We investigated the effect of 12 weeks of recombinant human GH therapy given in three different doses on serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) in patients with GH deficiency (GHD). We used low doses of recombinant human GH (Genotropin), as we and others recently found a strong decrease in physiological GH production with age in healthy controls, especially in those older than 30 yr. Sixty patients with GHD (aged 20-70 yr) were randomized to one of the three dose groups. Group 1 used a dose of 0.6 IU/day for 12 weeks. Group 2 started at a dose of 0.6 IU for 4 weeks followed by 1.2 IU/day for 8 weeks. Group 3 used 0.6 IU for 4 weeks, followed by 1.2 IU/day for 4 weeks and 1.8 IU/day thereafter. IGF-I concentrations (nanomoles per L) were determined by RIA after extraction and purification on ODS-silica columns. The measurement of IGFBP-3 (milligrams per L) was performed by RIA. The three groups were equal with regard to age, sex and body mass index. At the start of the study, we found lower levels of both serum IGF-I and IGFBP-3 in childhood-onset GHD than in adult-onset GHD. Moreover, there was a gender difference; female GHD patients had lower serum IGF-I levels than male patients. Serum IGF-I levels were low in both childhood-onset and adult-onset GHD. Serum IGFBP-3 levels, however, were low in patients with childhood-onset GHD, but normal in patients with adult-onset GHD. After 12 weeks of treatment, IGF-I levels were low normal in the low dose group and normal in groups 2 and 3 of both adult-onset and childhood-onset GHD. In adult-onset GHD, serum IGFBP-3 increased to high normal levels in all groups, whereas it increased to low normal levels in childhood-onset GHD. This study demonstrates differences in the biochemical characteristics of childhood-onset and adult-onset GHD. In patients with adult-onset GHD, serum IGFBP-3 levels are not significantly decreased and, therefore, cannot be used as a screening method for GHD or as a dose-finding parameter. GH therapy at doses of 0.6 and 1.2 IU/day in male and female patients, respectively, is, in general, able to increase serum IGF-I into the normal range after 12 weeks of treatment, without reaching supranormal levels of serum IGF-I. This dose could, therefore, be a starting dose in GH-deficient adults.
Adults with GH deficiency (GHD) suffer from muscle weakness, which can be caused by the frequently reported decrease in muscle mass. However, measurements of both muscle strength and mass of muscle tested are scarce in adults with GHD. The aim of the present study was, therefore, to investigate intrinsic muscle strength (strength expressed per muscle volume unit) in adults with GHD at baseline and after 52 weeks of recombinant human GH (rhGH) therapy given in low, more physiological doses. A second objective was to investigate the influence of GH on muscle bioenergetics in the resting muscle. Isometric and isokinetic quadriceps strengths were measured in 28 males with GHD and in healthy controls matched for age and height. Quadriceps mass, determined by magnetic resonance imaging, and muscle bioenergetics, determined by phosphorus nuclear magnetic resonance spectroscopy, were measured in 20 of 28 patients with GHD and in controls matched for age and height. All patients were treated with doses of rhGH ranging from 0.6-1.8 IU/day, given for 52 weeks. Measurements of muscle mass, strength, and bioenergetics were repeated after 52 weeks of treatment with rhGH. The mean GH dose at 52 weeks of rhGH treatment was 1.3 +/- 0.8 IU/day. The mean serum insulin-like growth factor I level at baseline was 9.4 +/- 0.7 nmol/L and significantly increased to 26.4 +/- 1.2 nmol/L after 52 weeks of rhGH treatment. Adults with GHD had significantly reduced quadriceps muscle mass (P = 0.034) and reduced isometric muscle strength (P = 0.002) and tended to have low isokinetic muscle strength (P = 0.06), which all improved after rhGH therapy. Intrinsic muscle strength was not significantly different in adults with GHD compared with that in healthy controls and did not change during rhGH therapy. No bioenergetic abnormalities at baseline or after rhGH therapy were found in males with GHD. In conclusion, quadriceps muscle mass is decreased in adults with GHD and increased with rhGH therapy. These changes in muscle mass account for the changes in muscle strength found in these patients, as no changes in intrinsic muscle strength were found.
A low bone mass in adults with childhood-onset GH deficiency (GHD) is likely to be caused by deficient bone accretion during childhood and early adulthood, whereas a decreased bone mass in patients with adult-onset GHD is likely to be caused by an imbalance in bone remodeling. Data on bone mineral density (BMD) and biochemical parameters of bone metabolism and data on response of these parameters to treatment with GH are scarce in patients with adult-onset GHD. It has been suggested that in patients with GHD, GH at the relatively high dose originally used may have beneficial effects on the skeleton. To address the question as whether lower, more physiological doses would have similar effects on the skeleton, we studied 47 patients with adult-onset GHD (27 women and 20 men, range 26-70 yr) randomized to receive one of three recombinant human GH (rhGH) dose regimens: 0.6 IU/day, 1.2 IU/day, or 1.8 IU/day as part of a study examining optimal GH dose replacement therapy. After 24 weeks of treatment, the dose of rhGH was individually adjusted to maintain the concentration of serum insulin growth factor-I within the normal laboratory reference range. Biochemical parameters of bone metabolism were measured at baseline and after 24 and 52 weeks and 2 yr of treatment. BMD of the lumbar spine was measured at baseline and after 52 weeks and 2 yr of treatment. Parameters of bone metabolism generally fell within the low-normal range and increased in a dose-dependent manner at 24 weeks of treatment. Between 24 and 52 weeks of rhGH treatment, mean serum osteocalcin levels and alkaline phosphatase activity further increased, whereas mean 24-h urine hydroxyproline/creatinine and N-telopeptide/creatinine excretion remained unchanged. After 52 weeks of treatment, serum alkaline phosphatase activity and 24-h urine hydroxyproline/ creatinine excretion decreased, although not to pretreatment levels. Mean BMD at the lumbar spine (Z-score) was normal at baseline (-0.20 +/- 0.16) and increased during treatment (at 2 yr of treatment: 0 +/- 0.20; P < 0.005). Our data suggest that a low physiological dose of rhGH, individually adjusted to maintain serum insulin-like growth factor I levels within the normal laboratory reference range, increased bone turnover in favor of bone formation, as suggested by the significant, albeit small increase in BMD observed after 2 yr of treatment. Further studies are required to establish whether in patients with adult-onset GHD the preservation and/or increase in bone mass observed with the use of physiological doses of rhGH could be maintained with longer-term treatment.
Objective: Recent studies suggest an involvement of the obese (ob) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. Design: Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. Methods: Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. Results: At baseline, serum leptin levels were exponentially related to body fat percentage (r=0.88; P<0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 Ϯ 2.9 to 10.8 Ϯ 2.1 mg/l; P ¼ 0:020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 Ϯ 2.1 to 33.8 Ϯ 2.5%; P < 0:0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. Conclusions:The influence of GH on serum leptin is indirect, via its effect on body fat percentage. European Journal of Endocrinology 137 650-654
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