Multifactorial control of the elimination kinetics of unbound (free) growth hormone (GH) in the human: Regulation by age, adiposity, renal function, and steady state concentrations of GH in plasma

To evaluate the principal determinants of the MCR and plasma t( 1/2 ) of unbound (free) GH in man, we performed steady state infusions of 3 doses of recombinant human GH during pharmacological suppression (iv octreotide) of endogenous GH secretion in 24 healthy adults and 32 patients 16 adults and 6 children) with chronic renal failure (CRF). Free plasma GH was calculated from total plasma GH (measured by immunoradiometric assay) and GH-binding protein activity (radioligand assay). The MCR of free GH was determined from free plasma GH and the rate of recombinant human GH infusion. The t( 1/2 ) of free plasma GH, and the concentration and the in vive dissociation constant (K(d)) of GH binding protein (GHBP) were estimated by dynamic modeling of the postinfusion total plasma GH concentration decay curves. The MCR of free GH decreased and the plasma GH t( 1/2 ) increased significantly with increasing plasma GH concentrations. The MCR of free GH over its physiological concentration range was positively correlated with the body mass index as a measure of relative obesity and negatively related to age, but only at supraphysiological GH concentrations. In the adult patients with CRF, the MCR of free GH was decreased at each infusion rate by 25-38%, and the t( 1/2 ) was increased by 80-170%. Children with CRF showed a significantly lower MCR and higher t( 1/2 ) of plasma free GH than adult patients. Modeling and direct measurements of the off-rate of GH from its high affinity GHBP indicated normal dissociation rate constants but decreased molar concentrations of the GHBP in uremic plasma. We conclude that the rate of elimination of free GH from plasma in man is controlled by 1) plasma total free GH concentrations, 2) relative obesity, and 3) renal function within the physiological GH concentration range, whereas 4) age is a negative predictor of MCR only at supraphysiological GH concentrations.