Hexarelin

Hexarelin is one of a series of growth hormone-releasing peptides (GHRPs), which are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. ^[1] It is a hexapeptide member of the growth hormone secretagogue class, alongside GHRP-1, GHRP-2 and GHRP-6, that acts as an effective releaser of growth hormone in animals and humans. ^[2] Growth hormone secretagogues have no structural homology with growth hormone-releasing hormone and act via specific receptors present at both the pituitary and the hypothalamic level. ^[3]

The growth hormone-releasing activity of hexarelin and related secretagogues is marked, dose-related and reproducible after intravenous, subcutaneous, intranasal and even oral administration, is synergistic with that of growth hormone-releasing hormone, and undergoes age-related variations. ^[3] Beyond the neuroendocrine axis, growth hormone-releasing peptides possess direct GH-independent cardiotropic actions, and hexarelin protects from ischemia-induced myocardial damage in aged and GH-deficient rats while showing a positive inotropic effect in humans. ^[4] Hexarelin has been identified as a potent inducer of the nuclear receptor PPARγ through activation of the scavenger receptor CD36, defining a pathway that regulates aspects of lipid and energy metabolism. ^[5] Specific hexarelin binding has been demonstrated in the human cardiovascular system, with the highest binding levels detected in the ventricles, and in vitro hexarelin showed anti-apoptotic activity in a cardiomyocyte-derived cell line. ^[4]

In rats the growth hormone secretagogue hexarelin exerts cardioprotective effects, and in humans growth hormone secretagogues increase growth velocity in children with short stature or GH deficiency. ^[6] The combination of growth hormone-releasing hormone and a peptidyl growth hormone secretagogue such as hexarelin has been shown to be a reliable test for the diagnosis of adult growth hormone deficiency. ^[7] In a review of the ageing field, hexarelin was listed among the most promising leads for longevity alongside caloric restriction, target of rapamycin, sirtuins and hormetic responses. ^[8] A narrative review classified hexarelin among unregulated performance-enhancing peptides intended to modulate the GH-IGF-1 axis that lack regulatory approval for physique- or performance-related indications. ^[9]

Few long-term, rigorously controlled studies have examined the efficacy and safety of growth hormone secretagogues, and although available studies indicate they are generally well tolerated there is some concern for increases in blood glucose because of decreases in insulin sensitivity. ^[10] Little is known about the possible direct effects of growth hormone secretagogues and there are few long-term studies, so it is not yet possible to fully evaluate their use. ^[6] Further work on the long-term safety of these compounds, including evaluation of cancer incidence and mortality, is needed. ^[10] Adverse effects reported for peptides modulating the GH-IGF-1 axis span endocrine and metabolic disturbances, fluid retention syndromes, musculoskeletal symptoms and injection-site reactions, compounded by uncertainty over product composition and dose in unregulated supply chains. ^[9]