Hexarelin

Hexarelin (also known as Examorelin) is a synthetic hexapeptide growth hormone secretagogue (GHS) with the sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2. It functions by binding to the growth hormone secretagogue receptor (GHS-R1a) in the pituitary gland, stimulating potent dose-dependent release of growth hormone with peak plasma concentrations occurring approximately 30 minutes after administration. Beyond its primary endocrine effects, research has revealed significant cardioprotective properties mediated through the cardiac CD36 receptor, independent of growth hormone release. Studies demonstrate protective effects against myocardial infarction, reduced cardiac fibrosis, and improved ventricular function. Hexarelin also exhibits neuroprotective properties, reducing brain injury by up to 39% in animal models through activation of Akt/GSK-3β pathways and enhanced hippocampal neurogenesis. While chronic administration results in partial desensitization (50-75% reduction in efficacy over weeks to months), effects are reversible upon discontinuation. Hexarelin is not FDA-approved for human use and remains classified as a research compound, appearing on WADA's prohibited substances list for athletic competition.

Growth Hormone Stimulation

• Dose-dependent GH release: Hexarelin produces potent growth hormone secretion with peak plasma concentrations reaching 26.9-55.0 ng/mL at doses of 0.5-2.0 µg/kg, with an ED50 of approximately 0.48 µg/kg ^[1][8]. The GH response plateaus at 140 mU/L at 1.0 µg/kg dosing ^[8].
• Synergistic effects: When combined with GHRH, low-dose hexarelin produces massive GH release with minimal cortisol elevation, demonstrating beneficial selective growth hormone stimulation ^[8].
• Pediatric applications: In short normal and obese children, hexarelin causes prompt and clear-cut increases in serum GH concentrations, with significantly stronger responses than GHRH , suggesting potential clinical utility as a diagnostic tool.

Cardiovascular Protection

• Cardiac function improvement: Hexarelin significantly improves left ventricular ejection fraction (70.7% vs 64.0%, p<0.03) in human subjects without affecting blood pressure or heart rate ^[2]. In post-infarction animal models, treatment improved stroke volume and cardiac output while reducing vascular resistance ^[6].
• Anti-fibrotic effects: Treatment for 21 days significantly reduces cardiac fibrosis markers, interstitial collagen deposition, TGF-β1 expression, and myofibroblast differentiation following myocardial infarction ^[3]. These effects are mediated through direct binding to cardiac CD36 receptors ^[2][7].
• Anti-inflammatory action: Hexarelin shifts autonomic nervous system balance toward parasympathetic predominance while decreasing cardiac troponin-I and TNF-α levels, demonstrating significant anti-inflammatory properties ^[3].
• Myocardial protection: Demonstrates protective activity against post-ischemic ventricular dysfunction, with effects likely due to direct cardiotropic action independent of growth hormone administration ^[7].

Neuroprotective Effects

• Brain injury reduction: In neonatal hypoxia-ischemia models, hexarelin reduces brain damage by 39% compared to vehicle groups, with significant protection in cerebral cortex, hippocampus, and thalamus ^[4]. The cerebroprotective effect is accompanied by reduced caspase-3 activity and increased Akt/GSK-3β phosphorylation ^[4].
• Neurogenesis promotion: Hexarelin significantly increases BrdU-positive cell numbers in the hippocampal granule cell layer by approximately 50%, indicating enhanced cell proliferation in neurogenic regions ^[13]. This suggests potential for recovery of proliferating cell populations damaged by radiation or injury ^[13].
• Neuroprotective mechanisms: Activates PI3K/Akt pathway in the hippocampus, protecting against excessive intracellular calcium concentrations and regulating nitric oxide synthesis and free radical production ^[4].

Body Composition and Metabolic Effects

• Fat metabolism: Beyond growth hormone stimulation, hexarelin improves fat metabolism through action at the CD36 scavenger receptor ^[2].
• Bone formation markers: Serum C-terminal propeptide of type I collagen increases significantly during treatment, suggesting enhanced osteoblast activity and bone formation ^[5].
• Appetite stimulation: Growth hormone secretagogues including hexarelin may aid weight gain in wasting states through appetite enhancement ^[12].

Clinical Safety Profile

Hexarelin has been attributed a favorable safety profile in research settings, with its ability to increase growth hormone while minimally disrupting auxiliary systems resulting in low potential for long-term damage ^[7][12]. However, current evidence is mainly from experimental animal models or in vitro cell lines, and clinical trials aimed at extending application in human subjects to observe long-term efficacy and potential side effects are warranted.

Regulatory Status

• Not FDA-approved: Hexarelin is not approved for human therapeutic use by the FDA or other major regulatory agencies. It is legal only for in vitro research and laboratory experimentation.
• Prohibited in sports: The World Anti-Doping Agency (WADA) has added hexarelin to its list of prohibited substances due to its growth hormone-releasing activity and potential performance-enhancing effects.
• Research compound: Currently classified as a research chemical without established clinical applications, though preclinical and early clinical evidence supports therapeutic potential for cardiovascular and neurological conditions ^[2][7].

Side Effects and Adverse Reactions

• Hormonal disruptions: Undesirable rises in cortisol and prolactin are associated with progressively higher doses ^[8]. Hexarelin may stimulate prolactin release, potentially leading to gynecomastia in men or menstrual irregularities in women.
• Physical symptoms: Reported side effects include fluid retention, joint and muscle pain, increased appetite, fatigue, injection site reactions, headaches, nausea, and dizziness.
• Desensitization: Chronic hexarelin therapy results in partial and reversible attenuation of GH response (50-75% decrease in efficacy over weeks to months) ^[5][10]. Serum IGF-I and IGF binding protein-3 do not change significantly during prolonged administration ^[5].
• Metabolic concerns: Increased risk for hyperglycemia is the primary metabolic concern with growth hormone secretagogues, though relatively few serious adverse events have been reported ^[12].

Research Gaps and Limitations

• Long-term safety data: Limited long-term human safety data exists, particularly regarding cancer incidence and extended cardiovascular outcomes ^[12].
• Optimal dosing: While dose-response relationships are established for acute GH release, optimal therapeutic dosing regimens for cardioprotective and neuroprotective applications remain undefined.
• Human clinical trials: Most cardioprotective and neuroprotective evidence derives from animal models; large-scale human clinical trials are needed to confirm therapeutic efficacy and safety ^[2][3][4].
• Mechanism clarification: While CD36 and GHS-R1a receptors mediate hexarelin's effects, the complete signaling cascades and tissue-specific mechanisms require further elucidation ^[9].