Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults

Abstract

To determine the effect of the GH releasing peptide (GHRP)-mimetic, MK-677, on the GH/insulin-like growth factor-I (IGF-I) axis in selected GH-deficient adults, we studied nine severely GH-deficient men [peak serum GH concentration in response to insulin-induced hypoglycemia of 1.2 +/- 1.5 micrograms/L, mean +/- SD (range 0.02-4.79)], age 17-34 yr, height 168 +/- 1.5 cm, body mass index 22.6 +/- 3.3 kg/m2, who had been treated for GH deficiency with GH during childhood. In a double-blind rising-dose design, subjects received once daily oral doses of 10 or 50 mg MK-677 or placebo for 4 days over two treatment periods separated by at least 28 days. Four subjects received placebo and 10 mg/day MK-677 in a cross-over fashion in periods 1 and 2. Five subjects received 10 mg and then 50 mg/day MK-677 in a sequential, rising-dose fashion in periods 1 and 2, respectively. Blood was collected every 20 min for 24 h before treatment and at the end of each period for GH measurement using an ultrasensitive assay. The drug was generally well tolerated, with no significant changes from baseline in circulating concentrations of cortisol, PRL, and thyroid hormones. Serum IGF-i and 24-H mean GH concentrations increased in all subjects after treatment with both 10 and 50 mg/day MK-677 vs. baseline. After treatment with 10 mg MK-677, IGF-I concentrations increased 52 +/- 20% (65 +/- 6 to 99 +/- 9 micrograms/L, geometric mean +/- intrasubject SE, P < or = 0.05 vs. baseline), and 24 h mean GH concentrations increased 79 +/- 19% (0.14 +/- 0.01 to 0.26 +/- 0.02 microgram/L, P < or = 0.05 vs. baseline). Following treatment with 50 mg MK-677, IGF-I concentrations increased 79 +/- 9% (84 +/- 3 to 150 +/- 6 micrograms/L, P < or = 0.05 vs. baseline) and 24-h mean GH concentrations increased 82 +/- 29% (0.21 +/- 0.02 to 0.39 +/- 0.04 microgram/L, P < or = 0.05 vs. baseline), respectively. Serum IGF binding protein-3 concentrations increased with both 10 mg (1.2 +/- 0.1 to 1.7 +/- 0.1 micrograms/L, P < or = 0.05) and 50 mg MK-677 (1.7 +/- 0.1 to 2.2 +/- 0.2 micrograms/L, P < or = 0.05). The GH response to MK-677 was greater in subjects who were the least GH/IGF-I deficient at baseline; by linear regression analysis the increase in 24-h mean GH concentration was positively related to both baseline 24-h mean GH concentration (r = 0.81, P = 0.009) and baseline IGF-I (r = 0.79, P = 0.01) for 10 mg MK-677. IGF-I responses were not significantly related to any baseline measurement. Fasting and postprandial insulin and postprandial glucose increased significantly after MK-677 treatment, and the clinical significance of these changes will need to be assessed in longer term studies. Oral administration of such GHRP-mimetic compounds may have a role in the treatment of GH deficiency of childhood onset.