The History of the Discovery of Hexarelin

Hexarelin (international nonproprietary name — examorelin) appeared in the early 1990s as one of the most potent synthetic peptides that stimulate the release of growth hormone. Its history is interesting in that scientists first created the "key" and only later found the "lock" — the receptor — and then the natural hormone for which that receptor exists. Our editorial team has traced hexarelin's path from laboratory chemistry to its current status.

Background: Cyril Bowers's Accidental Find

The history of hexarelin begins with the work of the American endocrinologist Cyril Bowers of Tulane University. In the mid-1970s, his group was studying analogs of enkephalins — endogenous opioid peptides — and noticed that some of them stimulated the release of growth hormone by pituitary cells in vitro, and not through opioid receptors.

This find seemed strange: at the time, the hypothalamic growth hormone-releasing hormone (GHRH) had not yet been isolated, and it was believed that GHRH itself should be the main stimulator of GH. Bowers, together with the chemist Frank Momany, began purposefully modifying the structure of the peptides, using early methods of computer modeling of conformations.

The result was a series of synthetic peptides named GHRP (growth hormone-releasing peptides). The most famous of them was the hexapeptide GHRP-6, published in the early 1980s. It proved active not only in the test tube but also in animals and humans, including when administered orally, though with low bioavailability.

In parallel, in 1982, the groups of Roger Guillemin and Wylie Vale isolated GHRH from pancreatic tumors of patients with acromegaly. It became clear that GHRP act differently from GHRH: together these substances produced a synergistic, much greater release of growth hormone than each one separately.

The Birth of Hexarelin

In the early 1990s, the chemist Romano Deghenghi of the company Europeptides proposed a modification of GHRP-6: replacing the D-tryptophan residue with 2-methyl-D-tryptophan. The resulting compound with the sequence His–D-2-Me-Trp–Ala–Trp–D-Phe–Lys–NH2 was named hexarelin.

The modification made the molecule more stable against enzymes and enhanced its activity. Already in the first human studies, hexarelin stimulated the release of growth hormone more strongly than GHRP-6 at comparable doses, and by some routes of administration — even more strongly than GHRH.

A key role in clinical study was played by the group of Ezio Ghigo of the University of Turin. In 1994, in the Journal of Clinical Endocrinology and Metabolism, they described the activity of hexarelin with intravenous, subcutaneous, intranasal and oral administration. The effect was greatest with parenteral administration, while oral bioavailability proved very low.

During the 1990s, Italian, Israeli and British groups studied hexarelin in children with growth retardation, in the elderly and in patients with various endocrine disorders. It was then that they found the drug raised not only GH but also prolactin, ACTH and cortisol — unlike the more selective compounds that came later.

A Receptor Found for an Artificial Key

For almost two decades, the mechanism of action of GHRP remained a mystery. It was clear that they acted through a separate receptor, distinct from the GHRH receptor, but neither the receptor nor the natural ligand was known. The impetus came from non-peptide analogs created at the company Merck: the compound L-692,429, and later ibutamoren (MK-677).

In 1996, the group of Howard and colleagues published in the journal Science the cloning of the receptor through which these substances act. It was named the growth hormone secretagogue receptor — GHS-R (now the subtype GHS-R1a). The receptor was located in the pituitary and hypothalamus, as well as in a number of peripheral tissues.

However, the natural hormone for this receptor remained unknown for another three years. Such a situation in pharmacology is called an "orphan receptor": synthetic ligands were already being actively studied in the clinic, while the endogenous one was not.

In 1999, the Japanese researchers Kojima, Kangawa and colleagues isolated from rat stomach a peptide that activates GHS-R, and named it ghrelin. The publication in Nature finally explained that hexarelin and its "relatives" mimic the action of a natural gastric hormone that regulates not only GH but also appetite and energy metabolism.

The Cardiac Trace and CD36

In the late 1990s, an unusual property of hexarelin attracted attention: in animals it protected the myocardium from ischemic damage, and this effect apparently did not depend on growth hormone. Italian groups reported cardioprotection by hexarelin in GH-deficient rats.

The search for an explanation led to yet another receptor. In 2002, Bodart and colleagues (Circulation Research) showed that in the heart hexarelin binds to CD36 — a membrane scavenger-receptor protein known for its role in fatty acid transport and the uptake of oxidized lipoproteins.

This discovery made hexarelin a useful tool for studying the "extrapituitary" effects of secretagogues. It also explained why some effects of hexarelin are not reproduced by ghrelin and why different GHRP are not fully interchangeable.

Small studies in humans, in particular in patients with heart failure and GH deficiency, showed acute hemodynamic effects of hexarelin. However, it never reached the large clinical trials that could have led to registration.

Why Hexarelin Never Became a Medicine

Despite its potent action, hexarelin has several properties that complicated its path to the clinic. The first is tachyphylaxis: with prolonged use, the growth hormone response gradually weakens. A British study by Rahim and colleagues (1998) demonstrated a partial decline in the response during long-term therapy.

The second is insufficient selectivity. The increase in cortisol, ACTH and prolactin is undesirable with prolonged use. Later compounds, in particular ipamorelin, were developed precisely as more selective alternatives.

The third is competition. Recombinant growth hormone became available, and for diagnosing GH deficiency the oral secretagogue macimorelin was later registered. For therapeutic purposes, hexarelin offered no advantages that would justify expensive phase III studies.

As a result, hexarelin remained a research molecule. Since the 2000s it has appeared mainly in experimental cardiology and on the illegal market of "research peptides," and in sport it is included on the WADA Prohibited List (class S2) as a growth hormone secretagogue.

• tachyphylaxis with prolonged use;
• an increase in cortisol, ACTH and prolactin;
• low bioavailability when taken orally;
• no advantages over recombinant GH in treatment;
• the absence of large phase III studies.

Editorial Conclusions

Hexarelin is the product of several decades of research that began with Bowers's accidental observation of enkephalin analogs and passed through the creation of GHRP-6.

The history of this molecule is unique: the synthetic "key" existed before its "lock" — the GHS-R receptor in 1996 — and the natural hormone ghrelin in 1999 were discovered. Later it turned out that hexarelin also acts through CD36.

However, because of tachyphylaxis, lack of selectivity and the absence of advantages over growth hormone, hexarelin never became a registered drug and remained a tool of science and a substance banned in sport.

Our editorial team also recommends familiarizing yourself with our materials about the myths surrounding hexarelin, about its effect on carbohydrate metabolism, and about the history of the discovery of BPC-157.

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. 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.
3. 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.
4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660.
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. Rahim A, O'Neill PA, Shalet SM. Growth hormone status during long-term hexarelin therapy. J Clin Endocrinol Metab. 1998;83(5):1644–1649.
7. World Anti-Doping Agency. Prohibited List. Montreal: WADA; 2025.