Growth hormone-releasing hormone transforms therapeutic potential in health and chronic disease

From enhancing wound healing to combating neurodegeneration and cancer, growth hormone-releasing hormone and its analogs reveal groundbreaking roles that could redefine future therapies.

In a recent study published in the journal Nature Reviews Endocrinology, researchers reviewed over four decades of research on the biological activities of growth hormone-releasing hormone (GHRH) and its analogs. The review presents in vitro and in vivo evidence for the beneficial roles of GHRH and its analogs in cell growth and wound healing, inflammation, cardiovascular diseases (CVDs), cancers, immunity, and psychiatric health, including neurodegenerative conditions.

What is GHRH?

Otherwise referred to as ‘somatoliberin,’ GHRH is a family of hypothalamic peptide hormones that trigger and modulate the synthesis and release of somatotropin or growth hormone (GH). First hypothesized in the 1960s, GHRH was clinically observed in the 1980s in carcinoid and pancreatic islet cells and subsequently isolated from human acromegaly-inducing pancreatic tumors.

Since then, extensive research on GHRH has led to the discovery of their functions including stimulation of the anterior pituitary gland to regulate GH concentrations, splice variants, and potential clinical applications. GHRH antagonists are of particular interest due to their anti-inflammatory, antitumor, and immunomodulatory activities.

GHRH analogs

Decades of research on GHRH has led to the discovery of several functions independent of GH modulation. Endogenous GHRH has an extremely short half-life and is highly susceptible to the action of endogenous proteolytic enzymes, thus limiting GHRH research efforts.

To overcome these limitations, researchers have developed synthetic GHRH analogs with improved stability through chemical alterations that make them resistant to degradation. There are three types of GHRH analogs, of which include agonists, antagonists, and GHRH receptors (GHRHRs).

GHRH analogs are synthesized by modifying amino acid residues along the N-terminal GRHR sequence, thereby retaining the functional efficacy of endogenous GHRH. The resultant synthetic peptides have been extensively investigated and appear to be involved in cell growth, repair, and chronic disease progression.

GHRH in cell growth, cancer proliferation, and wound repair

In addition to governing the GH-producing effects of the pituitary gland, GHRH is crucial for normal pituitary gland development, particularly during early life. Moreover, GHRH and its variants have been identified in a host of extrahypothalamic tissues, including carcinogenic tumors, where they perform mitogenic functions, thereby potentially accelerating cancer development and progression.

The GHRH SV1 variant has been extensively characterized, with research demonstrating that SV1-expressing cells depict abnormally high proliferation rates. In fact, SV1 activity has been observed in various cancer cells, including endometrial carcinoma and esophageal squamous cell carcinoma, wherein SV1 acts as a hypoxia-drive promoter of tumor progression.

Synthetic GHRH analogs, particularly GHRH(1–29)NH2 and JI-38, enhance the migration of embryonic fibroblasts to wound sites, thereby accelerating tissue repair following injury. Similarly, MR-409 and MR-502 have been shown to promote healing while simultaneously arresting fibrosis, thus underscoring their application in post-accident or post-surgery recovery.

GHRH in chronic disease

GHRH and its agonists have been implicated in several cardiovascular, metabolic, and nervous system conditions. For example, GHRH agonists enhance the regenerative potential of mesenchymal cells (MSCs), thereby combatting heart diseases.

GHRH may indirectly benefit cardiovascular health, such as through its effects on dyslipidemia. Dyslipidemia is a chronic and severe condition characterized by abnormal blood lipid concentrations. Tesamorelin, a GHRH agonist, has been shown to reduce cholesterol and low-density lipoprotein (LDL) levels, particularly in type 2 diabetes mellitus (T2DM) models.

The anti-inflammatory and antioxidant properties of GHRH analogs have also been observed in animal models for depression and anxiety. Furthermore, neuro-investigative studies have revealed unexpected effects of GHRH and its agonist in memory retention, cognition, and neurodegenerative disease progression.

Although some GHRH agonists like GHRH(1-44)NH₂ have been shown to suppress memory retention, others, such as MR-409, can to arrest neural apoptosis and cell death, thereby slowing neurological aging. Together, these findings highlight the neurological potential of GHRH, supporting future research into its clinical application.

Conclusions

The present review highlights the cardiovascular, cancer, and neurological effects of some GHRH agonists and antagonists. Nevertheless, additional research is needed to elucidate the various mechanisms involved in the activity of GHRH and its analogs.

Journal reference:

• Granata, R., Leone, S., Zhang, X. et al. (2024). Growth hormone-releasing hormone and its analogues in health and disease. Nature Reviews Endocrinology. doi:10.1038/s41574-024-01052-1