Growth Hormone Releasing Peptides: Analogs, Effects & Therapeutic Potential

Growth hormone releasing peptide and non-peptides (GHRPs, GHRP-GHS) are a new chemical class of GH secretagogues with a chemistry that ranges from small synthetic peptides to peptidomimetics. They release GH in animals and humans by a unique dual and complementary action on the hypothalamus and pituitary. Although the present Growth hormone releasing peptide are of unnatural origin, evidence by a number of investigators is gradually accumulating to support that GHRP reflects the GH-releasing action of a new natural hypothalamic hormone yet to be isolated and identified. Despite the de novo origin of Growth hormone releasing peptide, a major reason for the persistent investigation is because of the possible practical diagnostic and therapeutic value in humans as well as the potential theoretical value of new insight into the physiological regulation of GH secretion.

Growth hormone releasing peptide and their analogs

Growth hormone releasing peptide (GHRPs) are a series of hepta (GHRP-1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been described. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GHRPs and their analogs have no structural homology with GHRH and act via specific receptors present at either the pituitary or the hypothalamic level. The GHRP receptor has recently been cloned and it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. Although the exact mechanism of action of Growth hormone releasing peptide has not been fully established, there is probably a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin.[1]

Moreover, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. The marked GH-releasing activity of Growth hormone releasing peptide is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH and not affected by opioid receptor antagonists, while it is only blunted by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and even exogenous somatostatin. Growth hormone releasing peptide maintain their GH-releasing effect in somatotrope hypersecretory states, such as acromegaly, anorexia nervosa, and hyperthyroidism. On the other hand, GHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. A potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged.

Cytoprotective Effects of Growth hormone releasing peptide

The family of peptidyl growth hormone (GH) secretagogues with broad cytoprotective properties came to light by the American endocrinologist Cyril Bowers, who observed that chemical analogs of enkephalin amide showed GH-releasing activity upon their incorporation to pituitary cultures. It was far to be anticipated on those early days, however, that the GHRP-mediated cardiotropic and cytoprotective effects are superior to those shown by the exogenous administration of GH and are not shared by Growth hormone releasing peptide (GHRH) and that, importantly, GHRPs exert their pharmacological actions via GH-independent pathways that obviously represented another turning point in this history. The progresses obtained and the experiences accrued along the years of work with these pioneer synthetic, nonendogenous Growth hormone releasing peptides gradually led to the discovery of ghrelin, the 28-aminoacid hormone with GH-releasing action secreted by gastric cells with orexigenic, cardioprotective, and cytoprotective abilities for a myriad of cell populations. We deem that cardiologists, clinicians, and basic and clinical pharmacologists would receive some benefit from this text, in correspondence to the futuristic pharmacological opportunities offered by these agents. To date, cytoprotection remains as an orphan niche in contemporary medical armamentarium.[2]

The fact that synthetic Growth hormone releasing peptide bind at least two different and biologically significant receptors that seem not to be redundant in nature and are largely represented in most organs and tissues broadens their biological activities and increases their pharmacological potentialities. This suggests that GHRPs may stimulate multiple cells and simultaneously trigger different signaling pathways. The information gathered so far in terms of the molecular cytoprotective mechanism of Growth hormone releasing peptide is inconclusive and fragmentary, which has become difficult to disclose the hidden facts behind their biological effects. Nevertheless, it is reasonable that these molecules share the ability to knock life-sensitive pathways and restore critical organelle physiology at very proximal levels. Beyond their ability to enhance the survival of a diversity of cells and tissues before adverse episodes, Growth hormone releasing peptide members exert an agonistic effect of the GH/IGF-1 axis, promoting anabolia and deterring catabolism and sarcopenia. Despite all these pharmacological advantages and that GHRPs exhibit a broad safety profile, their clinical development has been erratic and irregular. This has been a deterrence factor for their definitive positioning within cardiology and intensive care medicine for years.

Therapeutic advances in cancer, regenerative medicine, and metabolic disorders

Growth hormone releasing peptide is a hypothalamic hypophysiotropic peptide that plays a central role in regulating the synthesis and secretion of growth hormone (GH) from the anterior pituitary gland. This regulation occurs by binding GHRH to its specific receptor, the pituitary GHRH receptor (pGHRH-R), triggering a cascade of intracellular signaling pathways. In addition to its classical endocrine functions, Growth hormone releasing peptide has been detected in extrahypothalamic tissues, including the placenta, ovaries, testes, gastrointestinal tract, and even tumors. This suggests that GHRH has broader physiological roles that extend beyond the pituitary gland. The discovery of GHRH receptors (GHRH-R) and their splice variants in various tissues and organs further supports the idea that Growth hormone releasing peptide may have direct autocrine and paracrine effects in these tissues. In the early 1990s, research into the potential role of GHRH in carcinogenesis spurred efforts to develop synthetic analogs of GHRH that could be used as therapeutic agents. These analogs fell into two broad categories: agonists and antagonists. [3]

The development of Growth hormone releasing peptide agonists focused on enhancing GH release, improving metabolic functions, and promoting tissue repair. MR-409 demonstrated therapeutic potential across various conditions, from cardioprotection to neuroprotection. The development of GHRH antagonists, particularly those in the MIA and AVR series, has provided new opportunities for cancer therapy and the treatment of other diseases. These antagonists have shown efficacy in antitumor and anti-inflammatory activities with minimal adverse effects, positioning them as favorable alternatives to conventional chemotherapeutic agents. MIA-602 and AVR-352 offer promising clinical applications for human cancers, inflammation-related diseases, and neurodegenerative disorders. The ongoing research and development of Growth hormone releasing peptide agonists and antagonists continue to highlight their potential as versatile therapeutic agents across a wide range of medical conditions.

References

[1]Camanni F, Ghigo E, Arvat E. Growth hormone-releasing peptides and their analogs. Front Neuroendocrinol. 1998 Jan;19(1):47-72. doi: 10.1006/frne.1997.0158. PMID: 9465289.

[2]Berlanga-Acosta J, Abreu-Cruz A, Herrera DGB, Mendoza-Marí Y, Rodríguez-Ulloa A, García-Ojalvo A, Falcón-Cama V, Hernández-Bernal F, Beichen Q, Guillén-Nieto G. Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects. Clin Med Insights Cardiol. 2017 Mar 2;11:1179546817694558. doi: 10.1177/1179546817694558. PMID: 28469491; PMCID: PMC5392015.

[3]Schally AV, Cai R, Zhang X, Sha W, Wangpaichitr M. The development of growth hormone-releasing hormone analogs: Therapeutic advances in cancer, regenerative medicine, and metabolic disorders. Rev Endocr Metab Disord. 2025 Jun;26(3):385-396. doi: 10.1007/s11154-024-09929-2. Epub 2024 Nov 26. PMID: 39592529; PMCID: PMC12137413.

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