Abstract
A thorough scientific review of Growth Hormone Releasing Peptide-2 (GHRP-2), covering its molecular structure, ghrelin receptor agonism, GH secretion kinetics, neuroendocrine effects, metabolic actions, and the extensive body of preclinical and clinical research establishing its pharmacological profile.
Growth Hormone Releasing Peptide-2 (GHRP-2), also known by its developmental designation KP-102 or pralmorelin, is a synthetic hexapeptide with the amino acid sequence D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH2. It belongs to the family of growth hormone secretagogues (GHS) that stimulate the release of growth hormone (GH) from the anterior pituitary gland through activation of the growth hormone secretagogue receptor type 1a (GHS-R1a), now more commonly known as the ghrelin receptor. GHRP-2 was developed in the early 1990s by Cyril Bowers and colleagues at Tulane University as part of a systematic effort to optimize the GH-releasing potency and pharmacological properties of synthetic peptide GH secretagogues. Among the classical GHRP family members—which include GHRP-1, GHRP-2, GHRP-6, and hexarelin—GHRP-2 is widely recognized as the most potent stimulator of GH release on a per-microgram basis.
The molecular mechanism of GHRP-2 centers on its high-affinity binding to the GHS-R1a receptor, a seven-transmembrane-domain G protein-coupled receptor expressed predominantly in the hypothalamus and anterior pituitary gland. Upon receptor binding, GHRP-2 activates the Gq/11 signaling pathway, leading to phospholipase C activation, inositol trisphosphate (IP3) generation, and subsequent mobilization of intracellular calcium stores. This calcium mobilization triggers GH release from somatotroph cells in the anterior pituitary. The GHS-R1a receptor was identified as the endogenous receptor for ghrelin, the 28-amino-acid acylated peptide hormone discovered in 1999 by Kojima and colleagues. GHRP-2 thus functions as a ghrelin mimetic, activating the same receptor as the endogenous hormone but with distinct binding kinetics and signaling properties.
GHRP-2 stimulates GH release through a dual mechanism involving both direct pituitary action and hypothalamic-mediated effects. At the pituitary level, GHRP-2 directly depolarizes somatotroph cells and promotes GH exocytosis. At the hypothalamic level, GHRP-2 stimulates the release of growth hormone-releasing hormone (GHRH) from arcuate nucleus neurons and simultaneously suppresses somatostatin release from periventricular nucleus neurons. This dual action—amplifying the stimulatory signal while removing the inhibitory brake—produces a synergistic GH release that exceeds the sum of individual pathway contributions. The synergy between GHRP-2 and GHRH has been extensively documented in clinical studies. When GHRP-2 is co-administered with GHRH, the resulting GH peak is approximately 5 to 10 times greater than that achieved by either peptide alone, making the combination the most powerful pharmacological stimulus for GH release known.
The pharmacokinetics of GHRP-2 following subcutaneous administration reveal rapid absorption with peak plasma concentrations achieved within 15 to 30 minutes. The elimination half-life is approximately 25 to 30 minutes, characteristic of small peptides subject to rapid enzymatic degradation. GH release begins within 5 to 15 minutes of subcutaneous injection, peaks at approximately 30 to 60 minutes, and returns to baseline within 3 to 4 hours. The GH release follows a dose-dependent curve with saturation occurring at approximately 200 to 300 micrograms in adult subjects. At saturating doses, GHRP-2 typically produces peak GH concentrations of 30 to 60 nanograms per milliliter, compared to basal levels of 0.5 to 3 nanograms per milliliter.
One of the most significant pharmacological characteristics of GHRP-2 is its influence on other pituitary hormones beyond GH. GHRP-2 produces a modest but consistent increase in prolactin secretion, typically elevating prolactin levels by 50 to 100 percent above baseline. This prolactin stimulation is attributed to the expression of GHS-R1a on lactotroph cells and possibly to indirect effects through hypothalamic dopamine pathway modulation. GHRP-2 also stimulates adrenocorticotropic hormone (ACTH) and cortisol release, particularly at higher doses. The cortisol elevation is generally modest (20 to 40 percent above baseline) and transient, resolving within 2 to 3 hours. These neuroendocrine side effects are dose-dependent and more pronounced with GHRP-2 than with some other GH secretagogues such as GHRP-6.
The effects of GHRP-2 on appetite and food intake are notable. As a ghrelin receptor agonist, GHRP-2 activates orexigenic pathways in the hypothalamic arcuate nucleus, stimulating neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons that drive hunger and food-seeking behavior. Clinical studies have demonstrated that GHRP-2 administration produces a transient increase in appetite, though the effect is less pronounced than that observed with GHRP-6 or ghrelin itself. This difference may relate to the distinct receptor binding kinetics and downstream signaling profiles of these ligands. The appetite-stimulating property of GHRP-2 has been explored as a potential therapeutic application for cachexia and anorexia associated with chronic illness.
Research on the metabolic effects of GHRP-2 extends beyond its GH-releasing properties. GHRP-2 administration has been associated with improvements in body composition in both preclinical and clinical settings. Chronic administration in animal models produces increases in lean body mass and reductions in fat mass that parallel the lipolytic and anabolic effects of GH itself. However, GHRP-2 also has direct metabolic effects independent of GH. The ghrelin receptor is expressed on adipocytes, hepatocytes, and pancreatic beta cells, and GHRP-2 activation of these peripheral receptors influences lipid metabolism, glucose homeostasis, and insulin secretion. Studies have shown that GHRP-2 can acutely increase blood glucose levels through suppression of insulin secretion and promotion of hepatic glucose output, effects that mirror endogenous ghrelin's role as a counterregulatory hormone.
The cardiovascular effects of GHRP-2 have attracted considerable research interest. The ghrelin receptor is expressed in cardiac tissue, and GHRP-2 has been shown to have direct cardioprotective effects in preclinical models of myocardial ischemia-reperfusion injury. GHRP-2 reduces infarct size, attenuates cardiomyocyte apoptosis, and improves post-ischemic cardiac function through mechanisms involving the PI3K/Akt and ERK1/2 survival signaling pathways. These cardioprotective effects appear to be independent of GH release, as they are observed at doses that do not significantly elevate circulating GH and are maintained in hypophysectomized animals.
Clinical applications of GHRP-2 have been explored extensively in the diagnosis of GH deficiency. The GHRP-2 stimulation test has been validated as a reliable provocative test for GH deficiency in both children and adults. A single intravenous dose of 1 microgram per kilogram of body weight reliably distinguishes GH-deficient patients from healthy controls, with a GH cutoff of approximately 10 to 15 nanograms per milliliter. The GHRP-2 test offers practical advantages over the insulin tolerance test (the historical gold standard) because it does not carry the risks of hypoglycemia and seizure, and it produces more reproducible GH responses. In Japan, GHRP-2 (as pralmorelin) has been approved as a diagnostic agent for GH deficiency under the brand name GHRP Kaken.
The immunological effects of GHRP-2 are an area of emerging research interest. The ghrelin receptor is expressed on various immune cells, including T lymphocytes, monocytes, and dendritic cells. GHRP-2 has been shown to modulate cytokine production, reducing pro-inflammatory cytokines (TNF-alpha, IL-6) while enhancing anti-inflammatory mediators (IL-10). In preclinical models of sepsis, GHRP-2 improved survival, reduced bacterial burden, and attenuated the exaggerated inflammatory response. These immunomodulatory effects suggest potential therapeutic applications in inflammatory and infectious conditions, though clinical evidence remains limited.
Safety data from clinical studies indicate that GHRP-2 is generally well tolerated. Common side effects include transient facial flushing, mild dizziness, and injection site reactions. The hormonal effects on prolactin and cortisol are transient and generally not clinically significant at standard doses. Chronic administration studies in animals have not revealed significant toxicity, though concerns about potential desensitization of the GH axis with prolonged use have been raised. Some studies have demonstrated that continuous GHRP-2 exposure leads to partial downregulation of GHS-R1a receptor expression and attenuation of the GH response over time, suggesting that pulsatile rather than continuous administration may be preferable for maintaining GH axis sensitivity.
In summary, GHRP-2 represents one of the most potent and well-characterized synthetic GH secretagogues developed to date. Its ability to robustly stimulate GH release through synergistic hypothalamic and pituitary mechanisms, combined with its favorable safety profile and additional cardioprotective and immunomodulatory properties, makes it a valuable tool in both clinical diagnostics and research. The extensive body of literature supporting GHRP-2 continues to expand as new therapeutic applications are explored.
