Background
Aging is associated with a progressive decline in GH secretion (somatopause), reduced IGF-1 levels, and associated changes in body composition including increased fat mass and reduced lean muscle mass. GH secretagogues (GHS) that stimulate pituitary GH release represent a potential strategy to reverse age-related GH deficiency while preserving physiological pulsatility.
MK-677 (ibutamoren) is an orally active, non-peptide GH secretagogue that acts as a ghrelin receptor agonist — mechanistically similar to peptide secretagogues like ipamorelin but taken orally.
Methods
Two-part study in healthy elderly men and women aged 64–81. Part 1: dose escalation (5, 10, 25, 50 mg daily oral) for 2 weeks. Part 2: 25 mg daily for 4 weeks with 24-hour GH pulse monitoring and IGF-1 measurement.
Key Findings
| Parameter | MK-677 25 mg | Placebo |
|---|---|---|
| 24-h GH secretion | +97% | No change |
| Mean IGF-1 | Restored to young-adult range | Remained age-typical |
| IGFBP-3 | Significantly increased | No change |
| Cortisol | No change | No change |
| Prolactin | No change | No change |
| Fasting glucose | Mild increase | No change |
Clinical Significance
Chapman 1996 was pivotal in demonstrating that pharmacological GH axis restoration in elderly subjects is achievable with a once-daily oral agent while preserving the pulsatile pattern and without ACTH or prolactin axis disruption. This laid the groundwork for subsequent trials examining body composition endpoints.
The lack of cortisol elevation is clinically important — distinguishing GH secretagogues from non-selective ghrelin agonists and from stress-related GH release.
Limitations
- Very small sample (32 subjects)
- Short duration (6 weeks) — insufficient for body composition endpoints
- MK-677 is an oral agent; peptide GHS (ipamorelin, GHRP-2) not directly studied in this paper
- Mild hyperglycemia noted — relevant for monitoring in at-risk populations