Half a century has passed since the discovery of growth hormone-releasing hormone (GHRH), a groundbreaking discovery that revolutionized our understanding of endocrine regulation and growth hormone (GH) physiology. From its initial discovery in pancreatic tumors associated with acromegaly [1] to the cloning of its receptor in the early 1990s [2, 3], GHRH research has continually evolved.

Initially identified for its pivotal role in stimulating GH secretion from the anterior pituitary, GHRH has since been recognized as far more than a simple hypophysiotropic peptide. Over the decades, research has revealed its widespread influence beyond the neuroendocrine axis, with implications in metabolism, immune function, cardiovascular health, neuroprotection, and cancer biology [4, 5].

The identification of its diverse receptor splice variants and extrapituitary functions has expanded our knowledge of its biological significance. Today, we understand that GHRH and its receptor system operate beyond the pituitary, exerting autocrine and paracrine effects that regulate cell proliferation, apoptosis, inflammation, and tissue repair. These findings have paved the way for the development of synthetic GHRH agonists and antagonists, which hold great promise for therapeutic applications in conditions ranging from GH deficiency and metabolic disorders to cancer, cardiovascular and neurodegenerative diseases [5].

As we celebrate 50 years of GHRH research, this special issue of REMD offers a comprehensive overview on the past, present, and future of this remarkable neuropeptide. Bringing together leading experts, it explores key aspects of GHRH, including its molecular mechanisms, physiological functions, and translational potential. This issue presents contributions that examine the regulatory mechanisms governing GHRH function and GH secretion, along with the complex interactions between hypothalamic, pituitary, and peripheral signals and their associated signaling pathways [6,7,8]. Furthermore, it provides a comprehensive overview of the activation, regulation, molecular mechanisms, and signaling pathways of GHRH-Rs and their splice variants in various tissues [9]. The history and clinical applications of GHRH testing, along with challenges like obesity, hypothalamic damage, and aging, are also explored. Combination tests, such as GHRH with arginine) or GH secretagogues, improved accuracy and gained clinical acceptance [10].

The paper by Recinella et al. offers an in-depth analysis of GHRH deficiency and its broad impact on both central and peripheral tissues, highlighting its role in neurobehavioral functions, metabolism, immune regulation, and pain perception [11]. The use of genetically engineered mouse models has been crucial in uncovering the diverse functions of GHRH and elucidating its intricate relationship with GH.

The potential therapeutic applications of GHRH analogs are described in the review by Schally et al. [12]. Prof. Andrew Schally and his team of chemists have indeed developed both agonistic and antagonistic molecules of GHRH, which showed promise in regenerative medicine, aiding tissue repair, cardiac function, islet cell survival in diabetes and neuroprotection [5]. In fact, GHRH and its analogs, especially MR class agonists like MR-409, enhance myocardial function by improving contractility, mitigating oxidative stress and inflammation, and inhibiting pathological remodeling. Studies in animal models have demonstrated their efficacy in various cardiomyopathies, highlighting their therapeutic potential [13].

Importantly, GHRH and its analogs also promote the survival of insulin-producing pancreatic β-cells in both in vitro experiments and animal models. These beneficial effects highlight the potential of GHRH agonists and antagonists for clinical applications in treating human metabolic diseases or improving β-cell survival in transplantable cells [14]. Furthermore, GHRH agonist MR-409 exerts neuroprotective functions and enhances neurological recovery following ischemic stroke by activating extrapituitary GHRH-R signaling and stimulating endogenous NSC-derived neuronal regeneration. Additionally, MR-409 ameliorates the pathological features of spinal muscular atrophy (SMA) and muscle atrophy [15].

Meanwhile, GHRH antagonists exhibit anticancer and anti-inflammatory properties, inhibiting tumor growth and modulating immune responses [16, 17]. Preclinical studies suggest GHRH antagonists as a low-toxicity cancer therapy, particularly in lung, prostate, breast, gastrointestinal cancers as well as acute myeloid leukemia and brain tumors [15, 16, 18, 19].

GHRH and its analogs have significant impacts on the vascular system [20]. GHRH and its agonists stimulate bone marrow-derived stem cells to enhance angiogenesis, reduce vascular smooth muscle cells ossification, and ultimately inhibit vascular calcification. Additionally, GHRH agonists and antagonists influence endothelial cells and immune cells, such as macrophages, exerting anti-inflammatory and antioxidant effects that help maintain vascular endothelial integrity [17, 20].

Among the various reviews, Pérez-Gómez et al. examine the GHRH/GHRH-R hormone axis as a key regulator of gonadal function. The authors also explore the presence of GHRH and GHRH-R in reproductive systems across different species and their potential physiological roles. Additionally, they discuss how reproductive disorders, such as infertility, endometriosis, and hormone-related cancers like prostate and ovarian cancer, could benefit from hormonal interventions targeting the GHRH axis [21].

Overall, GHRH analogs are emerging as versatile therapeutic agents with significant implications across multiple fields.

We sincerely appreciate the contributions of all authors, reviewers, and researchers involved in this issue, as well as the broader scientific community for their ongoing efforts in advancing our understanding of GHRH. As we reflect on five decades of discovery, the story of GHRH is far from complete. With emerging research uncovering novel functions and potential clinical applications, the next 50 years promise even greater advancements in this field. We hope that this special issue not only honors the legacy of GHRH research but also inspires new investigations into its untapped potential.