Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotrophic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth hormone-releasing hormone pulsatile infusion in men

Abstract

We here investigate the potential rescue of the relative hyposomatotropism of aging and obesity by 3-day pulsatile GHRH infusions (i.v. bolus 0.33 mg/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 GHRHdriven pulsatile GH secretion (in randomly ordered sessions) were quantitated by deconvolution analysis of 24-h (10-min sampling) serum GH concentration profiles measured in an ultrasensitive (threshold 0.005 mg/l) chemiluminescence assay. GHRH infusion significantly increased the mean (24-h) serum GH concentration (0.3 Ϯ 0.1 basal vs 2.4 Ϯ 0.4 mg/l treatment; P ¼ 0.0001), total daily pulsatile GH production rate (21 Ϯ 9.5 vs 97 Ϯ 17 mg/l/day; P ¼ 0.01), GH secretory burst frequency (11 Ϯ 0.5 vs 17 Ϯ 0.3 events/day; P ¼ <0.01), and mass of GH released per burst (1.1 Ϯ 0.4 vs 5.9 Ϯ 1 mg/l; P < 0.01), as well as serum IGF-I (261 Ϯ 33 vs 436 Ϯ 37 mg/l; P ¼ 0.005), insulin (45 Ϯ 13 vs 79 Ϯ 17 mU/l; P ¼ 0.0002), and IGF binding protein (IGFBP)-3 (3320 Ϯ 107 vs 4320 Ϯ 114 mg/l; P ¼ 0.001) concentrations, while decreasing IGFBP-1 levels (16 Ϯ 1.2 vs 14 Ϯ 0.09 mg/l; P ¼ 0.02). Serum total testosterone and estradiol concentrations did not change. GHRH treatment also reduced the half-duration of GH secretory bursts, and increased the GH half-life. GHRH-stimulated 24-h serum GH concentrations and the mass of GH secreted per burst were correlated negatively with age (R[value]:P[value] ¼ ¹0.67:0.002 and ¹0.58:0.009 respectively), and percentage body fat (R:P ¼ ¹0.80:0.0001 and ¹0.65:0.005 respectively), but positively with serum testosterone concentrations (R:P ¼ þ 0.55:0.016 and þ 0.53:0.019 respectively). GHRHstimulated plasma IGF-I increments correlated negatively with age and body mass index, and positively with serum testosterone, but not with percentage body fat. Cosinor analysis disclosed persistent nyctohemeral rhythmicity of GH secretory burst mass (with significantly increased 24-h amplitude and mesor values) but unchanged acrophase during fixed pulsatile GHRH infusions, which suggests that both GHRH-and non-GHRH-dependent mechanisms can modulate the magnitude (but only non-GHRH mechanisms can modulate the timing) of somatotrope secretory activity differentially 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 hypoandrogenemia. Preserved or increased tissue IGF-I responses to GHRH-stimulated GH secretion (albeit absolutely reduced, suggesting GHRH insensitivity in obesity) may distinguish the pathophysiology of adiposity-associated hyposomatotropism from that of healthy aging.

Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy

“…A similar inference was made for pulsatile GHRH-induced GH secretion in another analysis in aging men, which omitted L-arginine and included obese subjects (4). To the degree that L-arginine antagonizes hypothalamic somatostatin release, we infer that the negative relationship between combined L-arginine/ GHRH-stimulated GH secretion and AVF is not attributable solely to heightened somatostatin outflow.…”

Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation

“…The magnitude of GH bursts correlates with somatic growth and hepatic actions of the hormone. Decreased pulsatility may contribute to decreased IGF-I concentration as observed in aged subjects (22,23). Pulses are generated by interactions among GHRH, ghrelin, and somatostatin under negative feedback control by IGF-I and GH (24).…”

Relationship between reduced serum IGF-I levels and accumulation of visceral fat in Japanese men

“…12,13 The studies of larger numbers of obese and non-obese subjects indicated that IGF-I concentrations were negatively correlated with age and BMI; however, they were not associated with fat distribution, ie waist -hip ratio. 15 It is now generally accepted that the total IGF-I concentrations are normal or slightly reduced within the normal range in obesity despite the marked impairment of both basal and stimulated GH secretion. 29 No significant relation between fat distribution and IGF-I levels in the studies with large numbers of subjects may be due to inaccurate assessment of fat distribution such as waist -hip ratio.…”