Hexarelin

Hexarelin (also known as Examorelin or HEX) is a synthetic hexapeptide growth hormone secretagogue structurally related to GHRP-6 but featuring a 2-methyl modification on the D-tryptophan residue. This modification produces the most potent GH-releasing activity among all peptides in the GHRP family, with peak GH responses consistently exceeding those of GHRP-6, GHRP-2, and Ipamorelin in head-to-head comparisons. Developed in the 1990s by Mediolanum Farmaceutici, Hexarelin advanced through Phase I and II clinical trials for applications including GH deficiency and cardiac protection. While it did not achieve regulatory approval, the clinical research generated valuable data on its potent GH-releasing activity and unique cardioprotective properties — effects that distinguish it from all other GH secretagogues in its class. Hexarelin's most distinctive feature is its robust interaction with the CD36 scavenger receptor, a class B scavenger receptor expressed abundantly on cardiac tissue, macrophages, and endothelial cells. Through this pathway, Hexarelin exerts cardioprotective, anti-atherosclerotic, and anti-fibrotic effects that are entirely independent of growth hormone release. This dual-mechanism profile — potent GH secretion plus direct cardiac protection — has made Hexarelin a uniquely valuable compound in both endocrine and cardiovascular research.

Hexarelin operates through two major receptor systems, giving it a broader mechanism of action than any other GHRP: **Potent GHS-R1a Agonism**: Hexarelin binds the growth hormone secretagogue receptor 1a with exceptionally high affinity. The 2-methyl-Trp modification enhances hydrophobic pocket engagement within the receptor, producing maximal phospholipase C activation, calcium mobilization, and GH exocytosis from somatotrophs. This results in the largest acute GH release of any GHRP-class peptide. **CD36 Receptor Activation**: Uniquely among GH secretagogues, Hexarelin is a potent ligand for the CD36 receptor (scavenger receptor class B, type 3). On cardiomyocytes, CD36 activation triggers protective signaling cascades involving PPARγ activation, ERK1/2 phosphorylation, and upregulation of antioxidant defense enzymes — effects entirely independent of GH release. **Anti-Atherosclerotic Signaling**: Through CD36 on macrophages, Hexarelin modulates cholesterol efflux and inhibits foam cell formation, a critical step in atherosclerotic plaque development. Research has demonstrated reduced aortic fatty streak formation in ApoE-knockout mice treated with Hexarelin. **Hypothalamic and Pituitary Integration**: Like other GHRPs, Hexarelin acts both at the hypothalamus (stimulating GHRH release and suppressing somatostatin) and directly on pituitary somatotrophs. This dual-site action contributes to its outsized GH response but also produces cortisol and prolactin co-release more pronounced than GHRP-2. **Desensitization Kinetics**: A notable characteristic of Hexarelin is the development of partial tachyphylaxis (reduced GH response) with chronic daily use. Research shows the GH peak diminishes by approximately 50% over 4-8 weeks of continuous administration, though it does not fully extinguish. This desensitization is more pronounced than with GHRP-2 or GHRP-6 and is an important consideration in protocol design.

Hexarelin has been studied in multiple clinical and preclinical contexts with noteworthy findings: **Superior GH Release**: Clinical studies have consistently demonstrated that Hexarelin produces the highest peak GH levels among the GHRP family. In direct comparisons, Hexarelin elicited GH peaks 30-50% greater than GHRP-2 and approximately double those of GHRP-6 following equivalent weight-based dosing. This potency has been confirmed across pediatric, adult, and elderly populations. **Cardiac Protection Research**: The most distinctive body of Hexarelin research involves cardioprotection. Studies in animal models of myocardial ischemia-reperfusion injury demonstrated that Hexarelin significantly reduces infarct size, preserves left ventricular function, and decreases fibrosis. Importantly, these effects persist in GH-deficient models, confirming they are mediated through CD36 rather than GH pathways. Bhatt et al. showed a 40% reduction in infarct size in a rat coronary ligation model. **Anti-Atherosclerotic Effects**: In ApoE-knockout mice, chronic Hexarelin administration reduced aortic fatty streak area by approximately 50%. Mechanistic studies attributed this to enhanced macrophage cholesterol efflux via CD36-mediated PPARγ activation and ABCA1 upregulation. **Tachyphylaxis Studies**: Longitudinal research has documented the development of partial GH desensitization with chronic Hexarelin use. Rahim et al. showed that 16 weeks of twice-daily Hexarelin reduced the GH peak to approximately 50% of the initial response, while IGF-1 levels remained elevated. The desensitization is reversible upon washout. **Phase II Clinical Trials**: Hexarelin was evaluated in heart failure patients, where it improved cardiac output and ejection fraction independent of GH changes. These findings further support the GH-independent cardiac mechanism and have sustained research interest in CD36-targeting peptides.

Research protocols for Hexarelin reflect its high potency and desensitization characteristics: **Typical Research Doses**: Subcutaneous doses of 100-200 mcg per administration are standard. Due to its high potency, the effective GH-releasing dose is at the lower end of the GHRP range. Clinical trials used doses of 1-2 mcg/kg IV for acute studies and 200 mcg subcutaneous for chronic protocols. **Administration and Timing**: Subcutaneous injection on an empty stomach is the standard route. Protocols typically use 1-3 daily injections, with timing aligned to physiological GH windows (morning, post-exercise, and bedtime). Given the partial tachyphylaxis observed with chronic use, some research designs employ pulsed or intermittent dosing schedules (e.g., 5 days on / 2 days off or 4 weeks on / 2 weeks off) to preserve GH responsiveness. **Combination Protocols**: Hexarelin combined with GHRH analogs produces synergistic GH release, though the magnitude of synergy may diminish with chronic dosing due to Hexarelin's desensitization kinetics. For cardiac research applications, Hexarelin is often used alone to isolate CD36-mediated effects from GH-dependent changes. **Important Disclaimer**: Hexarelin is available for research purposes only. It has not received regulatory approval for any therapeutic indication. All dosing parameters are derived from published clinical and preclinical research. These parameters should not be construed as clinical recommendations.

Hexarelin's side effect profile reflects its potent receptor activity and is well-characterized from clinical trials: **Observed Effects**: The most commonly reported effects include transient flushing, headache, dizziness, and injection site reactions. Hexarelin produces the most pronounced cortisol and prolactin elevations of any GHRP, reflecting its potent and non-selective pituitary stimulation. Appetite stimulation occurs but is generally intermediate between GHRP-6 and Ipamorelin. Water retention is reported, particularly during initial weeks of use. **Potential Concerns**: The development of GH tachyphylaxis with chronic use is the most significant practical concern, as it limits the sustained GH-releasing utility of Hexarelin over extended protocols. Cortisol and prolactin elevations are more pronounced than with GHRP-2 or GHRP-6 and should be considered in protocol design. As with all GH-elevating agents, theoretical concerns regarding glucose metabolism and proliferative conditions apply. **Research Limitations**: While Hexarelin has generated substantial clinical data from Phase I and II trials, long-term chronic-use safety data is limited. The desensitization phenomenon complicates extrapolation from short-term pharmacodynamic studies to chronic use scenarios. The long-term cardiovascular effects — both protective and potential risks — of sustained CD36 activation require further investigation.