Background
By the mid-1990s, GHRP-2 and hexarelin had emerged as the most potent GH secretagogues in the GHRP family. This study directly compared their neuroendocrine profiles in healthy adult male volunteers to characterize their GH-releasing potency and pituitary/adrenal axis effects.
Understanding the breadth of neuroendocrine activation was critical for clinical translation: pure GH secretagogues like ipamorelin were preferred for protocols where cortisol elevation was undesirable, while GHRP-2’s broader activity might be acceptable in short-term protocols.
Methods
Ten healthy adult male volunteers received IV bolus injections of GHRP-2 (1 µg/kg), hexarelin (1 µg/kg), GHRH (1 µg/kg), or saline in a crossover design with washout periods between sessions.
Blood samples were collected at 15-minute intervals for 120 minutes post-injection for:
- Serum GH (primary endpoint)
- Serum prolactin
- Plasma ACTH
- Serum cortisol
Key Findings
| Hormone | GHRP-2 | Hexarelin | GHRH | Saline |
|---|---|---|---|---|
| Peak GH (µg/L) | ~60 | ~90 | ~30 | <2 |
| Prolactin | ↑ mild | ↑ mild | No change | No change |
| ACTH | ↑ mild | ↑ mild | No change | No change |
| Cortisol | ↑ mild | ↑ mild | No change | No change |
- Both GHRPs significantly outperformed GHRH in peak GH release
- GHRP-2 produced slightly lower peak GH than hexarelin but a comparable overall AUC
- Cortisol and ACTH elevations were transient (peaked ~60 min, returned to baseline by 120 min)
- No subjects reported significant adverse events
Clinical Significance
This study confirmed GHRP-2 as a potent GH secretagogue in humans, achieving ~2-fold greater peak GH than GHRH alone. The mild ACTH and cortisol co-stimulation is a clinically relevant distinction:
- For healthy adults using GHRP-2 in pulse-dosing protocols, transient cortisol elevation is unlikely to be physiologically problematic
- For patients with adrenal insufficiency or those seeking minimal cortisol modulation, the more selective ipamorelin or sermorelin may be preferred
The synergistic potential of GHRP-2 + GHRH was subsequently explored in combination studies, with combination protocols producing GH peaks 3–4x greater than either agent alone.
Limitations
- Small n (10 healthy males only); extrapolation to women, elderly, or disease states requires separate studies
- Single acute IV dose — does not reflect subcutaneous kinetics or chronic administration patterns
- No IGF-1 measurements (only acute GH pulse characterized)