Hexarelin or GHRP-6: what's the difference

Hexarelin and GHRP-6 are the two best-known synthetic hexapeptides that stimulate the release of growth hormone through the ghrelin receptor. Their formulas differ by only one modification, but that is enough to change the strength of action, the effect on appetite and other hormones. The editorial team explains what this difference consists of.

A common ancestor and a common receptor

The history of both peptides began with the work of the American endocrinologist Cyril Bowers. In 1984 his group described a synthetic hexapeptide that specifically stimulated the pituitary to release growth hormone. This molecule was named GHRP-6 (growth hormone-releasing peptide-6).

For a long time the mechanism of action remained a mystery: the peptide did not work through the GHRH receptor. Only in 1996 did Howard et al. clone the receptor through which such compounds act - the growth hormone secretagogue receptor (GHS-R1a). And in 1999 Kojima et al. discovered its natural ligand - the stomach hormone ghrelin.

Hexarelin appeared in the early 1990s as a derivative of GHRP-6. It was developed in Italy as a potentially more potent and more stable analogue, and it was then that the main human studies were conducted, notably the work by Ghigo et al. (1994).

So both peptides are ghrelin mimetics. They act synergistically with natural GHRH and partly suppress the influence of somatostatin, which produces a pronounced but short-lived peak of growth hormone.

Structure: one substitution with major consequences

GHRP-6 has the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2. The presence of D-amino acids makes the peptide more resistant to enzymes than ordinary protein fragments, although the half-life in the blood is still short.

In hexarelin, the D-tryptophan in the second position is replaced by 2-methyl-D-tryptophan. This small methyl group changes the conformation of the molecule and its interaction with the receptor, increasing affinity and stability.

The result is a higher potency of hexarelin for growth hormone release compared with GHRP-6 in human studies. Ghigo et al. also showed that hexarelin is active by various routes of administration - intravenous, subcutaneous, intranasal and oral - although the bioavailability of the latter is low.

In addition, hexarelin and some other GHRPs are able to bind to the CD36 receptor, which is present in the tissues of the heart and blood vessels. This opened up a separate line of research, discussed below.

Hormonal profile: not only growth hormone

None of the growth hormone secretagogues is fully selective. Stimulation of the ghrelin receptor in the pituitary and hypothalamus is also accompanied by a rise in adrenocorticotropic hormone (ACTH), cortisol and prolactin.

In hexarelin these hormonal side effects are described more clearly: in human studies, a rise in cortisol and prolactin was observed after its administration. This is precisely why hexarelin is less suited to the role of a «pure» GH-axis stimulator.

GHRP-6 also raises cortisol and prolactin, but its main feature is a strong effect on appetite. Because it mimics ghrelin, the «hunger hormone», many people experience a pronounced feeling of hunger after administration.

Another important difference is desensitization. With prolonged use of hexarelin, the growth hormone response gradually weakens. This effect is partly reversible after a break, but it limits the practical value of the peptide.

Heart and blood vessels: a separate line of research

Bodart et al. (2002) showed that the cardiovascular action of GHRPs in the heart is mediated by the CD36 receptor - the same one involved in the uptake of fatty acids and oxidized lipoproteins. Hexarelin proved to be one of the most active ligands of this receptor.

In animal models, hexarelin demonstrated cardioprotective effects in ischemia and myocardial injury, independent of growth hormone. Small clinical observations assessed the effect on cardiac contractility.

However, these data are mainly preclinical or obtained in small samples. They provide no grounds for regarding hexarelin as a means of «strengthening the heart» in healthy people.

For GHRP-6 there are fewer dedicated cardiological studies, although in experiments it also showed a certain cytoprotective activity. Comparing the two peptides in this respect is correct only at the level of experimental models.

Legal status and risks

Neither hexarelin nor GHRP-6 is registered as a medicine for general medical use. They are available on the market only as substances «for research», without guarantees of composition and sterility.

Both peptides are named directly in the WADA Prohibited List among the growth hormone secretagogues in section S2 and are prohibited at all times. Laboratories detect them and their metabolites in urine.

Among the described adverse effects:

• increased appetite (especially GHRP-6) and weight gain;
• a rise in cortisol and prolactin;
• fluid retention and worsened insulin sensitivity due to increased GH/IGF-1;
• injection-site reactions and risks associated with a non-sterile product.

The long-term safety of both substances in humans has not been established, since no long-term controlled studies have been conducted.

It is worth remembering separately the risks associated not with the molecule but with the product: incorrect content, impurities and endotoxins in unregulated peptides can cause reactions that are mistakenly attributed to the substance itself.

Editorial conclusions

Hexarelin and GHRP-6 are close relatives, ghrelin mimetics that stimulate the release of growth hormone through the GHS-R1a receptor. One methyl group makes hexarelin more potent, but also less selective and prone to loss of effect with prolonged use.

GHRP-6 is distinguished by a pronounced effect on appetite, which follows directly from its similarity to ghrelin.

Both peptides are not approved as medicines, are prohibited in sport and have an unstudied long-term safety profile.

We also recommend reading our materials on the mechanism of action of GHRP-6, on the side effects of GHRP-2 and on the status of peptides on the WADA list.

References

1. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537–1545.
2. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–977.
3. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
4. Ghigo E, Arvat E, Gianotti L, et al. 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.
5. Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002;90(8):844–849.
6. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; актуальна редакція.