Overview
GHRP-6 (Growth Hormone Releasing Peptide-6) is one of the first synthetic growth hormone secretagogues developed. This hexapeptide stimulates growth hormone (GH) release through the ghrelin/growth hormone secretagogue receptor (GHS-R), a mechanism distinct from Growth Hormone Releasing Hormone (GHRH).
As a met-enkephalin analog containing unnatural D-amino acids, GHRP-6 lacks opioid activity but potently stimulates GH release. It has become a foundational compound in understanding GH secretagogue mechanisms and serves as a reference for newer peptides in this class.
Molecular Structure
| Property | Value |
|---|---|
| Type | Synthetic hexapeptide |
| Classification | Growth Hormone Secretagogue |
| Receptor | GHS-R (Ghrelin receptor) |
| Related to | Met-enkephalin (analog) |
| Opioid Activity | None |
Mechanism of Action
Receptor Binding
GHRP-6 acts through two characterized receptors:
- GHS-R1a: Primary receptor for GH release
- CD36: Involved in cytoprotective effects
Intracellular Signaling
GHRP-6 triggers a distinct signaling cascade:
- Protein Kinase C (PKC) activation (primary pathway)
- Calcium mobilization from intracellular reserves
- Phosphatidylinositol (PI) turnover stimulation
- cAMP-independent (unlike GHRH)
Research using human pituitary somatotrophinomas demonstrated:
- Powerful effects on membrane PI turnover
- Dose-dependent stimulation
- Parallel increases in GH secretion
Hypothalamic vs Pituitary Action
GHRP-6 appears to act at both levels:
- Pituitary: Direct stimulation of somatotrophs
- Hypothalamic: Requires endogenous GHRH for maximal effect
Evidence shows:
- More efficacious than GHRH alone in humans
- Striking synergistic action when combined with GHRH
- Double mechanism hypothesis: Both pituitary and hypothalamic actions
Comparison with GHRH
| Feature | GHRP-6 | GHRH |
|---|---|---|
| Receptor | GHS-R (ghrelin) | GHRH-R |
| Signaling | PKC/Calcium | cAMP |
| Efficacy | Higher than GHRH | Baseline |
| Synergy | Yes (with GHRH) | Yes (with GHRP-6) |
| Mechanism | Partially hypothalamic | Primarily pituitary |
Beyond GH Release: Cytoprotective Effects
Cardioprotection
Research demonstrates GHRP-6's cardioprotective properties:
- Attenuates doxorubicin-induced myocardial damage
- Protects against ischemia-reperfusion injury
- Enhances pro-oxidant/antioxidant balance
- Attenuates mitochondrial ultrastructural damage
- Increases Bcl-2 (anti-apoptotic gene) expression
Molecular mechanisms involve:
- PI-3K/AKT1 pathway activation
- HIF-1α induction (hypoxia-inducible factor)
- Both committed to cellular survival
Systemic Cytoprotection
Studies indicate systemic protective effects:
- Controls inflammatory response in acute ischemia-reperfusion
- Prevents multiple organ damage from shock
- Attenuates reactive oxygen species (ROS) generation
- Preserves antioxidant defense reserves
Anti-Fibrotic Effects
RT-PCR experiments show GHRP-6:
- Significantly reduces TGF-β1 expression
- Reduces CTGF (connective tissue growth factor) expression
- No effect on PDGF-B expression
- Potential in organ fibrosis prevention
Anti-Inflammatory Properties
Multiple studies demonstrate:
- Prevention of internal organ parenchymal activation
- Suppression of systemic inflammatory response syndrome
- Downregulation of pro-inflammatory cytokines
- Suppression of NF-κB activation
- Chemokine receptor antagonism
Wound Healing Research
A study published in Plastic Surgery International found:
- GHRP-6 enhances healing process
- Improves aesthetic outcome of wounds
- Potential applications in surgical healing
Clinical Considerations
Hypothyroidism Effects
Research on GHRP-6 in hypothyroidism:
- GH responses altered by thyroid status
- Important consideration for research design
Hypothalamic-Pituitary Disconnection
Studies in patients with HP disconnection showed:
- Blocked GHRP-6-induced GH secretion
- Absent synergistic action with GHRH
- Confirms significant hypothalamic component to GHRP-6 action
Comparison with Other GHRPs
| Peptide | Selectivity | Side Effects | GH Release |
|---|---|---|---|
| GHRP-6 | Moderate | Hunger increase | Strong |
| GHRP-2 | Higher | Less hunger | Strong |
| Ipamorelin | Highest | Minimal | Moderate |
| Hexarelin | Low | Multiple | Very strong |
GHRP-6 is known for:
- Significant appetite stimulation (ghrelin mimetic effect)
- Robust GH pulse generation
- Foundational research compound status
Safety Profile
Research indicates:
- Generally well-tolerated in studies
- Appetite increase (can be benefit or drawback)
- Transient cortisol elevation possible
- Prolactin effects minimal at typical doses
Research Applications
GHRP-6 serves as:
- Reference compound for GHS research
- Tool for studying GH axis physiology
- Model for cytoprotective peptide mechanisms
- Foundation for newer secretagogue development
Regulatory Status
GHRP-6 is:
- Not approved for human therapeutic use
- Available for research purposes only
- Prohibited in competitive sports (WADA)
- Subject to research chemical regulations
References
Key sources include Journal of Molecular Endocrinology publications, Frontiers in Pharmacology (2024) on cardioprotection, PMC reviews on GHRPs (PMC5392015), and foundational PubMed studies (PMID: 7772238, 7883854, 9543138).