Age-related Variations in the Neuroendocrine Control,More Than Impaired Receptor Sensitivity,Cause The Reduction in the GH-releasing Activity of GHRPs in Human Aging

The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66–81 yr) and 12 young controls (Y, 24–28 yr) we studied the effects of 1.0, 2.0 and 3.0 g/kg iv Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 g/kg), GHRH (2.0 g/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 g/kg; AUC0;v–120 ± SEM: 1728.4 ± 406.4 vs. 2265.9 ± 298.4 vs. 2934.3 ± 482.2 g//L/h, p < 0.05 for 1.0 vs. 2.0 g/kg) and GHRH (649.6 ± 111.4 vs. 792.2 ± 117.6 vs. 1402.6 ± 363.0 g/L/h) showed a progressive increase. Two g/kg HEX and 1 g/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 ± 50.0 vs. 742.8 ± 157.9 vs. 1205.1 ± 178.1 g/L/h, p < 0.05 for 1.0 vs. 2 g/kg, p < 0.001 for 1.0 vs. 3.0 g/kg and p < 0.03 for 2.0 vs. 3.0 g/kg) and GHRH (183.8 ± 27.3 vs. 260.9 ± 17.3 vs. 356.1 ± 46.3 g/L/h, p < 0.005 for 1.0 vs. 3.0 g/kg and p < 0.05 for 2.0 vs. 3.0 g/kg) showed a progressive increase. In E the GH response to 3 g/kg HEX or GHRH were clearly higher than those to 2 g/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 ± 308.0 g/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 ± 273.6 g/L/h, p < 0.01) but not the HEX-induced one (2371.7 ± 387.2 g/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 ± 360.8 g/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 ± 306.0 g/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 ± 172.8 g/L/h, p < 0.01) and even those to HEX (2069.5 ± 528.7 g/L/h, p < 0.01) and HEX + GHRH (4406.0 ± 1079.2 g/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.