NEUROENDOCRINE RESPONSES TO A NOVEL GROWTH-HORMONE SECRETAGOGUE, L-692,429, IN HEALTHY OLDER SUBJECTS

L-692,429 (L), a novel nonpeptide mimic of GH-releasing peptide (GHRP) , is a potent GH secretagogue in animals and young men. To assess the safety and efficacy of L in stimulating GK release in healthy older me n and women, 16 subjects were admitted to a randomized, double blind, cross-over comparison of iv administered placebo, GH-releasing hormone [GHRH-(1-29)-NH2; 1 mu g/kg] and two doses of L (0.2 and 0.75 mg/kg). Blood samples were obtained at 5-min intervals for 60 min before and 240 min after each dose for measurement of GH; cortisol, PRL, and insu lin-like growth factor-I (IGF-I) were measured less frequently. Peak a nd integrated GH concentrations increased significantly after L in a d ose-dependent manner. Responses to L at either dose were significantly greater than the response to GHRH: peak GH responses in older men and women were (mean +/- se; micrograms per L): after placebo, 1.2 +/- 0. 2; L (0.2 mg/kg), 16.5 +/- 1.8; L (0.75 mg/kg), 32.2 +/- 3.9; and GHRH , 7.6 +/- 1.3 (P < 0.05, L vs. placebo or GHRH). Serum cortisol and PR L concentrations increased after both doses of L, but to values within the respective normal ranges. Serum IGF-I values did not change consi stently in any group. The GH responses to GHRH and L (0.75 mg/kg) were highly correlated (r(2) = 0.61; P < 0.0004). Deconvolution analysis d emonstrated that the increase in serum GH concentrations stimulated by L and GHRH resulted from enhanced GH secretion rates, with no change in the half-life of GH disappearance. Amplitudes of GH secretory pulse s were increased 11-, 18-, and 4-fold after L (0.2 mg/kg), L (0.75 mg/ kg), and GHRH treatments, respectively. The number of GH secretory pul ses was significantly increased by L (0.75 mg/kg; 4.6 +/- 0.4) and GHR H (4.4 +/- 0.3) compared to placebo (2.6 +/- 0.5), but the interval be tween pulses was shorter after L (0.75 mg/kg; 28.6 +/- 3.6 min) than a fter GHRH (50.7 +/- 7.7 min; P < 0.05). Adverse experiences were limit ed to brief episodes of flushing or a warm sensation about the upper b ody. L-692,429 is a potent GH secretagogue that is well tolerated in h ealthy older men and women. At the doses employed in this study, L eli cited greater increases in GH secretion rates and serum GH concentrati ons than GHRH. L-692,429 may have therapeutic advantages over peptide GH secretagogues to restore endogenous GH secretion in GH deficiency s tates or the hyposomatotropism of aging.