STIMULATION OF THE GROWTH-HORMONE (GH)-INSULIN-LIKE GROWTH-FACTOR-I AXIS BY DAILY ORAL-ADMINISTRATION OF A GH SECRETAGOGUE (MK-677) IN HEALTHY ELDERLY SUBJECTS

Aging is associated with declining activity of the GH axis, possibly c ontributing to adverse body composition changes and increased incidenc e of cardiovascular disease. The stimulatory effects on the GH-insulin -like growth factor I (IGF-I) axis of orally administered MK-677, a GH -releasing peptide mimetic, were investigated. Thirty-two healthy subj ects (15 women and 17 men, aged 64-81 yr)were enrolled in a randomized , double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods o f 14 and 28 days. At baseline and on day 14 of each study period, bloo d was collected every 20 min for 24 h to measure GH, PRL, and cortisol . Attributes of pulsatile GH release were assessed by 3 independent al gorithms. MK-677 administration for 2 weeks increased GH concentration s in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH c oncentration 97+/-23% (mean+/-SE; P <0.05 US. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH p ulse height and interpulse nadir concentrations increased significantl y without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the n ormal range for young adults (141+/-21 mu g/L at baseline, 219+/-21 mu g/L at 2 weeks, and 265+/-29 mu g/L at 4 weeks; P <0.05). MK-677 prod uced significant increases in fasting glucose (5.4+/-0.3 to 6.8+/-0.4 mmol/L at 4 weeks; P <0.01 vs. baseline) and IGF-binding protein-3. Ci rculating cortisol concentrations did not change, and PRL concentratio ns increased 23%, but remained within the normal range. Once daily tre atment of older people with oral MK-677 for up to 4 weeks enhanced pul satile GH release, significantly increased serum GH and IGF-I concentr ations, and, at a dose of 25 mg/day, restored serum IGF-I concentratio ns to those of young adults.