Body composition and circulating levels of insulin, insulin-like growth factor-binding protein-1 and growth hormone (GH)-binding protein affect the pharmacokinetics of GH in adults independently of age.
The aim of our study was to scrutinize the association among age, body composition, and GH status in healthy adults. Using two-step, primed constant infusions of GH during suppression of endogenous GH secretion with octreotide in a group of 26 healthy nonobese men [mean age, 37.3 yr (range, 22-55 yr); body mass index, 24.6 +/- 0.4 kg/m(-2)] we investigated the contributions of age, body composition, insulin, and binding proteins to the variability in the pharmacokinetics and acute actions of GH. All subjects were investigated twice, with the infusion rates of GH calculated according to either total body weight or intraabdominal fat mass. Body composition was determined using computed tomography and bioimpedance measurements. There was no correlation between age and body weight, yet strong positive correlations were observed between age and intraabdominal fat area (r = 0.78; P < 0.0001) and waist to hip ratio (r = 0.71; P < 0.0001) and to a lesser degree to sc fat area (r = 0.42; P < 0.03). The between-subject variability in steady state GH levels was significantly larger when GH was administered per cm(2) intraabdominal fat area than per kg BW (P < 0.001). During primed constant infusions of GH at rates of 1.5 and 3.0 microg/kg x h, the corresponding MCRs of GH were 148.8 +/- 5.4 and 89.8 +/- 2.4 ml/min x m(-2), respectively, and the MCRs were inversely related to the achieved steady state GH levels (P < 0.0001). The MCR was unrelated to age, but was negatively correlated to baseline concentrations of IGF-binding protein-1 (IGFBP-1; r = -0.53, P < 0.01) and positively correlated to basal levels of insulin (r = 0.46; P < 0.05), GH-binding protein (GHBP; r = 0.52; P < 0.01), IGFBP-3 (r = 0.47; P < 0.05), and total body fat (r = 0.44; P < 0.05). GH infusion caused significant changes in the concentrations of IGF-I, free fatty acids, GHBP, IGFBP-1, and insulin, but none of these effects was correlated to age. Based on our results we conclude that 1) the clearance of GH is concentration dependent; 2) the pharmacokinetics and acute effects of GH are not affected by age per se; and 3) basal levels of insulin, IGFBP-1, and GHBP as well as age-related changes in body composition are important predictors of GH pharmacokinetics.
Hansen
Troels Krarup
TK
Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, DK-8000 Aarhus C, Denmark. tkh@dadlnet.dk
Jørgensen
Jens Otto L
JO
Christiansen
Jens Sandahl
JS
D000328:Adult; D000375:Aging / Q000502:physiology*; D001823:Body Composition; D002352:Carrier Proteins / Q000097:blood*; D004338:Drug Combinations; D013006:Growth Hormone / Q000493:pharmacokinetics; D006728:Hormones / Q000494:pharmacology; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D007328:Insulin / Q000097:blood*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D009994:Osmolar Concentration; D011897:Random Allocation; D013997:Time Factors
D002352:Carrier Proteins; D004338:Drug Combinations; D006728:Hormones; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D019382:Human Growth Hormone; D013006:Growth Hormone; D015282:Octreotide; C051815:somatotropin-binding protein