What Has Published Research Reported About Hexarelin?

What is hexarelin?

Hexarelin is a synthetic six-residue peptide that belongs to the growth hormone releasing peptides, or GHRPs, a family of small synthetic molecules that stimulate growth hormone (GH) release from the pituitary. A 1995 study in Endocrine Research by Giustina and colleagues described it as an analog of GHRP-6 in which the D-tryptophan residue was replaced by its 2-methyl derivative (source 3). Written out, the sequence is His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2, with an amidated C-terminus.

That single methyl group is the only structural difference from the parent peptide. Working from the sequence, the molecular formula of the free peptide comes out as C47H58N12O6, about 887.1 daltons. GHRP-6, without the methyl group, calculates to C46H56N12O6, about 873.0 daltons. These are calculated values from the published sequence rather than figures quoted from a cited paper, but the 14-dalton gap matters for laboratories, as discussed below.

This Steadfast Research Group profile summarizes what the primary literature reported about hexarelin, from its first characterization in rats to the cardiac receptor work of the early 2000s. It is written for researchers reading that record and covers published observations only.

How was hexarelin first characterized in animals?

The founding animal paper appeared in Life Sciences in 1994. Deghenghi, Cananzi, Torsello, Battisti, Müller and Locatelli tested the peptide in two rat models (source 1). In conscious 10-day-old rats, the authors reported that hexarelin was highly active at stimulating GH secretion. In anesthetized adult male rats, both GHRP-6 and hexarelin produced a prompt GH release, with peak GH levels within 10 minutes, and the two peptides were similarly effective at every amount tested (source 1).

Route of administration changed the picture. When hexarelin was given subcutaneously, the authors reported a long-lasting GH release that was slightly greater than the release produced by GHRP-6 by the same route (source 1). On that basis the paper concluded that hexarelin was a highly effective GH releaser. The comparison with GHRP-6 is the core of the early record: the 2-methyl substitution was tested head to head against the unmodified parent molecule in the same animals.

What did the first human study measure?

The first human pharmacology study was published the same year in the Journal of Clinical Endocrinology & Metabolism by Ghigo, Arvat, Gianotti and colleagues (source 2). It enrolled 12 healthy young volunteers and compared GH release after intravenous, subcutaneous, intranasal and oral administration. The investigators reported that the GH response to intravenous hexarelin was greater than the response to growth hormone-releasing hormone (GHRH), the hypothalamic peptide that normally drives GH secretion (source 2).

The study also estimated what it called biological bioavailability, a figure derived from the size of the GH response by each route relative to the intravenous route rather than from direct measurement of the peptide in blood. That estimate was highest for the subcutaneous route, in the single digits for the intranasal route and below 1 percent for the oral route (source 2). Because the estimate was based on GH output, it describes the hormonal response by each route rather than the concentration of hexarelin reached in blood.

Which receptor does hexarelin act on?

Hexarelin was characterized before its receptor was known. In 1996, Howard and colleagues reported in Science the cloning of a G protein-coupled receptor in the pituitary and hypothalamus that functioned in GH release and served as the target of synthetic growth hormone secretagogues (source 4). Three years later, Kojima and colleagues reported in Nature the purification of ghrelin, a 28-residue acylated peptide from rat stomach that bound this receptor and released GH (source 5).

The 1994 hexarelin papers therefore predate both discoveries, which is why they describe the compound simply as a GH-releasing peptide. A 2014 review by Mao, Tokudome and Kishimoto in the Journal of Geriatric Cardiology later summarized the field: hexarelin acts on the growth hormone secretagogue receptor, the receptor that binds ghrelin, and also binds a second, unrelated receptor called CD36 (source 11). The review described hexarelin as more chemically stable than ghrelin (source 11).

Growth hormone releasing peptide (GHRP)

A small synthetic peptide that stimulates GH release from the pituitary. GHRP-6 is the parent compound of hexarelin (source 3).

Growth hormone secretagogue receptor (GHS-R)

The G protein-coupled receptor cloned in 1996 as the target of synthetic GH secretagogues and later shown to bind ghrelin (sources 4 and 5).

CD36

A scavenger receptor glycoprotein, identified in 2002 as the cardiac binding site for hexarelin (source 10).

Biological bioavailability

In the 1994 human study, an estimate of how much of the intravenous GH response each other route reproduced (source 2).

Langendorff preparation

An isolated heart perfused through the coronary arteries outside the body, used to measure coronary perfusion pressure in the cardiac studies (sources 9 and 10).

Did hexarelin change hormones other than growth hormone?

Several studies asked whether hexarelin was selective for GH. In 1996, Massoud, Hindmarsh and Brook reported a study in healthy adult men who received intravenous hexarelin across a range of amounts, with GH, prolactin and cortisol measured afterward (source 6). The authors reported that all three hormones rose as the amount increased. At the low end of the range, hexarelin acted synergistically with GHRH and was potent for GH release with minimal effect on the other hormones (source 6).

A 1997 study in Peptides by Arvat, di Vito, Maccagno and colleagues compared hexarelin with GHRP-2, another synthetic secretagogue, in healthy young adults (source 7). The two peptides produced a similar, strong GH response that was higher than the response to GHRH (p < 0.05). The same study measured prolactin, ACTH and cortisol and compared those responses with the reference stimuli TRH and human corticotropin-releasing hormone (source 7). Together with the 1996 data, this places hexarelin among the older GHRPs that were reported to affect the pituitary-adrenal axis as well as GH. The later peptide covered in the Steadfast Research Group profile of ipamorelin was characterized largely around that same selectivity question.

The 1995 Giustina study tested a different interaction (source 3). In ten adults with active acromegaly, hydrocortisone alone lowered GH by about 47 percent from baseline. The peak GH response to hexarelin given with hydrocortisone did not differ significantly from the response to hexarelin alone, and the authors concluded that the response to hexarelin resisted the inhibitory effect of raised glucocorticoid levels (source 3).

Did the growth hormone response change with repeated administration?

Rahim, O’Neill and Shalet addressed this in a 1998 study in the Journal of Clinical Endocrinology & Metabolism (source 8). Participants received repeated subcutaneous hexarelin for 16 weeks, and the GH response to a single test administration was measured at intervals. Compared with baseline, the area under the GH curve was significantly lower at week 4 (P < 0.05) and at week 16 (P < 0.01) (source 8).

The reduction was not permanent. Four weeks after the 16-week period ended, the GH response had risen significantly compared with week 16 and was no longer significantly different from baseline (source 8). Serum IGF-I and IGF binding protein-3 did not change significantly over the full 20 weeks (P = 0.24 and P = 0.74) (source 8). The authors therefore described a partial, reversible attenuation of the acute GH response rather than a complete loss of it.

What is CD36, and how was it linked to hexarelin?

The cardiac thread began with a 1999 paper in Circulation Research by Bodart, Bouchard, McNicoll and colleagues (source 9). In isolated perfused rat hearts, hexarelin raised coronary perfusion pressure, and the rise grew with concentration. The effect was partially blocked by nifedipine, chelerythrine and bisindolylmaleimide, which the authors read as pointing to L-type calcium channels and protein kinase C (source 9).

The binding work was the more surprising result. Using a photoactivatable hexarelin derivative, the authors labeled a binding protein with an apparent molecular mass of 84,000 in rat cardiac membranes. MK-0677 and EP51389, two potent GH secretagogues, did not displace that binding, and the authors proposed that the heart carried a new class of hexarelin receptor distinct from the pituitary secretagogue receptor (source 9).

In 2002 the same group identified the protein (source 10). Its N-terminal sequence matched rat CD36, a scavenger receptor glycoprotein. The coronary pressure response to hexarelin was absent in hearts from CD36-null mice and from spontaneously hypertensive rats that lack CD36, and the size of the response tracked CD36 expression (source 10). The 2014 review described CD36 as a specific cardiac receptor for hexarelin and summarized later animal and isolated-heart studies built on that finding (source 11).

What remains unresolved in the hexarelin literature?

The record has clear limits. Most of the human data come from small studies published between 1994 and 1998, including a pharmacology study with 12 volunteers (source 2). Several key papers share investigators: Deghenghi is an author on the first rat study, the first human study, the acromegaly study and the GHRP-2 comparison (sources 1, 2, 3 and 7). Within the sources reviewed here, most findings rest on a single study each rather than on independent replications.

Interpretation is also complicated by hexarelin’s two binding sites. An effect observed with hexarelin could involve the secretagogue receptor, CD36 or both, and the receptor work showed that other secretagogues did not share the cardiac binding (sources 9 and 10). The 16-week study showed that the acute GH response itself can fall during repeated administration (source 8), so findings from single administrations may not describe longer study periods.

For laboratories, the practical issue is identity. Hexarelin and GHRP-6 differ by one methyl group, and the calculated masses of about 887.1 and 873.0 daltons are separated by roughly 14 daltons, a gap that mass spectrometry resolves easily. Checking purity by HPLC and confirming the expected mass against a batch-matched Certificate of Analysis are the routine ways to tell closely related GHRPs apart.