UNEQUAL IMPACT OF AGE, PERCENTAGE BODY-FAT, AND SERUM TESTOSTERONE CONCENTRATIONS ON THE SOMATOTROPIC, IGF-I, AND IGF-BINDING PROTEIN RESPONSES TO A 3-DAY INTRAVENOUS GROWTH HORMONE-RELEASING HORMONE PULSATILEINFUSION IN MEN

Mie here investigate the potential rescue of the relative hyposomatotr opism of aging and obesity by 3-day pulsatile GHRH infusions (i.v bolu s 0.33 mu g/kg every 90 min) in 19 healthy men of varying ages (18 to 66 years) and body compositions (12 to 37% total body fat). Baseline ( control) and GHRH-driven pulsatile GH secretion tin randomly ordered s essions) were quantitated by deconvolution analysis of 24-h (10-min sa mpling) serum GH concentration profiles measured in an ultrasensitive (threshold 0.005 mu g/l) chemiluminescence assay GHRH infusion signifi cantly increased the mean (24-h) serum GK concentration (0.3 +/- 0.1 b asal vs 2.4 +/- 0.4 mu g/l treatment; P = 0.0001), total daily pulsati le GH production rate (21 +/- 9.5 vs 97 +/- 17 mu g/l/day: P = 0.01), GH secretory burst frequency (11 +/- 0.5 vs 17 +/- 0.3 events/day: P= <0.01). and mass of GH released per burst (1.1 +/- 0.4 vs 5.9 +/- 1 mu g/l; P<0.01), as well as serum IGF-I (261 +/- 33 vs 436 +/- 37 mu g/l ; P= 0.005), insulin (45 +/- 13 vs 79 +/- 17 mU/l: P=0.0002), and IGF binding protein (IGFBP)-3 (3320 +/- 107 vs 4320 +/- 114 mu g/l: P=0.00 1) concentrations, while decreasing IGFBP-1 levels (16 +/- 1.2 vs 14 /- 0.09 mu g/l: P = 0.02). Serum total testosterone and estradiol conc entrations did not change. GHRH treatment also reduced the half-durati on of GH secretory bursts, and increased the GH half-life. GHRH-stimul ated 24-h serum GH concentrations and the mass of GH secreted per burs t were correlated negatively with age (R[value]:P[value] = -0.67:0.002 and -0.58:0.009 respectively), and percentage body fat (R:P=-0.80:0.0 001 and -0.65:0.005 respectively), but positively with serum testoster one concentrations (R:P=+0.55:0.016 and +0.53:0.019 respectively). GHR H-stimulated plasma IGF-I increments correlated negatively with age an d body mass index, and positively with serum testosterone, but not wit h percentage body fat. Cosinor analysis disclosed persistent nyctoheme ral rhythmicity of GH secretory burst mass (with significantly increas ed 24-h amplitude and mesor values but unchanged acrophase during fixe d pulsatile GHRH infusions, which suggests that both GHRH and non-GHRH -dependent mechanisms can modulate the magnitude (but only non-GHRH me chanisms can modulate the timing) of somatotrope secretory activity di fferentially over a 24-h period. In summary diminished GHRH action and /or non-GHRH-dependent mechanisms (e.g. somatostatin excess, putative endogenous growth hormone-releasing peptide deficiency etc.) probably underlie the hyposomatotropism of aging, (relative) obesity and/or hyp oandrogenemia. Preserved or increased tissue IGF-I responses to GHRH-s timulated GH secretion (albeit absolutely reduced, suggesting GHRH ins ensitivity in obesity) may distinguish the pathophysiology of adiposit y-associated hyposomatotropism from that of healthy aging.