.

objective To investigate the characteristics of spontaneous GH secretion in four male children with short stature due to partial GH insensitivity. Their molecular defect consists of inclusion of a mutant intronic pseudoexon in the region of the GH receptor involved in homodimerization.

Growth Hormone-Binding Protein Levels over One Year in Healthy Prepubertal Children: Intraindividual Variation and Correlation with Height Velocity

The role of GH-binding protein (GHBP) in growth regulation is still under debate. We investigated 29 prepubertal healthy children (13 girls/16 boys; mean age 9.3 y to study intraindividual variation in serum GHBP and to explore whether any such variation was related to changes in IGF-I, IGF-binding protein-3 (IGFBP-3) or urinary excretion of GH. The relationship between changes in GHBP concentrations, short-term height velocity, and changes in body composition was also studied. Blood samples were taken every month for 1 y, for measurements of GHBP, IGF-I, and IGFBP-3. The mean coefficient of variation in monthly GHBP concentrations in individual children was 18%(range, 6.7-33.0%). The values for each child were normalized by expressing the concentration as a ratio to the mean GHBP concentration. GHBP values were highest in January and lowest in August (22% difference). Maximal monthly changes in GHBP correlated with simultaneous changes in weight(rs = 0.38, p < 0.05) and IGF-I(rs = 0.38, p < 0.05). The mean GHBP concentration during the year correlated with height velocity(rs = 0.37, p < 0.05) and the mean serum concentration of IGF-I (rs = 0.42, p < 0.05) and IGFBP-3 (rs = 0.60, p < 0.001). We conclude that there is a significant monthly variation in GHBP concentrations in healthy prepubertal boys and girls, which is correlated to changes in weight and IGF-I. The mean GHBP concentration during the year is correlated with the mean serum concentrations of IGF-I, IGFBP-3, and with height velocity. Thus, the variation in GHBP concentrations appears to mirror GH sensitivity, because no parallel changes in urinary GH excretion were observed.

Short-term gluten challenge in children with coeliac disease does not impair spontaneous growth hormone secretion.

BACKGROUND Growth retardation in children with coeliac disease has been attributed to impaired growth hormone (GH) secretion observed in stimulation tests. OBJECTIVE This study aimed at investigating the possible change in spontaneous GH secretion during a standardised gluten challenge. PATIENTS Twelve children with previous enteropathy suggesting coeliac disease and a normal pre-challenge biopsy on a gluten-free diet were included; eight of them completed all parts of the study, including repeated 24-h GH sampling. METHODS At the start and the end of a 5-6 weeks standardised gluten challenge, blood was drawn at a constant rate for 24 h and collected for GH analysis at 20-min intervals. The graph of plotted GH values was analysed by means of a computer program (PULSAR). RESULTS No significant changes were seen in the measures of maximum GH peak, baseline GH values, area under the curve over the baseline (AUCb), the number of GH peaks or mean GH concentration. GH secretion rate (GHt) increased slightly. None of the characteristics of the 24-h profile was significantly correlated to the change of IGF-I. CONCLUSION No impaired GH secretion was found. Thus, we speculate that decreased growth rate in celiac disease may not be primarily caused by changes in GH secretion. Instead it may be caused by changed peripheral sensitivity to GH.

GROWTH HORMONE SECRETION IN HEALTHY CHILDREN IS NOT A MAJOR DETERMINANT OF BODY COMPOSITION MEASURED AS BIOELECTRICAL IMPEDANCE

Bioelectric Impedance (BIA) correlates wiih anthropometric methods as well as oiher methods to estimate body composition in humans. In children BIA has mainly been used in nutritional studies, whereas hormonal influences have not been studied. In adults excess and deficiency of GH markedly change the body composition.Aim: The aim of this study was to find out if the variation of GH secretion in children influences their body composition measured as BIA.Material and methods: BIA measurements (n=221) were performed at standardized conditions in 189 children (140 male, 87 prepub/53 pub, 81 female, 31/50) with a mean age of 11.8 (SD 3.5) and range 2.0-19.9 years; mean height SDS of -1.09, range -4.3 to 4.4 and with a mean spontaneous 24h-GH secretion expressed as peak secretion (AUCb) of GH mU/L/24h (range 25-268 mU/L/24h). The children were investigated due to short or tall stature or were normal controls. Only children with severe GH deficiency (AUCb < 25 mU/L) were excluded. The technical error of the BIA measnremenl was 2%. The BIA measure is expressed as Height2/Resistance (H2/R) or as fat free mass (FFM) calculated by formulas by Deurenberg et al, for prepubertal (Eur-J-Clin-Nutr. 1989:43,623-9) and pubcrtal children (Eur-J-Clin-Nutr. 1990:44. 261-8).Results: In a multiple regression model, weight followed by sex and pubertal stage were the main determinants of H2/R (r=0.97) and FFM (r=0.99). Baseline-GH(*) and AUCb(***) add a significant but minor part to the model. All GH parameters where significant for prepubertal boys (GHt(***), AUCb(*), baseline(*) but not for the other subgroups (pre/pub girls and pub boys).Conclusion: Body composition measured by BIA in healthy children varies with weight, sex and puberial stage, but only 10 a minor degree with GH secretion. Therefore the dose response curves of GH are different for growth and metabolic effect, measured by BIA. The relationship in severely GH deficient or hypersecreiing children remains to be studied.