Background
This NEJM trial evaluated the effects of testosterone (T) alone, GH alone, both combined, or placebo in older men with low-normal testosterone and IGF-1 levels — addressing whether restoring youthful GH/T levels improves functional outcomes beyond body composition.
While using exogenous GH rather than GH secretagogues, this trial provides the strongest human RCT evidence base for the expected physiological effects of GH axis restoration that secretagogues like sermorelin and ipamorelin aim to achieve.
Methods
2×2 factorial RCT. 122 men aged 65+. Arms: testosterone gel + placebo injection, placebo gel + GH injection, both active, or double placebo for 26 weeks.
GH dose: titrated to achieve IGF-1 in young-adult range (200–350 ng/mL).
Primary outcomes: body composition (DXA), muscle strength (isokinetic), physical performance, insulin sensitivity (hyperinsulinemic-euglycemic clamp).
Key Findings
| Outcome | GH group | Placebo | p-value |
|---|---|---|---|
| Lean body mass | +2.0 kg | −0.4 kg | <0.001 |
| Fat mass | −2.4 kg | +0.2 kg | <0.001 |
| Knee extension strength | No change | — | NS |
| Physical performance (SPPB) | No change | — | NS |
| Insulin sensitivity | No change | — | NS |
| Glucose | Mildly increased | — | — |
Testosterone produced independent improvements in strength but not body composition when given without GH.
Clinical Significance
This trial is frequently cited to temper expectations about GH axis restoration: it produces real, measurable body composition improvements (lean mass gain, fat loss) but does not translate to strength or functional performance gains at 26 weeks in older men.
For GH secretagogue users, this suggests that body composition benefits are achievable but physical performance improvements likely require concurrent resistance training. The modest glucose elevation mirrors MK-677 data — an important monitoring consideration.
Limitations
- Used exogenous GH (not secretagogues) — pulsatility differences may affect outcomes
- 26 weeks may be insufficient for strength adaptations
- Only men studied; effects in women not assessed
- Older demographic (65+); responses in middle-aged adults with milder GH decline may differ