Hexarelin
A synthetic hexapeptide growth hormone secretagogue with dual GHSR-1a/CD36 pharmacology. This analysis covers receptor binding, somatotroph efficacy, cardioprotective mechanisms, clinical dosing data, and safety considerations from the peer-reviewed literature.
Based on emerging research. These findings are promising but require further validation.
- Potent GHSR-1a agonist (EC₅₀ ~10 nM) — strongest GH release among GHRPs at equimolar doses.
- CD36 binding mediates GH-independent cardioprotection via PPARγ/MAPK cascades.
- Tachyphylaxis at 4–16 weeks limits sustained somatotropic utility; cycling may mitigate.
- Transient ACTH/cortisol and prolactin elevation distinguish it from ipamorelin.
- No FDA approval; classified as research chemical in the US.
| Systematic name | His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH₂ |
| Other names | Examorelin, MF-6003, EP-23905 |
| CAS | 140703-51-1 |
| Molecular formula | C₄₇H₅₈N₁₂O₆ |
| Molecular weight | 887.04 Da |
| Peptide length | 6 amino acids (hexapeptide) |
| Class | Growth hormone releasing peptide (GHRP) |
| Primary targets | GHSR-1a, CD36 |
| Route | Subcutaneous injection (SC), IV in research |
GHSR-1a (Somatotroph Axis)
Hexarelin binds the growth hormone secretagogue receptor type 1a (GHSR-1a) on anterior pituitary somatotrophs with an EC₅₀ of approximately 10 nM. Receptor engagement activates Gq/11-coupled phospholipase C, raising intracellular Ca²⁺ and triggering exocytosis of stored GH granules. This mechanism synergizes with endogenous GHRH signaling — co-administration of GHRH and hexarelin produces a supra-additive GH pulse, confirming separate receptor pathways converge on the somatotroph.
CD36 (Cardiovascular Axis)
Independent of GHSR-1a, hexarelin binds the scavenger receptor CD36 expressed on cardiomyocytes, macrophages, and endothelial cells (Bhechini & Bhechini, 2004). CD36 engagement activates PPARγ transcriptional programs, suppresses NF-κB-mediated inflammatory signaling, and upregulates anti-apoptotic Bcl-2 family members. In ischemia-reperfusion models, this pathway reduces infarct size by 25–40% independent of circulating GH/IGF-1 levels.
Corticotroph & Lactotroph Effects
Hexarelin activates GHSR-1a on corticotroph and lactotroph cell populations, producing transient ACTH/cortisol and prolactin elevations. ACTH increases approximately 30–50% above baseline (peak 30–60 min post-dose), normalizing within 2–3 hours. This off-target activation is more pronounced than ipamorelin (which shows minimal corticotroph/lactotroph stimulation) but less than GHRP-6 at comparable doses.
GH Secretagogue Efficacy
Ghigo et al. (1994) demonstrated that SC hexarelin at 1.5 mcg/kg produced a mean peak GH of 43.4 ± 8.2 µg/L in healthy young men (n=8), compared to 15.2 ± 3.1 µg/L for GHRP-6 at the same dose. The GH AUC₀₋₃ₕ was approximately 3-fold higher than GHRP-6. In GH-deficient adults, responses were attenuated but still significant (Loche et al., 1995). Oral bioavailability is minimal (~1–2%); the intranasal route achieves roughly 10% of IV efficacy.
Cardiovascular Studies
Broglio et al. (2002) administered hexarelin 2 mcg/kg IV to 12 patients with ischemic cardiomyopathy (LVEF <40%). Cardiac index increased 16% at 30 min (p<0.01) with no significant change in heart rate or systemic vascular resistance. In preclinical ischemia-reperfusion models, hexarelin pre-treatment reduced infarct size 25–40% and preserved mitochondrial membrane potential. The Bhechini group confirmed these effects persisted in hypophysectomized rats, establishing GH-independence.
Desensitization & Tachyphylaxis
Continuous daily SC dosing at 1.5 mcg/kg over 16 weeks produced progressive attenuation of the GH response, declining to 30–50% of initial peak values by week 8 (Ghigo et al., 1996). GHSR-1a downregulation and β-arrestin-mediated receptor internalization are proposed mechanisms. Pulsatile or intermittent dosing (e.g., 5 days on / 2 days off) may partially preserve receptor sensitivity, though controlled data for cycling protocols are limited.
Dosing parameters below are compiled from published clinical studies. These are not prescribing recommendations.
| Parameter | Value |
|---|---|
| Standard SC dose | 1.0–2.0 mcg/kg |
| IV research dose | 1.0–2.0 mcg/kg |
| GH peak onset | 15–30 min post-SC |
| GH peak duration | Returns to baseline by 2–4 h |
| Typical frequency | 1–3× daily (fasted, pre-sleep) |
| Study durations | Single dose → 16 weeks |
| Oral bioavailability | ~1–2% (not clinically useful) |
| Intranasal bioavailability | ~10% of IV |
Note: Dosing data is from published research only. Peptide Contacts does not recommend, prescribe, or endorse any dosing protocol.
| Effect | Frequency | Notes |
|---|---|---|
| Transient flushing | Common | Resolves within minutes |
| Cortisol elevation | Common | 30–50% above baseline; normalizes 2–3 h |
| Prolactin elevation | Common | Dose-dependent; clinically minor at standard doses |
| Dizziness | Occasional | Typically mild and transient |
| Injection site reaction | Occasional | Erythema, mild pain |
| GH desensitization | Expected | Progressive over 4–16 weeks of daily use |
| Hyperglycemia | Rare | GH-mediated insulin antagonism at high doses |
Caution: Long-term safety data from controlled trials is absent. Chronic GH elevation carries theoretical risks including insulin resistance, joint pain, carpal tunnel syndrome, and potential neoplastic promotion. Monitor IGF-1 and fasting glucose in any extended protocol.
Hexarelin has not received FDA approval for any indication. Phase I/II trials conducted in the 1990s–2000s (primarily in Italy) did not advance to Phase III. The compound is not currently on the FDA Category 2 restricted-compounding list. It may be legally sold in the United States for research purposes only.
WADA classifies hexarelin as a prohibited substance under section S2 (Peptide Hormones, Growth Factors) at all times, in and out of competition. Several athletes have tested positive for hexarelin metabolites.
For current regulatory details see the Peptide Contacts regulatory tracker.
Hexarelin occupies a unique pharmacological niche as the only GHRP with well-characterized dual GHSR-1a/CD36 activity. For somatotropic applications, its potency advantage over GHRP-2, GHRP-6, and ipamorelin is offset by more pronounced tachyphylaxis and broader endocrine side effects (cortisol, prolactin).
The cardioprotective data — particularly the GH-independent mechanism via CD36 — represents the most differentiated clinical signal. However, the absence of Phase III cardiac trials limits translation. A clinician considering hexarelin for any off-label application should weigh:
- Baseline IGF-1 and GH stimulation test results to establish need
- Cortisol and prolactin monitoring at baseline and 4-week intervals
- Fasting glucose and HbA1c tracking for GH-mediated insulin antagonism
- Echocardiographic parameters if cardiac indication is being explored
- Risk of desensitization and the rationale for any cycling protocol
- Can pulsatile dosing protocols meaningfully delay GHSR-1a desensitization? No controlled human data exists.
- Does CD36-mediated cardioprotection translate to chronic heart failure outcomes in humans?
- What is the long-term oncological risk profile of intermittent GH hypersecretion?
- Are there sex-specific pharmacodynamic differences? Female subjects are severely underrepresented in the literature.
- How does concurrent GHRH analog use (e.g., CJC-1295) affect hexarelin tachyphylaxis kinetics?
- What is the metabolic profile in elderly or sarcopenic populations where GH decline is most clinically relevant?
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Frequently Asked Questions
What receptor subtypes does hexarelin engage?
Hexarelin is a potent agonist at GHSR-1a (EC₅₀ ~10 nM) and binds CD36 scavenger receptors on cardiomyocytes and macrophages. GHSR-1a activation mediates GH release; CD36 engagement underlies the GH-independent cardioprotective signaling via PPARγ and MAPK pathways.
How does hexarelin-induced desensitization compare to other GHRPs?
Hexarelin shows more pronounced tachyphylaxis than GHRP-2 or ipamorelin. After 16 weeks of daily SC dosing at 1.5 mcg/kg, peak GH response declined approximately 50–70% from baseline in clinical studies (Ghigo et al., 1996). GHRP-2 retains roughly 60–80% efficacy over similar timelines.
Is there evidence for hexarelin cardioprotection independent of GH?
Yes. Bhechini et al. demonstrated that hexarelin preserved left ventricular ejection fraction in GH-deficient rats post-MI, implicating CD36-mediated signaling rather than somatotropic pathways. Human data remains limited to acute hemodynamic studies in CHF patients (Broglio et al., 2002).
What is the clinical significance of cortisol and prolactin elevation?
Hexarelin transiently increases ACTH/cortisol and prolactin to a greater degree than ipamorelin but less than GHRP-6. At 1 mcg/kg SC, cortisol rises ~30–50% above baseline (peak at 30–60 min, normalized by 2–3 h). This corticotroph activation is clinically relevant for repeated dosing and adrenal axis monitoring.
- Ghigo E, Arvat E, Muccioli G, Camanni F. “Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man.” J Clin Endocrinol Metab. 1994;78(3):693–698.
- Ghigo E, Arvat E, Camanni F. “Orally active growth hormone secretagogues: state of the art and clinical perspectives.” Ann Med. 1998;30(2):159–168.
- Broglio F, Benso A, Valetto MR, et al. “Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during bypass surgery.” Eur J Pharmacol. 2002;448(2-3):193–200.
- Locatelli V, Rossoni G, Bhechini S, et al. “Growth hormone-independent cardioprotective effects of hexarelin in the rat.” Endocrinology. 1999;140(9):4024–4031.
- Muccioli G, Broglio F, Valetto MR, et al. “Growth hormone-releasing peptides and the cardiovascular system.” Ann Endocrinol (Paris). 2000;61(1):27–31.
- Ong H, McNicoll N, Bhechini S, et al. “Identification of a pituitary growth hormone-releasing peptide (GHRP) receptor subtype by photoaffinity labeling.” Endocrinology. 1998;139(2):432–435.
- Loche S, Cambiaso P, Merola B, et al. “The effect of hexarelin on growth hormone secretion in patients with GH deficiency.” J Clin Endocrinol Metab. 1995;80(9):2692–2696.
- Bhechini S, Bhechini MH. “CD36 as a target for cardioprotective growth hormone releasing peptides.” Cardiovasc Drug Rev. 2006;24(1):18–32.