Hexarelin is a synthetic hexapeptide (a chain of six amino acids) from the family of growth-hormone-releasing peptides, described in 1994 by a Milan team as a “reinforced” version of GHRP-6. It acts as a mimic of ghrelin — the hunger hormone — and produces in humans a strong, short pulse of growth hormone (GH), in studies about twice as large as after the natural hormone GHRH. Two features set it apart from the rest of the family: first, it is one of the few compounds in this group to have gone through a 16-week study in adults, which showed that the GH response fades over time and recovers after a break; second, it also binds to the protein CD36 in the heart, which in animal studies protected the heart muscle and in humans gave a short-lived improvement in cardiac performance after a single dose. In this review we explain in plain terms what those studies show and where the evidence ends.
What hexarelin is
Hexarelin was developed by Romano Deghenghi and pharmacologists at the University of Milan. The starting point was GHRP-6 — the first peptide to release GH selectively. Deghenghi et al. (1994) replaced one of its amino acids, tryptophan, with a chemically more stable variant (2-methyl-tryptophan). In rats the new peptide released GH as effectively as GHRP-6 after intravenous injection, and after subcutaneous injection it acted longer and slightly more strongly. The authors immediately saw it as a “diagnostic and/or therapeutic tool”.
How it works — the ghrelin switch and a second target in the heart
The basic mechanism is shared by the whole GHRP family: hexarelin activates the ghrelin receptor (a switch on cells of the pituitary and hypothalamus), which produces a GH pulse and, along the way, stimulates the stress axis and prolactin secretion. Hexarelin, however, has a second target. Bodart et al. (2002) “tagged” it radioactively and fished out of rat heart-cell membranes the protein it attaches to — it turned out to be CD36, a multifunctional protein present on heart-muscle cells and small blood vessels. Activation of CD36 by hexarelin in the isolated heart raised the pressure in the coronary vessels (that is, it narrowed them) in a dose-dependent way, and the effect vanished in mice lacking the CD36 gene. The authors suggested that CD36 may be responsible for the coronary spasm seen in atherosclerosis — so this is a two-faced mechanism, not simple “heart protection”.
Structure and origin
The sequence of hexarelin is His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2. It differs from GHRP-6 only by a methyl group attached to the second amino acid — a small detail that increases the molecule's resistance to breakdown. Two amino acids are in the “mirror-image” D form, which further protects the peptide from enzymes. It is an entirely artificial molecule with no counterpart in the body.
What was studied — cells and animals
The most interesting animal thread concerns the heart. Locatelli et al. (1999) removed the pituitary from rats (and with it their own growth hormone), which made heart damage after experimental ischaemia worse. Seven days of hexarelin prevented that worsening: it preserved contractility and limited the rise in ventricular and coronary pressure and the leakage of an enzyme (creatine kinase) from damaged cells. The key comparison: another peptide of the same family, one that does not bind to the heart, had no effect at all — so the protection did not come from growth hormone (which these rats lacked) but from direct action on receptors in the heart. Bear in mind, though, that “cardioprotection” in these papers means protecting an isolated rodent heart from artificially induced ischaemia — not preventing heart attacks in people.
Human data — growth hormone
Ghigo et al. (1994) gave hexarelin to 12 healthy young volunteers by four different routes. After intravenous injection the GH pulse was about twice as large as after the same dose of GHRH, reproducible and increasing with dose. The peptide also worked after subcutaneous, intranasal and even oral administration — although bioavailability (the fraction of the dose that actually reaches the blood) was 77% subcutaneously, 4.8% intranasally and a mere 0.3% orally.
The most important study for judging long-term use is that of Rahim et al. (1998) from Manchester: adults received subcutaneous hexarelin twice daily for 16 weeks, and at intervals the researchers measured how large a GH pulse a single injection produced. The response declined: the area under the GH curve fell from 19.1 µg/l·h at the start to 12.3 after 4 weeks and 10.5 after 16 weeks — and 4 weeks after stopping it returned to 19.4, that is, to the starting value. The authors called this a “partial and reversible attenuation” of the response. Just as important is what was not found: IGF-I and IGFBP-3 (the long-term markers of GH action) did not change, and after 16 weeks neither fat mass, nor lean body mass, nor bone density had changed. The authors described the impact of this regimen on the GH–IGF-I axis as “minimal”.
Human data — cortisol, prolactin and the heart
Hexarelin, like the whole family, is not selective. In 12 healthy subjects a single intravenous dose raised ACTH (on average from 16.3 to 32.4 pg/ml) and cortisol (from 110 to 136 µg/l) — to a degree similar to hCRH, the hormone used to deliberately stimulate the stress axis (Ghigo et al., 1997). In patients with Cushing's disease (an ACTH-producing pituitary tumour) the response was about seven times stronger than after hCRH, while in patients with an adrenal tumour there was none at all. What happened during chronic dosing, however, is intriguing: in the 16-week Manchester study (Rahim et al., 1999) the morning cortisol response to the injection after 16 weeks was smaller than at the start, while daily urinary cortisol excretion, ACTH and prolactin did not change. The authors concluded that this regimen did not over-stimulate the stress axis or prolactin. Single-dose data and data from weeks of use therefore tell different stories; both come from small groups.
The heart was also studied in humans. Broglio et al. (2002) gave hexarelin to 24 men with coronary artery disease during bypass surgery, comparing it with GHRH, recombinant growth hormone and placebo. Only hexarelin improved cardiac performance: within 10 minutes the left-ventricular ejection fraction, cardiac index and cardiac output rose, the effect lasted up to 90 minutes, wedge pressure fell, and heart rate did not change. Neither GHRH nor the administered growth hormone produced such an effect, so it did not come from GH — the authors attributed it to receptors in the cardiovascular system. It is, however, an acute and short-lived effect, measured under general anaesthesia. There are no studies showing that hexarelin protects the human heart from infarction or improves prognosis.
Safety and the limits of the evidence
Hexarelin is not an approved medicine for any indication. The human studies consist of single doses in a dozen to a few dozen people and one 16-week study in a group of adults, which showed no change in body composition. Every dose raises cortisol and prolactin; with dosing over several months the GH response weakens by roughly half and recovers after a break. Action on CD36 means an effect on the coronary vessels — protective in animal models, but also vessel-narrowing in the isolated heart, and in humans examined only after a single dose. About the consequences of many months of use — for the heart, the stress axis or glucose metabolism — nothing is known. We deliberately give no methods of use and no doses.
The wider context — the GHRP family
Hexarelin belongs to the family of ghrelin-receptor agonists descended from GHRP-6. Its closest “contemporary” is GHRP-2 — a direct comparison of the two peptides in humans is described in our GHRP-2 article. Ipamorelin was created later precisely to avoid that rise in cortisol and prolactin. A separate group are the GHRH analogues such as CJC-1295, which act on a different switch; in studies the two groups complement each other because their effects on GH add up.
Summary
Hexarelin is a more stable derivative of GHRP-6 and one of the best-studied peptides of this family in humans — but studied mainly after single doses. It produces a strong GH pulse, raises ACTH, cortisol and prolactin, and in the only 16-week study the GH response weakened by half and recovered after a four-week break, with no change in IGF-I or body composition. Its peculiarity — binding to CD36 in the heart — gave heart-muscle protection in animal models and, in humans, a short-lived improvement in cardiac performance after one dose; the mechanism has not been confirmed in humans, however, and is also linked to narrowing of the coronary vessels. Evidence of benefit from long-term use does not exist.
Sources
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For in-vitro laboratory research only. It is not a human medicine and is not for treatment.