Hexarelin

Overview

Hexarelin is a synthetic hexapeptide in the family of growth hormone secretagogues. It triggers growth hormone release by binding to the GHS-R1a receptor, the same receptor used by the body's own hormone ghrelin. Structurally it is derived from GHRP-6, with two added methyl groups that make the peptide more stable. Its international nonproprietary name is examorelin.

In humans, Hexarelin is well characterised as a growth hormone stimulator. Several studies from the 1990s showed a strong, dose-dependent growth hormone response after intravenous, subcutaneous, intranasal and even oral administration. Two of those were randomised. Throughout this body of work the endpoint is the growth hormone response itself, not a clinical treatment effect.

What distinguishes Hexarelin within this database is a second research thread independent of growth hormone: a strikingly consistent cardioprotective profile. Multiple independent groups have reported in animal models that Hexarelin protects cardiac tissue during oxygen deprivation, inhibits cardiac fibrosis and improves cardiac function after infarction. This effect runs partly through GHS-R1a and partly through CD36, a scavenger receptor in cardiac tissue also involved in fat metabolism and inflammation. A scavenger receptor is a receptor that clears the body's own waste and signalling molecules.

The distinction matters and is kept strict throughout this text. The growth hormone action is confirmed in humans. The cardioprotective profile is not: it rests entirely on preclinical work in cell and animal models. Whether that protection translates to humans is an open research question.

Mechanism of action

Hexarelin acts along two routes: GHS-R1a activation at the pituitary explains growth hormone release, while CD36 binding in cardiac tissue underlies the cardioprotection observed in preclinical models.

GHS-R1a activation

• Binds with high affinity to GHS-R1a, the primary growth hormone secretagogue receptor
• Stimulates pulsatile release of growth hormone from the pituitary
• Activates downstream signalling via the PKC and cAMP pathways. PKC is an enzyme that propagates signals inside the cell.

CD36-mediated cardioprotection (preclinical)

• In cardiac tissue, binds CD36 independently of GHS-R1a
• In animal models this was accompanied by reduced programmed cell death of cardiomyocytes
• In ischemic cardiac tissue, lower levels of oxidative-stress markers were measured. Oxidative stress is damage caused by reactive oxygen species.

Anti-fibrotic and anti-inflammatory effects (preclinical)

• In cultured cardiac fibroblasts, Hexarelin inhibited cell proliferation and collagen synthesis. Fibroblasts are connective-tissue cells; collagen accumulation is the core of fibrosis.
• A reduction of TGF-β, a central driver of fibrosis, has been observed in cell models
• In ischemic cardiac tissue, IL-1 signalling was modulated. IL-1 is a pro-inflammatory signalling molecule.

Research findings

• A strong, dose-dependent growth hormone response was observed in healthy volunteers after intravenous, subcutaneous, intranasal and oral administration (Ghigo 1994, n=12)
• The response was reproducible and stronger than that to GHRH; the combination with GHRH was synergistic (Massoud 1996, randomised, n=6)
• Repeated subcutaneous administration selectively raised 24-hour growth hormone output, without lasting changes in prolactin, ACTH or cortisol secretion (Maccario 2002, randomised, n=6)
• In an isolated rat heart, seven days of pretreatment protected against damage from the calcium-paradox phenomenon (Rossoni 2000)
• In isolated working hearts, Hexarelin reduced infarct size after oxygen deprivation, partly via PKC (Frascarelli 2003)
• In rats with chronic heart failure, it improved left-ventricular function and reduced cardiac cachexia and cardiomyocyte cell death (Xu 2005)
• In ghrelin knockout mice, Hexarelin produced better post-infarction cardiac function and lower mortality than ghrelin itself (Mao 2013)
• A single oral dose shortly after infarction preserved chronic cardiac function (Mao 2014)
• In a mouse model of acute lung injury, Hexarelin improved lung function and reduced fibrosis (Zambelli 2021)

Human studies (growth hormone release)

• Strong, dose-dependent GH response across four administration routes in healthy volunteers (Ghigo 1994, n=12)
• Reproducible response stronger than GHRH, with synergy when combined (Massoud 1996, randomised, n=6)
• Selective increase in 24-hour GH output without sustained effects on prolactin, ACTH or cortisol (Maccario 2002, randomised, n=6)
• Endpoints across these studies are hormonal measures. Clinical endpoints have not been investigated.

Animal and cell models (cardioprotection)

• Protection against calcium-paradox damage in isolated rat hearts (Rossoni 2000)
• Reduction of infarct size in ex vivo working hearts, partly PKC-mediated (Frascarelli 2003)
• Improved LV function, reduced cachexia and apoptosis in rat chronic heart failure (Xu 2005)
• Superior post-infarction cardiac function and survival in ghrelin knockout mice (Mao 2013)
• Single oral dose preserves chronic cardiac function after infarction in mice (Mao 2014)
• Improved lung function and reduced fibrosis in a mouse model of acute lung injury (Zambelli 2021)

Human cardioprotection

• No human intervention studies on cardioprotective effects published
• The translation of the animal data to protection in humans has not been investigated

Research context

Hexarelin has an exceptionally consistent preclinical cardioprotective profile. The findings have been replicated by multiple independent groups across models ranging from the isolated heart to in vivo infarction studies. This level of consistency is rare in this research field.

The dual receptor mechanism, via both GHS-R1a and CD36, offers a biologically plausible explanation for effects independent of growth hormone release. CD36 signalling is an active area of cardiovascular pharmacology, which makes Hexarelin interesting as a pharmacological tool for studying that route.

The dividing line in the evidence matters most here. The growth hormone action is confirmed in humans; the cardioprotection is not. The phase II development once initiated for growth hormone deficiency and heart failure was not completed and yielded no published outcome data. The absence of human cardioprotection data is therefore the central limitation.

Open questions

The consistency of the preclinical cardioprotective data is a strong scientific signal. The translational step to human research is, however, entirely missing. This is the priority research question for Hexarelin.

• No human intervention studies on cardioprotective effects exist. For cardiology research groups this is the first, most direct next step: a safety and feasibility study in humans.
• The relative contribution of GHS-R1a versus CD36 to cardioprotection is not resolved. Receptor-specific studies with selective antagonists could separate them.
• Optimal dosing, route of administration and long-term pharmacokinetics in humans are not established.
• The long-term risk profile in humans is not characterised. This requires studies with systematic monitoring.
• Interaction with existing cardiovascular medication has not been investigated.

Research outlook

First human safety studies are needed before the cardioprotective potential can be clinically evaluated

CD36 as a target for cardiovascular protection has broad scientific interest

Comparative studies with ghrelin and other GHS peptides may further separate the mechanism

The signal in acute lung injury warrants additional preclinical work before translation can be considered

Scientific interest

Cardioprotection via the dual route GHS-R1a and CD36

Inhibition of cardiac fibrosis and ventricular remodelling

Growth hormone secretion as the human-confirmed anchor

Inflammation modulation, including in acute lung injury

Specifications

References

1. GH-releasing activity of Hexarelin, a new growth hormone-releasing peptide, in infant and adult subjects · Ghigo E, Arvat E, Gianotti L, et al. · J Clin Endocrinol Metab · 1994
2. Repeated administration of hexarelin and growth hormone-releasing hormone (GHRH) on GH responsivity · Massoud AF, Hindmarsh PC, Brook CG · Clin Endocrinol (Oxf) · 1996
3. Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium. · Rossoni G, Locatelli V, Gennaro Colonna V, Müller EE, Berti F. · Pharmacological Research · 2000
4. Effects of two or three daily subcutaneous administrations of hexarelin on growth hormone (GH), prolactin, adrenocorticotropin and cortisol secretion in healthy young men · Maccario M, Arvat E, Procopio M, et al. · Eur J Endocrinol · 2002
5. Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart. · Frascarelli S, Ghelardoni S, Ronca-Testoni S, Zucchi R. · Basic Research in Cardiology · 2003
6. GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure. · Xu XB, Pang JJ, Cao JM, et al. · American Journal of Physiology — Heart and Circulatory Physiology · 2005
7. Hexarelin suppresses cardiac fibroblast proliferation and collagen synthesis in rat. · Xu X, Pang J, Yin H, et al. · American Journal of Physiology — Heart and Circulatory Physiology · 2007
8. Hexarelin treatment in male ghrelin knockout mice after myocardial infarction. · Mao Y, Tokudome T, Kishimoto I, et al. · Endocrinology · 2013
9. One dose of oral hexarelin protects chronic cardiac function after myocardial infarction. · Mao Y, Tokudome T, Kishimoto I, et al. · Peptides · 2014
10. The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From in vivo Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway. · Huang J, Li Y, Zhang J, Liu Y, Lu Q. · International Heart Journal · 2017
11. Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury. · Zambelli V, Rizzi L, Delvecchio P, et al. · Drug Target Insights · 2021

Availability

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