Hexarelin: Complete Guide

Hexarelin (His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH2), also known by its research name examorelin, was developed by Romano Deghenghi and collaborators at Mediolanum Farmaceutici in Milan, Italy. It is a synthetic hexapeptide with no structural resemblance to GHRH but produces the most robust acute GH release of any commonly studied peptidyl GH secretagogue.

Hexarelin was the subject of extensive clinical research in the 1990s and 2000s, including studies in healthy volunteers, elderly subjects, obese patients, and patients with GH deficiency. These studies characterized both its potent GH-releasing properties and its cardiovascular effects. Bisi et al. (1999) demonstrated significant acute cardiovascular and hormonal effects of hexarelin in humans, establishing it as a compound with clinically relevant pharmacological activity beyond simple GH release.

Despite its potency, hexarelin has a critical limitation: receptor desensitization. With continuous daily administration, the GH response diminishes progressively over 4–8 weeks, eventually reaching a plateau at approximately 50–60% of the initial response. This desensitization of GHSR-1a distinguishes hexarelin from ipamorelin and GHRP-2, which show significantly less attenuation with chronic use, and limits hexarelin's utility for long-term GH optimization protocols.

Hexarelin acts through two distinct receptor systems, giving it a uniquely dual pharmacology:

GH Release (GHSR-1a)

Hexarelin binds ghrelin receptors on pituitary somatotrophs with high affinity, triggering GH release through PLC/IP3/PKC-mediated intracellular calcium mobilization. The GH response is dose-dependent and additive with GHRH co-administration. At standard doses (1–2 mcg/kg IV), hexarelin produces peak GH levels of 40–80 ng/mL in healthy young adults — among the highest of any GHRP. Like other GH secretagogues, hexarelin also activates hypothalamic pathways that increase ACTH/cortisol and prolactin secretion.

Cardioprotection (CD36)

Independently of GHSR-1a, hexarelin activates CD36 scavenger receptors — a class B scavenger receptor expressed on cardiomyocytes, endothelial cells, and macrophages. Bhatt et al. (2002) identified CD36 as the specific receptor mediating hexarelin's cardiovascular effects. Key cardiac mechanisms include:

• Ischemia-reperfusion protection: Hexarelin reduces infarct size by 50–60% in cardiac ischemia-reperfusion models. Locatelli et al. (1999) showed this effect was independent of GH — cardioprotection persisted when GH release was blocked with somatostatin
• Anti-atherogenic effects: CD36 activation by hexarelin promotes reverse cholesterol transport from macrophages and reduces oxidized-LDL uptake, potentially slowing atherosclerotic plaque development
• Cardiac remodeling: Hexarelin attenuates adverse left ventricular remodeling after myocardial infarction in animal models, preserving ejection fraction and reducing fibrosis
• Anti-inflammatory signaling: Hexarelin suppresses NF-κB-mediated inflammatory cascades in cardiac tissue, reducing inflammatory cytokine production during ischemic injury

The cardioprotective effects are particularly notable because they distinguish hexarelin from every other GH secretagogue — ghrelin itself was found to be far less effective (only ~15% protection vs hexarelin's ~60% in ischemia-reperfusion models), suggesting CD36-specific mechanisms beyond simple ghrelin receptor activation.

Hexarelin's primary clinical limitation is GH response desensitization — a progressive decline in GH release with continuous daily administration:

• Timeline: GH response begins declining within 1–2 weeks of daily use, reaching a plateau at ~50–60% of initial response by 4–8 weeks
• Mechanism: GHSR-1a receptor downregulation and intracellular signaling adaptation. The receptor undergoes internalization and reduced surface expression with sustained agonist exposure
• Recovery: GH response recovers after a 2–4 week washout period, during which GHSR-1a expression normalizes
• Clinical implication: Research protocols typically use 4-week cycles with 2-week breaks to maintain GH response

Importantly, ipamorelin and GHRP-2 show significantly less desensitization — their GH-releasing effects remain relatively stable over months of continuous use. This is likely related to differences in receptor binding kinetics and signaling efficacy. For sustained GH optimization, ipamorelin is preferred specifically because it avoids this desensitization problem.

One interesting finding: hexarelin's cardioprotective effects through CD36 do NOT appear to desensitize, as cardiac protection persists even after GH response has diminished. This suggests the cardiac benefits may be maintained independently of GH axis activity.

GH-Deficient Adults

Studies in GH-deficient adults showed that hexarelin produces robust GH release even in patients with reduced pituitary capacity, though the response is attenuated compared to healthy subjects. This suggested that hexarelin acts through a partially pituitary-independent mechanism, possibly involving hypothalamic GHRH neuron activation.

Elderly Subjects

Hexarelin maintains significant GH-releasing activity in elderly subjects, despite the age-related decline in GH secretory capacity. Arvat et al. (2001) compared GH responses to hexarelin, ghrelin, and GHRH in young and elderly volunteers, finding that hexarelin's relative potency was maintained with aging — though absolute GH peaks were lower in the elderly.

Cardiac Studies

The most distinctive research on hexarelin relates to its cardiac effects. Locatelli et al. (1999) demonstrated GH-independent cardioprotection — hexarelin reduced infarct size and improved cardiac function in rats even when GH release was blocked with somatostatin infusion. Bhatt et al. (2002) subsequently identified CD36 as the receptor mediating these cardiac effects, showing that hexarelin binds a specific domain (Asn132-Glu177) on the CD36 protein. This discovery opened a new area of research into growth hormone secretagogue-CD36 interactions in cardiovascular biology.

Comparison to Ghrelin

Direct comparisons between hexarelin and ghrelin reveal important pharmacological differences despite both activating GHSR-1a. Ghrelin is far less effective than hexarelin in cardiac ischemia-reperfusion protection (~15% vs ~60%), suggesting that hexarelin's CD36 interactions — which ghrelin does not share — are the primary cardioprotective mechanism. Hexarelin also produces larger peak GH responses than equimolar ghrelin doses.

Protocol	Dose	Frequency	Notes
GH release	100–200 mcg	2–3× daily	Fasted; SC injection
Cardiac research	100–200 mcg	1–2× daily	SC injection; may not require fasting
Clinical research (IV)	1–2 mcg/kg	Single dose	IV bolus for acute studies

Hexarelin undergoes GH receptor desensitization — GH response typically diminishes after 4–8 weeks of continuous use. Research protocols generally follow 4-week on / 2-week off cycling. During the off period, an alternative GH secretagogue (ipamorelin, GHRP-2) without desensitization issues can be used to maintain GH support.

Fasted administration is important for GH release (as with all GH secretagogues). Cardiac benefits through CD36 may be less affected by fed/fasted state, as they operate through a separate receptor system. Use the peptide calculator for reconstitution.

• Cortisol elevation: Hexarelin increases cortisol through ACTH stimulation — more than ipamorelin. The effect is dose-dependent and most pronounced at higher doses. Chronic cortisol elevation can counteract anabolic benefits and promote visceral fat deposition
• Prolactin elevation: Can increase prolactin levels, potentially causing reproductive effects, reduced libido, or mood changes with chronic use
• Appetite stimulation: Moderate ghrelin-mimetic hunger effect — less intense than GHRP-6 but more noticeable than ipamorelin
• GH desensitization: The most significant limitation. GH response diminishes with continuous daily use, requiring 4-week on / 2-week off cycling. This distinguishes hexarelin from ipamorelin and GHRP-2, which maintain GH response with chronic use
• Injection site reactions: Mild redness and occasional itching at subcutaneous injection sites
• Flushing and warmth: Common immediately after injection, lasting 5–10 minutes
• Water retention: Mild, related to GH elevation

Hexarelin's clinical safety profile in acute and short-term studies is generally favorable. The lack of long-term safety data for chronic use (beyond clinical trial periods) represents the primary safety unknown.

Hexarelin's unique combination of potent acute GH release, cardioprotection, and desensitization creates a distinct pharmacological niche:

Feature	Hexarelin	Ipamorelin	GHRP-2	GHRP-6
Acute GH potency	Highest	Moderate	Very high	High
Sustained GH (chronic)	Diminishes (desensitization)	Stable	Mostly stable	Stable
Cardioprotection	Strong (CD36-mediated)	None documented	None documented	Moderate (NF-κB)
Cortisol increase	Moderate	Minimal	Moderate	Significant
Appetite stimulation	Moderate	Minimal	Moderate	Intense
Ideal use case	Short cycles; cardiac research	Long-term GH optimization	Maximum GH potency	Appetite + GH (bulking)

For long-term GH optimization, ipamorelin or GHRP-2 are generally preferred due to maintained efficacy. Hexarelin's niche is short-term intensive GH support (e.g., recovery periods) or cardiac research applications where its CD36-mediated effects are specifically desired.