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 micrograms/kg i.v. Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 micrograms/kg), GHRH (2.0 micrograms/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 micrograms/kg; AUC0;v-120 +/- SEM: 1728.4 +/- 406.4 vs. 2265.9 +/- 298.4 vs. 2934.3 +/- 482.2 micrograms/L/h, p < 0.05 for 1.0 vs. 2.0 micrograms/kg) and GHRH (649.6 +/- 111.4 vs. 792.2 +/- 117.6 vs. 1402.6 +/- 363.0 micrograms/L/h) showed a progressive increase. Two micrograms/kg HEX and 1 microgram/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 micrograms/L/h, p < 0.05 for 1.0 vs. 2 micrograms/kg, p < 0.001 for 1.0 vs. 3.0 micrograms/kg and p < 0.03 for 2.0 vs. 3.0 micrograms/kg) and GHRH (183.8 +/- 27.3 vs. 260.9 +/- 17.3 vs. 356.1 +/- 46.3 micrograms/L/h, p < 0.005 for 1.0 vs. 3.0 micrograms/kg and p < 0.05 for 2.0 vs. 3.0 micrograms/kg) showed a progressive increase. In E the GH response to 3 micrograms/kg HEX or GHRH were clearly higher than those to 2 micrograms/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 micrograms/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 +/- 273.6 micrograms/L/h, p < 0.01) but not the HEX-induced one (2371.7 +/- 387.2 micrograms/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 +/- 360.8 micrograms/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 +/- 306.0 micrograms/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 micrograms/L/h, p < 0.01) and even those to HEX (2069.5 +/- 528.7 micrograms/L/h, p < 0.01) and HEX + GHRH (4406.0 +/- 1079.2 micrograms/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.