ARGININE AND GROWTH HORMONE-RELEASING HORMONE RESTORE THE BLUNTED GROWTH HORMONE-RELEASING ACTIVITY OF HEXARELIN IN ELDERLY SUBJECTS

Although both spontaneous and stimulated GH secretion undergo an age-related decline, the secretory capacity of somatotrope cells is preserved in human aging. In the present study we compared the GH responses to hexarelin, GHRH, and the combined administration of hexarelin and GHRH or arginine in young and elderly subjects. Thirteen young (24- to 30-yr-old) and 16 elderly (65- to 84-yr-old) normal males were divided into 2 groups. The first group (7 young and 8 elderly subjects) received the following as single iv injections during 3 different treatment sessions: hexarelin (2 mu g/kg), GHRH (2 mu g/kg), or hexarelin (2 mu g/kg) plus GHRH (2 mu g/kg). The second group (6 young and 8 elderly subjects) was administered single iv injections of hexarelin (2 mu g/kg) or hexarelin (2 mu g/kg) plus arginine (0.5 g/kg) during 2 different treatment sessions. In both groups basal IGF-I levels in the elderly were lower than those in young subjects (114.5 +/- 18.7 vs. 211.5 +/- 19.1 mu g/L; P < 0.001). In the first group the GH response to hexarelin was greater in young compared to elderly subjects (area under the curve from 0-120 = 4849 +/- 601 vs. 2112 +/- 683 mu g.min/L; P < 0.001). GHRH elicited a lower GH response than that induced by hexarelin in both young (1455 +/- 102 mu g/h.L; P < 0.02) and elderly subjects (563 +/- 87 mu g/min.L; P < 0.02). GHRH potentiated the somatotrope response to hexarelin in both young (7725 +/- 503 mu g/min.L; P < 0.02) and elderly subjects (3895 +/- 612 mu g/min.L; P < 0.02), but to a lesser extent in the latter (P < 0.001). In the second group, the GH response induced by hexarelin was also higher in young subjects than in elderly subjects (4819 +/- 668 vs. 1649,+/- 459 mu g/min.L; P < 0.001). The GH response to hexarelin was potentiated by arginine in elderly (4139 +/- 1057 mu g/min.L; P < 0.001), but not in young subjects (4743 +/- 774 mu g/min.L). This study shows that the maximal effective dose of hexarelin releases more GH than the maximal effective dose of GHRH in both normal young and elderly subjects. The effect of hexarelin on GH secretion is age dependent, and the GH response to the combined administration of hexarelin and GHRH was significantly higher in young subjects compared to elderly subjects. Arginine does not potentiate the GH response to hexarelin in young subjects, whereas it significantly enhances it in elderly subjects. These findings suggest that hexarelin acts, at least partially, independently from GHRH and/or somatostatin. These results also support the presence of a somatostatinergic hyperactivity in aging, which is probably related to a concomitant reduction in the activity of GHRH-secreting neurons.