Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) deficiencies have been associated with osteopenia in both children and adults. To examine the effects of growth hormone resistance on bone mineral and body composition, we studied 11 adults (mean age 30 years) with growth hormone receptor deficiency (GHRD, Laron syndrome) and 11 age- and gender-matched controls from Southern Ecuador. Bone mineral and body composition were determined by dual-energy X-ray absorptiometry. Bone physiology was assessed with biochemical markers of bone turnover and dynamic bone histomorphometry. Bone size and body composition differed markedly between subjects with GHRD and controls. Affected adults were 40 cm shorter than controls, had significantly less lean body mass, and had increased percent body fat. Bone mineral content and density (BMD) at the spine, femoral neck, and whole body were significantly lower in adults with GHRD than in controls. Mean BMD Z scores were -1.5 to -1.6 at all sites in affected women and -2.2 to -2.3 in men with GHRD. Estimated volumetric bone density (BMAD) at the spine and femoral neck, however, was not reduced in GHRD. Spine BMAD was 0.210 +/- 0.025 versus 0.177 +/- 0.021 for affected women versus controls (p < 0.05) and 0.173 +/- 0.018 versus 0.191 +/- 0.025 for men with GHRD versus normals (p = 0.31). Urinary pyridinoline concentrations were significantly greater in adults with GHRD than in controls, while type I collagen C-telopeptide breakdown products and markers of bone formation did not differ. Differences in histomorphometry were limited to a reduction in trabecular connectivity; bone volume and formation rate were similar to controls. These data confirm the importance of the GH/IGF axis in regulating bone size and body composition. The contribution of these peptides to the acquisition and maintenance of bone mineral is less certain since volumetric bone density was preserved despite low levels of IGF-I and IGFBP-3 associated with GH resistance.

Kinetics of insulin-like growth factor (IGF) and IGF-binding protein responses to a single dose of growth hormone.

The in vivo physiological relationships among GH, the insulin-like growth factors (IGFs), and the IGF-binding proteins (IGFBPs) are not completely defined, and single random measurements of these serum proteins do not completely reveal their dynamic relationships. We report the kinetic responses of the IGFs and IGF-binding proteins to exogenous GH in 23 subjects with untreated GH deficiency [5 women and 18 men; age, 15.0 +/- 6.2 yr (+/- s.d.), height z-score = -4.4 +/- 2.2 (+/- s.d.); body mass index = 19.3 +/- 2.4 kg/m2]. After an overnight fast, subjects were given a sc dose of recombinant human GH (2.85 i.u./m2), and blood was sampled from an indwelling peripheral venous catheter 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 h after the injection. Subjects were then treated with recombinant human GH (2.85 i.u./m2.day); fasting samples were obtained at 3 months (n = 22), and timed sampling was repeated at 6 months (n = 21). Fasting levels of IGF-I, free IGF-I, IGF-II, IGFBP-3, and insulin increased significantly within 3 months of GH treatment, whereas IGFBP-1, IGFBP-2, and IGFBP-6 showed no change. In the timed sampling studies at 0 and 6 months, GH levels peaked 3 h after treatment; the degree of rise and the rate of decline were both greater at 6 months. IGF-I levels increased beginning at 4 h, continuing throughout the 24-h period at month 0, whereas a plateau was observed after 6-8 h during the 6-month study. Free IGF-I paralleled total IGF-I except during fasting, when it varied inversely with IGFBP-1. IGFBP-3 and IGF-II both showed late (> 20 h) responses to a dose of GH, whereas IGFBP-2 and IGFBP-6 showed minimal changes. IGFBP-1 varied inversely with insulin, which, in turn, varied with meal intake. Comparative studies in 2 subjects with GH receptor deficiency showed no response to exogenous GH. However, both IGFBP-1 and IGFBP-2 were several-fold elevated, and IGFBP-1 varied inversely with the low insulin levels. Our data are the first to examine multiple elements of the serum IGF system in response to GH in both GH-deficient and replete states. The relationships of the different response patterns provide insight into the physiology of this system and may guide future studies.

Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dosage levels and to GH-treated GH deficiency.

We have reported 1-yr results of a double blind, placebo-controlled trial of recombinant human insulin-like growth factor I (rhIGF-I) replacement in 16 children from the Ecuadorian GH receptor-deficient (GHRD) population. This report extends observations of rhIGF-I efficacy at two dosage levels [120 micrograms/kg BW twice daily (n = 15) and 80 micrograms/kg twice daily (n = 7)] over 2 yr, compares biochemical responses [serum IGF-I and IGF-binding protein-3 (IGFBP-3)] and their relationship to growth effects, and compares treatment effects of rhIGF-I in GHRD to rhGH in idiopathic GH deficiency (GHD). There were no baseline differences between the low and high dose groups for growth velocity (GV), bone age (BA), SD score for height, or percent mean body weight for height (MBWH). Over 2 yr of rhIGF-I treatment, there were no differences in GV or in changes in height SD score, height age (HA), or BA between the two groups; a subgroup of six subjects at the higher dose followed for a third year continued at the second year GV. The higher dose resulted in a greater change in percent MBWH. GV in yr 1 and 2 for the entire group and in yr 3 for a subgroup were greater for GH-treated GHD (n = 11). The GHD group showed a greater change in SD score for height and HA, but did not differ from the rhIGF-I-treated GHRD group in the change in BA (delta BA) or delta HA/delta BA over 2 yr. There was a greater change in percent MBWH in GHRD. There were no differences between dosage groups for serum IGF-I levels at baseline or the near-normal trough levels 12 h after rhIGF-I injection; these individual levels correlated with HA gain in yr 1 and 2. IGFBP-3 levels were markedly low, with no changes of significance with treatment. Comparable growth responses to the two dosage levels and the biochemical changes indicate a plateau effect at or below 80 micrograms/kg BW twice daily. The growth response and favorable trough levels of IGF-I despite the overall lack of increase in circulating IGFBP-3 levels suggest an alternative mechanism for sustaining IGF-I levels and avoiding rapid clearance of rhIGF-I. The greater increase in MBWH with treatment of GHRD than with treatment of GHD may reflect comparable effects on lean body mass without the lipolytic effects of GH in the GHRD subjects. The difference in growth response between rhIGF-I-treated GHRD and rhGH-treated GHD groups is consistent with the hypothesis that 20% or more of GH-influenced growth is due to the direct effects of GH on bone. Nonetheless, the comparable delta HA/delta BA suggests similar long term effects of replacement therapy in the two conditions.

Long-term effects of insulin-like growth factor (IGF)-I treatment on serum IGFs and IGF binding proteins in adolescent patients with growth hormone receptor deficiency.

OBJECTIVE: The aim of this investigation was to study the effect of relatively high dose IGF-I therapy given for several months, on serum levels of IGF-I, IGF-II and IGFBP-3, and on IGF-I pharmacokinetics in patients with growth hormone insensitivity due to GH receptor dysfunction. DESIGN AND PATIENTS: Two adolescent subjects from Ecuador were treated with recombinant IGF-I at a dosage of 120 micrograms/kg s.c. twice daily, in combination with a GnRH analogue for 8 months. MEASUREMENTS: Serum was sampled at baseline and at 3-8 months, for determination of IGF-I, IGF-II and IGFBP-3 by radioimmunoassay, and for evaluation of IGFBPs and IGFBP-3 protease activity by Western ligand blot and protease assay, respectively. RESULTS: Peak serum IGF-I levels ranged from 272 to 492 micrograms/l. Mean serum IGF-II levels were decreased concurrently with the increase in IGF-I. Serum IGFBP-3 levels failed to rise with prolonged IGF-I treatment. There was no apparent change in the half-life of IGF-I during the treatment period. CONCLUSIONS: IGF-I administration does not increase serum levels of IGFBP-3 or significantly alter IGF-I pharmacokinetics.

A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency.

GH insensitivity due to GH receptor deficiency is a rare autosomal recessive condition, characterized by deletions or mutations of the GH receptor gene. Patients are refractory to both endogenous and exogenous GH, resulting in severe growth retardation. Therapy with recombinant human insulin-like growth factor-I (rhIGF-I) can bypass the defect in the GH receptor and potentially stimulate growth. We previously identified a genetically homogeneous group of patients in southern Ecuador, thus providing a patient base for a controlled clinical trial of rhIGF-I therapy. Seventeen prepubertal patients were entered in a randomized, double blind, placebo-controlled trial. Subjects received either a 12-month course of rhIGF-I (120 micrograms/kg, sc, daily) or 6 months of placebo followed by 6 months of rhIGF-I. Subjects receiving rhIGF-I showed a significant increase in growth rate, which was sustained over the 1-yr course of therapy (from 2.9 +/- 0.6 to 8.6 +/- 0.4 cm/yr). Incidents of hypoglycemia were equal in frequency in the placebo and rhIGF-I groups. One recipient of rhIGF-I developed papilledema, which resolved spontaneously. rhIGF-I therapy did not alter serum IGF-binding protein-3 concentrations. rhIGF-I treatment is effective in stimulating skeletal growth in GH receptor deficiency. Although the therapy proved to be safe, the potent metabolic actions of rhIGF-I and the persistently low levels of serum IGF carrier protein necessitate continued careful observation for side-effects.

Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: preliminary results.

Auxological and body composition changes were studied in three adolescent patients (2 female, 1 male) with growth hormone receptor deficiency (GHRD) given insulin-like growth factor I (IGF-I), 120 micrograms/kg s.c. twice daily, plus a monthly intramuscular injection of 7.5 mg of a luteinizing hormone-releasing hormone (LHRH) analogue. Preliminary results from the first 12 months of the study show that height velocity was increased compared with the pretreatment values. This increase was probably due to the IGF-I therapy, as the LHRH analogue would have suppressed gonadotrophins and gonadal steroid production. There was a reduction in percentage body fat, and increases in lean mass and the lean:fat ratio, whole body mineral content and body calcium content, even when expressed per kg body weight. There was also a trend towards increased bone mineral density of the whole skeleton, lumbar spine and femoral structures, as well as a maturation of facial features. These preliminary results indicate that concomitant therapy with IGF-I and an LHRH analogue is safe and efficacious in inducing growth without advancing bone age in patients with GHRD.

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I.

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin-like growth factor I (IGF-I) during part of a clinical trial. The IGF-I was given subcutaneously twice daily at a dose of 40 micrograms/kg on days 1 and 2, 80 micrograms/kg on days 3 and 4, and 120 micrograms/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1-7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF-I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non-significant glucose and electrolyte changes did not appear to be associated with the cardiac events.