Hexarelin
Also known as: Hexarelin acetate, HEX, EP-23905, Growth Hormone-Releasing Peptide Hexarelin
5 notable studies · 8 references
TLDR
Hexarelin is a synthetic ghrelin-receptor growth hormone secretagogue with established acute GH-releasing activity in humans and intriguing GH-independent cardiovascular effects involving pathways such as CD36, but long-term safety and therapeutic benefits have not been established.
Research Supports
- Studied for dose-dependent stimulation of endogenous growth hormone release
- Investigated for interactions with GHRH and somatostatin in GH regulation
- Studied for acute, apparently GH-independent effects on cardiac function
- Investigated as a CD36-mediated cardiovascular signaling molecule
- Examined in animal models of ischemia-reperfusion injury
Observations Reported in Research
- Dose-response trial (1994): peak GH rose from ~3.9 ng/mL (placebo) to 26.9-55.0 ng/mL across doses
- Acute dosing increased left-ventricular ejection fraction in healthy men without raising heart rate or blood pressure
- Recombinant GH raised GH similarly but did not reproduce the cardiac effect
- CD36 identified as a mediator (Bodart et al., 2002): response absent in CD36-null hearts
- In GH-deficient rats, chronic treatment reduced signs of ischemic ventricular dysfunction
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Synthetic hexapeptide; growth hormone secretagogue; ghrelin/growth hormone secretagogue receptor agonist
Hexarelin is a synthetic six-amino-acid growth hormone secretagogue related to GHRP-6. It stimulates endogenous growth hormone secretion primarily through the growth hormone secretagogue receptor (GHS-R1a), commonly called the ghrelin receptor. Controlled human studies from the 1990s demonstrated strong, dose-dependent GH release after hexarelin administration. In one placebo-controlled study of healthy men, GH peaked approximately 30 minutes after administration and returned toward baseline within several hours. Hexarelin is particularly interesting because researchers also identified biological activity in cardiovascular tissue that appears at least partly independent of growth hormone release. Small human studies reported acute changes in cardiac performance, while laboratory work subsequently identified CD36 as one molecular target associated with some cardiovascular actions of hexarelin. These findings remain experimental. Hexarelin is not FDA-approved, and controlled evidence has not established commonly promoted uses involving muscle growth, fat loss, recovery, anti-aging, or cardiovascular treatment.
What Is Hexarelin?
Hexarelin is a synthetic hexapeptide with the sequence: His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH₂ It was developed from the same broad family of synthetic growth hormone-releasing peptides as GHRP-6. Researchers modified the peptide structure in an attempt to produce a potent and relatively stable growth hormone secretagogue. Human studies subsequently showed that hexarelin could stimulate GH after several routes of administration. One early study involving 12 healthy volunteers investigated intravenous, subcutaneous, intranasal, and oral administration and found measurable GH responses across multiple routes, although potency differed substantially. Like GHRP-2, GHRP-6, and ipamorelin, hexarelin acts through the growth hormone secretagogue/ghrelin receptor system rather than acting as a GHRH analogue. However, research eventually revealed that hexarelin's biology may extend beyond GHS-R1a. Cardiovascular experiments identified additional hexarelin-binding sites, with later research identifying the scavenger receptor CD36 as an important mediator of some cardiac effects.
What Are Researchers Studying?
Growth hormone secretion
Growth hormone release is the best-established human effect of hexarelin. A double-blind, placebo-controlled dose-response study in 12 healthy men demonstrated dose-dependent increases in circulating GH. Mean peak GH concentrations rose from approximately 3.9 ng/mL with placebo to 26.9, 52.3, and 55.0 ng/mL following increasing hexarelin doses. GH generally peaked around 30 minutes after administration. These experiments establish endocrine activity but do not demonstrate long-term clinical benefit.
GHRH and somatostatin interactions
Researchers have used hexarelin to study regulation of the growth hormone axis. Human experiments found that combining hexarelin with GHRH produced greater GH release than hexarelin alone. Somatostatin strongly suppressed GHRH-induced GH secretion but only partially suppressed the response to hexarelin. These findings helped researchers understand how GHRPs interact with the normal hypothalamic-pituitary control of growth hormone.
Cardiac function
Hexarelin has an unusual cardiovascular research history compared with other GHRPs. In a study of seven healthy men, acute hexarelin administration increased left-ventricular ejection fraction without significant changes in heart rate or mean blood pressure. Recombinant growth hormone produced a similar increase in circulating GH but did not reproduce the cardiac effect, suggesting that hexarelin's acute cardiovascular activity was not simply a consequence of increased GH. This finding generated considerable subsequent interest in direct cardiac actions of hexarelin.
Growth hormone-independent cardiovascular signaling
Researchers subsequently investigated whether hexarelin interacts directly with receptors in cardiac tissue. Specific hexarelin-binding sites were identified in cardiac membranes, and later molecular work identified CD36, a multifunctional membrane glycoprotein, as one mediator of hexarelin's cardiovascular effects. In experimental hearts, some vascular responses to hexarelin disappeared when CD36 was absent. This suggests that hexarelin can produce biological effects outside the classical pituitary GH pathway.
Ischemia and cardioprotection
Animal studies have investigated whether hexarelin influences cardiac responses to ischemia and reperfusion. In GH-deficient rats, chronic hexarelin treatment reduced several signs of ischemic and post-ischemic ventricular dysfunction. These findings contributed to the hypothesis that hexarelin or related pathways might influence cardiac tissue independently of circulating GH. Clinical evidence demonstrating cardioprotection in humans has not been established.
Coronary artery disease
A small human experiment studied 24 men with coronary artery disease undergoing bypass surgery. Researchers compared acute hexarelin with GHRH, recombinant GH, and placebo. Hexarelin produced short-term increases in left-ventricular ejection fraction, cardiac index, and cardiac output. The other interventions did not reproduce the same hemodynamic response. This provides intriguing human mechanistic evidence but does not establish hexarelin as a treatment for coronary artery disease.
Growth hormone deficiency
Hexarelin has also been studied in people with GH deficiency. In seven adults with severe GH deficiency, the GH response to hexarelin was negligible compared with controls, yet researchers still observed an acute increase in left-ventricular ejection fraction. That separation between GH release and cardiac response strengthened the hypothesis that hexarelin has direct cardiovascular activity.
How Does It Work?
Hexarelin has at least two important areas of pharmacology. GHS-R1a / ghrelin receptor signaling Hexarelin activates the growth hormone secretagogue receptor. Within the hypothalamic-pituitary system, this promotes endogenous growth hormone release. This places it in the same broad mechanistic family as: Ipamorelin → GHS-R1a GHRP-2 → GHS-R1a GHRP-6 → GHS-R1a Hexarelin → GHS-R1a while: CJC-1295 / Tesamorelin → GHRH receptor Hexarelin can interact synergistically with GHRH signaling, demonstrating that the pathways are distinct but interconnected. Cardiovascular / CD36 signaling Hexarelin also appears capable of interacting with cardiovascular targets not fully explained by GHS-R1a. Researchers identified specific hexarelin-binding sites in cardiac tissue. Subsequent experiments identified CD36 as one receptor involved in its cardiovascular effects. This is scientifically important because it suggests that not every biological effect of hexarelin should automatically be attributed to increased GH or IGF-1.
What Does the Research Show?
Human research
Hexarelin has direct human experimental evidence dating back several decades. Studies have demonstrated: • Dose-dependent GH release • Activity through several routes of administration • Interaction with GHRH and somatostatin • Acute cardiovascular effects • Responses in GH-deficient patients • Acute effects in people with coronary artery disease The human studies are generally small and short-term, however. For example, the classic dose-response trial involved only 12 healthy men. The initial cardiovascular experiment involved seven healthy men. The GH-deficiency cardiac study included seven patients and nine controls. And the coronary-bypass experiment involved 24 men divided among intervention groups. These studies establish interesting human pharmacology. They do not establish long-term cardiovascular benefit, improved survival, improved athletic performance, muscle growth, fat loss, recovery, or anti-aging effects.
Animal research
Animal research provides much of the evidence underlying proposed cardiovascular effects of hexarelin. Experiments in GH-deficient and aged rats have examined: • Ischemia-reperfusion injury • Ventricular function • Coronary vascular responses • Endothelial function • Cardiac remodeling • Myocyte survival Some studies found that hexarelin reduced ischemic dysfunction even under conditions suggesting that the effects were not dependent solely on GH secretion. Animal research also helped identify CD36 as an important cardiovascular molecular target.
In-vitro research
Laboratory experiments have characterized hexarelin binding in pituitary, cardiac, vascular, and other tissues. Radiolabeled hexarelin derivatives identified binding sites in human and animal myocardium. One study examining peripheral human tissues detected substantial specific binding in the myocardium as well as several other tissues. Cellular experiments have also investigated apoptosis, vascular signaling, receptor binding, and cardiac mechanisms. These findings support a broader biological role for hexarelin but cannot establish clinical efficacy.
Notable Studies
Growth Hormone-Releasing Activity of Hexarelin, a New Synthetic Hexapeptide, After Intravenous, Subcutaneous, Intranasal, and Oral Administration in Man
humanTwelve healthy young volunteers received hexarelin through several administration routes. Intravenous hexarelin produced a strong GH response that exceeded the response produced by the comparator GHRH exposure in the experiment. Subcutaneous, intranasal, and oral administration also produced measurable GH responses, although the magnitude differed by route. The study established that hexarelin is biologically active in humans and demonstrated that its endocrine activity was not limited to intravenous exposure.
Limitations: The study was small and evaluated acute hormone responses rather than long-term clinical outcomes. It did not establish therapeutic benefits from repeated administration.
View publication →Growth Hormone-Releasing Activity of Hexarelin in Humans: A Dose-Response Study
humanTwelve healthy male volunteers received increasing doses of intravenous hexarelin or placebo. Growth hormone increased dose-dependently and generally peaked approximately 30 minutes after administration. Mean peak GH concentrations were approximately 3.9 ng/mL with placebo and 26.9, 52.3, and 55.0 ng/mL across increasing hexarelin doses. The apparent elimination half-life was approximately 55 minutes.
Limitations: Only 12 healthy men participated. The study characterized acute pharmacology rather than long-term efficacy or safety.
View publication →Acute Cardiovascular and Hormonal Effects of GH and Hexarelin, a Synthetic GH-Releasing Peptide, in Humans
humanResearchers compared acute recombinant GH and hexarelin administration in seven healthy men. Both interventions increased circulating GH to a similar extent. Hexarelin, but not recombinant GH, produced a short-lived increase in left-ventricular ejection fraction. The observation suggested that hexarelin could exert acute cardiac effects independently of its ability to increase circulating GH.
Limitations: Only seven participants were studied. The effect was acute and short-lived. An increase in ejection fraction during an experiment does not establish improved cardiovascular health, treatment efficacy, or long-term cardioprotection.
View publication →CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart
animalResearchers used a photoactivatable hexarelin derivative to identify cardiac proteins interacting with the peptide. An 84-kDa binding protein was identified as CD36. Hexarelin altered coronary perfusion pressure in experimental hearts, while the response was absent in hearts from CD36-null mice and animals genetically deficient in CD36. The study provided evidence that CD36 mediates at least some cardiovascular actions associated with hexarelin.
Limitations: The mechanistic experiments were primarily preclinical. Identification of CD36 as a molecular target does not establish that hexarelin prevents or treats cardiovascular disease in humans.
View publication →Effects of Acute Hexarelin Administration on Cardiac Performance in Patients With Coronary Artery Disease During By-Pass Surgery
humanResearchers studied 24 men with coronary artery disease undergoing bypass surgery. Participants received hexarelin, GHRH, recombinant GH, or placebo. Hexarelin produced acute increases in left-ventricular ejection fraction, cardiac index, and cardiac output that persisted for up to approximately 90 minutes. GHRH, recombinant GH, and placebo did not produce comparable hemodynamic effects. The findings further supported the hypothesis of a GH-independent cardiovascular action.
Limitations: The study was very small, involved a highly specific surgical population, and evaluated only acute physiological responses. It does not demonstrate prevention of cardiovascular events, improvement in long-term heart function, or clinical benefit from chronic hexarelin administration.
View publication →What We Still Don't Know
Important unanswered questions include: • Long-term human safety • Whether repeated hexarelin administration produces clinically meaningful benefits • Whether cardiovascular effects observed acutely translate into improved cardiovascular outcomes • Whether CD36-mediated effects are beneficial, neutral, or potentially harmful during long-term human exposure • Long-term effects on glucose metabolism • Effects of repeated GH and IGF-1 stimulation • Effects of repeated ACTH/cortisol stimulation • Immunogenicity • Cardiovascular effects outside tightly controlled experimental settings • Whether animal cardioprotection translates into humans • Whether hexarelin improves body composition • Whether it improves muscle strength or physical performance • Whether it improves injury or exercise recovery • Whether chronic receptor stimulation causes desensitization • Safety of currently marketed non-approved formulations The gap between interesting acute physiology and demonstrated clinical benefit is particularly important for this compound.
Related Compounds
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Sources & References
- Growth Hormone-Releasing Activity of Hexarelin, a New Synthetic Hexapeptide, After Intravenous, Subcutaneous, Intranasal, and Oral Administration in Man. Journal of Clinical Endocrinology & Metabolism. 1994.
- Growth Hormone-Releasing Activity of Hexarelin in Humans: A Dose-Response Study. 1994.
- Modulation of Growth Hormone-Releasing Activity of Hexarelin in Man. 1995.
- Bisi F, Podio V, Valetto MR, et al. Acute Cardiovascular and Hormonal Effects of GH and Hexarelin, a Synthetic GH-Releasing Peptide, in Humans. 1999.
- Bodart V, Bouchard JF, McNicoll N, et al. Identification and Characterization of a New Growth Hormone-Releasing Peptide Receptor in the Heart. Circulation Research. 1999;85(9):796–802. doi:10.1161/01.RES.85.9.796.
- Broglio F, Benso A, Valetto MR, et al. Growth Hormone-Independent Cardiotropic Activities of Growth Hormone-Releasing Peptides in Normal Subjects, in Patients With Growth Hormone Deficiency, and in Patients With Idiopathic or Ischemic Dilated Cardiomyopathy. Endocrine. 2001;14(1):105–108.
- Bodart V, Febbraio M, Demers A, et al. CD36 Mediates the Cardiovascular Action of Growth Hormone-Releasing Peptides in the Heart. Circulation Research. 2002.
- Effects of Acute Hexarelin Administration on Cardiac Performance in Patients With Coronary Artery Disease During By-Pass Surgery. 2002.
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