Growth Hormone Release Research Articles

Growth hormone-releasing hormone signaling and manifestations within the cardiovascular system.

Growth hormone (GH)-releasing hormone (GHRH), a hypothalamic peptide initially characterized for its role in GH regulation, has gained increasing attention due to its GH-independent action on peripheral physiology, including that of the cardiovascular system. While its effects on the peripheral vasculature are still under investigation, GHRH and synthetic agonists have exhibited remarkable receptor-mediated cardioprotective properties in preclinical models. GHRH and its analogs enhance myocardial function by improving contractility, reducing oxidative stress, inflammation, and offsetting pathological remodeling. Studies performed in small and large animal models have demonstrated the efficacy of these compounds in diverse cardiomyopathies, suggesting their potential as promising therapeutic agents. However, the clinical translation of GHRH synthetic analogs still faces challenges related to the route of administration and potential side effects mainly associated with activation of the GH/IGF-I axis. Despite these hurdles, the compelling evidence supporting their role in cardiac repair makes GHRH analogs attractive candidates for clinical testing in the treatment of various cardiac diseases.

P-433. Impact of Tesamorelin on Cardiovascular Disease Risk Prediction Scores in Phase 3 Studies Treatment Arms: Subanalysis

Abstract Background The risk of cardiovascular disease (CVD) is nearly twice as high for persons with HIV (PWH) as the general population. Excess visceral abdominal fat (EVAF), the key characteristic of central adiposity, has also been associated with an increased risk of CVD in PWH. Tesamorelin, a growth hormone-releasing hormone analog, has previously demonstrated significant reductions in EVAF in two phase 3 randomized controlled trials in PWH. Yet, the impact of the reduction of EVAF from tesamorelin on CVD outcomes has been unknown. Tesamorelin Treatment Effect on CV Risk Score Methods To assess this impact, combined datasets from the phase 3 studies’ treatment arms were utilized to calculate 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores at baseline and 26 weeks. A mediation analysis was conducted to characterize the significance of treatment impact via intermediate variables that factor into ASCVD risk prediction changes. Modifiable variables included systolic and diastolic blood pressure, total cholesterol (TC), high-density and low-density lipoprotein (HDL, LDL). The analysis population included 543 subjects randomized to tesamorelin treatment, 86% of which were male and 22% non-white; the median age was 47 years old. The percentage of subjects on lipid-lowering therapies, hypertension treatment, or diabetic were 46%, 37%, and 18%, respectively. Results Although the majority had low CVD risk at baseline, 44% had borderline to high CVD risk. Participants in the tesamorelin treatment arm tended toward a modest reduction in 10-year ASCVD risk prediction with estimated decrease in ASCVD risk of -0.40% (95% CI -0.89%, 0.05%). The reduction in CVD risk was relatively larger among subjects with higher CVD risk at baseline (p=0.038 for overall trend among all participants). Reductions in ASCVD risk score were driven predominantly by reductions in TC, independent of lipid lowering therapies. Conclusion In summary, this analysis provides evidence that reductions in excess visceral fat with tesamorelin lead to a significant reduction in forecasted CVD risk in PWH, resulting from reduction in TC even among a group heavily treated with lipid-lowering therapy. Given the increasing prevalence of obesity and central adiposity in PWH, more attention should be given to targeting visceral fat when considering CVD risk management. Disclosures Steven K. Grinspoon, MD, Gilead: Grant/Research Support|Kowa: Grant/Research Support|Theratechnologies: Advisor/Consultant|Viiv: Grant/Research Support Lindsay Fourman, MD, Chiesi Farmaceutici: Advisor/Consultant|Chiesi Farmaceutici: Grant/Research Support|Theratechnologies: Advisor/Consultant Takara Stanley, MD, Pfizer: Grant/Research Support Colleen McGary, PhD, Theratechnologies: Employee R Brandon Cash, PharmD, Theratechnologies: Employee

The Effects of a Novel Astragalus-Based Extract (Keyfobell Powder (KFB)) on Longitudinal Bone Growth via IGF-1 Upregulation: A Potential Growth Hormone Alternative

Background/Objectives: This study evaluated the effects of a novel Astragalus extract (Keyfobell powder [KFB]) composed of Astragalus membranaceus, red ginseng (Panax ginseng C. A. Meyer), and Cervi Parvum Cornu as a potential growth hormone (GH) alternative. The primary focus was placed on its impact on longitudinal bone growth through the upregulation of circulatory insulin-like growth factor (IGF)-1. Methods: We performed in vitro and in vivo experiments using a hypothalamic cell line and Sprague–Dawley (SD) rats. Quantitative RT-PCR was performed to determine growth hormone-releasing hormone (GHRH) and ghrelin mRNA expressions in GT1-7 cells. The treatment groups were administered KFB at various dosages, and the positive controls received recombinant human GH. Body weight, bone length, and density were assessed, along with serum levels of insulin-like growth factor binding protein (IGFBP)-3 and IGF-1. Results: KFB and somatropin exhibited no cytotoxic effect in GT1-7 cells and increased GHRH and ghrelin mRNA levels in a dose-dependent manner. KFB administration resulted in a significant dose-dependent increase in body weight and bone growth (femur and tibia). Changes in IGF-1 and IGFBP-3 levels were comparable to those observed in the GH-treated group. Based on network pharmacological analysis, multiple compounds in KFB ((20S)-20-hydroxypregn-4-en-3-one, 2-isopropyl-3-methoxypyrazine, caproic acid, daidzein, furfuryl alcohol, lauric acid, octanal, and salicylic acid) may synergistically regulate the PI3K-Akt, Ras, and Rap1 signaling pathways linked to growth control and cartilage formation, leading to a possible increase in height. Conclusions: Our results suggest that KFB can function as a GH-mimetic agent that promotes bone growth through IGF-1 upregulation.

Intranasal delivery of a ghrelin mimetic engages the brain ghrelin signalling system in mice.

Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor (GHSR), promotes food intake, other feeding behaviours and stimulates growth hormone (GH) release from the pituitary. Growth hormone secretagogues (GHS), such as GHRP-6 and MK-0677, are synthetic GHSR ligands that activate orexigenic Neuropeptide Y neurons that co-express Agouti-Related Peptide (AgRP) in the arcuate nucleus of the hypothalamus when administered systemically. Systemic GHRP-6 also stimulates GH release in humans and rats. Thus, GHS and ghrelin have therapeutic relevance in patients who could benefit from its orexigenic and/or GH-releasing effects. This study examined whether intranasal delivery of ghrelin, GHRP-6, or MK-0677 engages the brain ghrelin signalling system. Effective compounds and doses were selected based on increased food intake after intranasal application in mice. Only GHRP-6 (5 mg/kg) increased food intake without adverse effects, prompting detailed analysis of meal patterns, neuronal activation in the arcuate nucleus (via Fos mapping) and neurochemical identification of c-fos mRNA-expressing neurons using RNAscope. We also assessed the impact of intranasal GHRP-6 on serum GH levels. Intranasal GHRP-6 increased food intake by increasing meal frequency and size. Fos expression in the arcuate nucleus was higher in GHRP-6-treated mice than saline controls. When examining the neurochemical identity of c-fos-mRNA-expressing neurons, we found co-expression with 63.5±1.9% Ghsr-mRNA, 79±6.8% Agrp-mRNA and 11.4±2.5% Ghrh-mRNA, demonstrating GHRP-6's ability to engage arcuate nucleus neurons involved in food intake and GH release. Additionally, intranasal GHRP-6 elevated GH serum levels. These findings suggest that intranasal GHRP-6, but not ghrelin or MK-0677, can engage the brain ghrelin signalling system.

Effects of Tesamorelin on Neurocognitive Impairment in Abdominally Obese Persons with HIV.

In people with HIV (PWH) who are virally suppressed (VS) on antiretroviral therapy (ART), abdominal obesity (AO) is linked to neurocognitive impairment (NCI), potentially due to visceral adiposity, inflammation, and reduced insulin-like growth factor 1 (IGF-1). Tesamorelin, a growth hormone-releasing hormone, reduces AO and increases IGF-1, suggesting it might mitigate NCI in VS PWH. This 6-month, Phase II randomized, open-label clinical trial compared Tesamorelin versus standard-of-care (SOC) for NCI in abdominally obese PWH. Participants had VS, NCI, and AO (elevated waist circumference [WC]). Exclusions included conditions other than HIV causing NCI, active substance use disorder, and malignancy. Seventy-three participants were randomized 3:2 to Tesamorelin or SOC (2mg subcutaneously daily). The primary outcome was the change in neurocognitive performance at 6 months, with secondary outcomes including WC, mood, and daily functioning. The groups were well-matched at baseline. The Tesamorelin group showed a trend toward improved neurocognitive performance after 6 months (mean change: 0.146, 95% CI: -0.002 to 0.294, p=0.060), while the SOC group did not (0.103, 95% CI: -0.095 to 0.301, p=0.295), but the between-group difference was not significant (p=0.673). IGF-1 levels increased, but changes did not correlate with sRCS or WC. The Tesamorelin group had a greater reduction in WC than the SOC group (median difference -2.7 cm, p=0.015). While tesamorelin reduced WC, the cognitive benefits did not significantly differ between groups. Recognizing the limitations of insufficient power and no placebo arm, this study suggests no clear benefit of short-term AO reduction with tesamorelin on NCI.

Gender-Specific effects of L-arginine supplementation on bone mineral density and trabecular bone volume in Sprague-Dawley rats; stereological study

BackgroundL-arginine (Arg) is a semi-essential amino acid that can be used as a key mediator for the release of growth hormone (GH), insulin-like growth factor-1(IGF-1), and other growth factors. In this study, we comprehensively evaluated the effect of Arg intake on bone growth and associated markers.MethodsThe study involved 24 Sprague-Dawley rats (12 males, 12 females) divided into two groups (Age = 24 days). One group received a standard diet, while the other was injected with 10 mg/kg of Arg daily for 90 days. Serum bone markers like calcium (Ca), phosphorous(P), and alkaline phosphatase (ALP) were analyzed via colorimetric assays. stereological study and bone mineral density (BMD) were conducted via dissector method and Hologic Dual-energy x-ray absorptiometry (DXA) system; respectively.ResultsBiochemical assays showed no significant differences in Ca, P, and ALP levels between groups. Male rats in the case group exhibited lower testosterone levels (p.value = 0.009). Stereological and bone mineral density (BMD) analyses revealed contrasting gender-specific outcomes. Female rats in the case group had higher BMD (p.value = 0.001), while males had lower BMD compared to controls (p.value = 0.018). Arg consumption affects trabecula volume values differently in females compared to males (p.value = 0.022). Furthermore, the study observed decreased osteocytes and osteoblasts in male case rats. The gender-based differences in BMD were attributed to Arg’s paradoxical impact on testosterone levels in males.ConclusionOverall, Arg supplementation was found to influence BMD and trabecular bone volume, with outcomes varying depending on gender. The study highlights the intricate interplay between Arg, sex hormones, and bone health, offering insights into these complex relationships.

Effects of growth hormone-releasing hormone deficiency in mice beyond growth.

This paper provides a critical overview on GHRH and its deficiency, discussing its multiple roles in both central and peripheral tissues. Genetically engineered mice have been instrumental in elucidating the multifaceted roles of GHRH and GH, each offering unique insights into the physiological and pathological roles of these hormones, although in many of these models dissecting the direct effect of GHRH from the effect of GH is not possible. Key findings highlight the effects of GHRH deficiency on emotional behavior, including anxiety and depression, its impact on memory and learning capabilities, as well as on adipose tissue, immune system, inflammation and pain.

The history of an effective, specific and sensitive diagnostic test: the GHRH test in clinical practice.

Growth hormone (GH) secretion is pulsatile, entropic, and nycthemeral and is mainly controlled by the hypothalamus through two neurohormones, the stimulating growth hormone releasing hormone (GHRH) and the inhibiting somatostatin. Shortly after its discovery and synthesis, GHRH was intensely investigated diagnostically to define GH secretion. The nascent enthusiasm for using GHRH as a single diagnostic tool to investigate GH deficiency (GHD) dropped down quickly due to a flawed reproducibility. The subsequent combinatory use of molecules implicated in GH secretion through inhibition of the somatostatinergic tone, such as arginine (ARG), or the synthesis of receptor-orphan pharmaceutical compounds capable of stimulating pituitary somatotrophs to release GH, such as the GH secretagogues (GHSs), improved the reproducibility of GH response to GHRH alone, thus gaining access into the clinical practice by means of different diagnostic approaches. This review will focus on the history of the GHRH test, with main emphasis on GHRH plus ARG as a dynamic testing for the diagnosis of GHD. Our attention will extend crosswise from studies aimed at validating GHRH-based tests for the clinical practice, to address main pitfall conditions capable of affecting per se GH secretion, such as obesity, hypothalamic damage, and ageing. The history of GHRH test has been progressively dismantled due to the cease of its production for business reasons, opening a gap in the diagnostic workup of patients with GHD. In the urgency to seek further robust, safe, and validated diagnostic tests or tools, we hope to stimulate attention on a so important peptide for the health of our patients suffering from pituitary diseases.

The Effects of Leptin and Ghrelin Hormones on Metabolism

Leptin was first identified in 1994 by Zhang and colleagues as a signaling factor originating from adipose tissue. Its name is derived from the Greek word “leptos,” meaning “thin” or “slender”. While its primary site of secretion is white adipose tissue, leptin is also secreted in smaller amounts by brown adipose tissue, as well as by the placenta, skeletal muscle, stomach, mammary epithelium, and brain tissue. By acting at the hypothalamic level, leptin reduces appetite. Leptin is a 16-kilodalton, single-chain polypeptide hormone. Initially recognized for its role in satiety and energy balance, leptin was later identified as an anti-obesity factor that exerts feedback effects from adipocytes to the hypothalamus. It has been reported as a key physiological factor in mammals for preventing fat accumulation.Ghrelin, discovered in 1999 by Kojima and colleagues in the stomachs of mice, is a 28-amino acid oligopeptide hormone that stimulates the release of growth hormone. Although primarily secreted by stomach tissue, ghrelin is also produced by the brain, intestines, placenta, kidneys, pituitary gland, and pancreas. The name “ghrelin” is derived from the root “ghre,” meaning “grow,” in Indo-European languages, combined with “relin,” which implies secretion. Ghrelin is also referred to as the "appetite hormone. Isolated from mouse stomach tissue, this 28-amino acid peptide plays crucial physiological roles. Ghrelin has been reported to increase food intake, promote positive energy balance, and influence gastrointestinal motility, cell proliferation, bone metabolism, and reproduction.

Unfolded protein response modulates the effects of GHRH antagonists in experimental models of in vivo and in vitro lung injury

ABSTRACT The development of efficient targeted therapies to ameliorate endothelial disorders is of the utmost need, as evident by the devastating outcomes of the recent pandemic. Recent findings suggest that unfolded protein response (UPR) modulates barrier function. In the current study, we reveal that the aforementioned highly conservative mechanism is involved in the protective effects of growth hormone-releasing hormone antagonists (GHRHAnt) in lung injury, both in vivo and in vitro. In bovine pulmonary artery endothelial cells, UPR suppression counteracted the protective effects of GHRHAnt in lipopolysaccharide (LPS)–induced endothelial hyperpermeability. In mouse lungs, UPR activation enhanced the beneficial effects of GHRHAnt against LPS-induced acute lung injury. Our observations – which are focused on lung endothelial cells and tissues – enhance our knowledge on the mechanisms mediating the barrier function and contribute to the development of novel therapies toward sepsis, direct and indirect lung injury. The effects of UPR modulation on the effects of GHRHAnt in other tissues are unknown, and they are the subject of future investigations.

The Aggravating Role of Failing Neuropeptide Networks in the Development of Sporadic Alzheimer's Disease.

Alzheimer's disease imposes an increasing burden on aging Western societies. The disorder most frequently appears in its sporadic form, which can be caused by environmental and polygenic factors or monogenic conditions of incomplete penetrance. According to the authors, in the majority of cases, Alzheimer's disease represents an aggravated form of the natural aging of the central nervous system. It can be characterized by the decreased elimination of amyloid β1-42 and the concomitant accumulation of degradation-resistant amyloid plaques. In the present paper, the dysfunction of neuropeptide regulators, which contributes to the pathophysiologic acceleration of senile dementia, is reviewed. However, in the present review, exclusively those neuropeptides or neuropeptide families are scrutinized, and the authors' investigations into their physiologic and pathophysiologic activities have made significant contributions to the literature. Therefore, the pathophysiologic role of orexins, neuromedins, RFamides, corticotrope-releasing hormone family, growth hormone-releasing hormone, gonadotropin-releasing hormone, ghrelin, apelin, and natriuretic peptides are discussed in detail. Finally, the therapeutic potential of neuropeptide antagonists and agonists in the inhibition of disease progression is discussed here.

GHRH and reproductive systems: Mechanisms, functions, and clinical implications.

Growth hormone-releasing hormone (GHRH) has classically been considered a regulatory neuropeptide of the hypothalamic-pituitary system, which mediates its anabolic effects through hepatic GH/IGF-I axis. However, during the last decades it has been demonstrated that this key regulatory hormone may be produced in numerous peripheral tissues outside the central nervous system, participating in fundamental physiological functions through a complex balance between its purely endocrine action, and the recently local (autocrine/paracrine) discovered role. Among peripheral sites, its presence in the male and female reproductive systems stands out. In this review, we will first explore the role of the GHRH/GHRH-R hormone axis as a central player in the gonadal function; then, we will discuss available information regarding the presence of GHRH/GHRH-R and the potential physiological roles in reproductive systems of various species; and finally, we will address how reproductive system-related disorders-such as infertility problems, endometriosis, or tumor pathologies (including prostate, or ovarian cancer)-could benefit from hormonal interventions related to the manipulation of the GHRH axis.

Reducing Cardiovascular Risk in HIV: The Unseen Impact of Visceral Fat

While modern antiretroviral therapy (ART) for people with HIV (PWH) increases life expectancy, there is still an increased risk of developing cardiovascular disease (CVD) in this population. As one factor associated with this increased risk is excess visceral abdominal fat (EVAF), the Visceral Adiposity Measurement and Observations Study (VAMOS) aimed to assess the impact of EVAF on CVD risk in PWH taking modern ART. Participants were grouped according to visceral adipose tissue (VAT) surface area <130 cm2 (non-EVAF group) or ≥130 cm2 (EVAF group), quantified by CT scan. Findings presented at IDWeek 2024 revealed significant differences between EVAF and non-EVAF groups in 10-year atherosclerotic CVD (ASCVD) risk score, as well as many of their individual components. VAMOS also showed correlations between increasing VAT surface area and increasing 10-year ASCVD risk score and insulin resistance measures. Accordingly, VAT may represent a targetable factor to reduce ASCVD risk. Also shown was an inverse relationship between growth hormone (GH) levels and VAT surface area. As GH reductions related to obesity are associated with elevated CVD risk, increasing GH levels may consequently reduce ASCVD risk score. Analysis of two Phase III trials of the GH-releasing hormone (GHRH) analogue tesamorelin, which can significantly reduce VAT in PWH, was also presented at IDWeek 2024. A significant overall trend in 10-year ASCVD risk score reduction was shown in tesamorelin-treated participants, around half of which were already taking lipid lowering therapies. This suggests a benefit of targeting and reducing EVAF to further impact ASCVD risk.

The development of growth hormone-releasing hormone analogs: Therapeutic advances in cancer, regenerative medicine, and metabolic disorders.

Growth Hormone-Releasing Hormone (GHRH) and its analogs have gained significant attention for their therapeutic potential across various domains, including oncology, regenerative medicine, and metabolic disorders. Originally recognized for its role in regulating growth hormone (GH) secretion, GHRH has since been discovered to exert broader physiological effects beyond the pituitary gland, with GHRH receptors identified in multiple extrahypothalamic tissues, including tumor cells. This review explores the development of both GHRH agonists and antagonists, focusing on their mechanisms of action, therapeutic applications, and future potential. GHRH agonists have shown promise in promoting tissue regeneration, improving cardiac function, and enhancing islet survival in diabetes. Meanwhile, GHRH antagonists, particularly those in the MIA and AVR series, demonstrate potent antitumor activity by inhibiting cancer cell proliferation and downregulating growth factor pathways, while also exhibiting anti-inflammatory properties. Preclinical studies in models of lung, prostate, breast, and gastrointestinal cancers indicate that GHRH analogs could offer a novel therapeutic approach with minimal toxicity. Additionally, GHRH antagonists are being investigated for their potential in treating neurodegenerative diseases and inflammatory conditions. This review highlights the versatility of GHRH analogs as a promising class of therapeutic agents, poised to impact multiple fields of medicine.

Impact of Full-Spectrum and Infrared Lighting on Growth, Oxidative Stress, and Cecal Microbiota in Broilers.

Lighting is crucial for the development of broilers as it affects their growth performance, oxidative stress, and overall health. This study investigates the impact of full-spectrum light, infrared light, and LED white light exposure on the growth performance, oxidative stress markers, and cecal microbiota of medium-growth yellow-feathered broilers. A total of 216 medium-growth yellow-feathered chicks (Yuhuang No. 5), five days old, were randomly divided into three groups: 72 chicks in each group, with three replicates of 24 chicks. The birds were raised under different lighting conditions, including LED infrared light (II), full-spectrum therapy light (FB), and LED white light (CG) until day 87. This experiment comprised the early growth phase and measured critical hormones such as Melatonin (Mel), Growth Hormone (GH), and Growth Hormone Releasing Hormone (GHRH), as well as Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase (CAT). Additionally, this study examined the differences in microbiota diversity and composition. The results demonstrated that LED infrared and full-spectrum light exposure significantly (p < 0.05) increased broiler body weight. Particularly, full-spectrum light was effective in comb redness and reducing final comb length and oxidative stress. Furthermore, full-spectrum light improved microbial prosperity and diversity compared with the other lighting conditions. Overall, the findings suggest that full-spectrum lighting is more beneficial for broiler growth, reducing oxidative stress, and promoting gut health compared with LED infrared lighting. These insights can be applied to optimizing broiler farming practices, thereby improving productivity and animal welfare.

Effects of GHRH and its analogues on the Vascular System.

Growth hormone-releasing hormone (GHRH) is a crucial endocrine hormone that exerts its biological effects by binding to specific receptors on the cell surface, known as GHRH receptors (GHRH-R). This binding activates downstream signaling pathways. In addition to promoting growth hormone secretion by the pituitary gland, GHRH also functions to maintain multisystem homeostasis by interacting with peripheral tissues that express GHRH-R. Due to the multiple roles of GHRH in body development and tissue repair, a variety of GHRH analogue peptides have been synthesized. Based on their effects on GHRH-R, these GHRH analogues can be classified as GHRH-R agonists and antagonists. Recently, the interaction of GHRH and its analogues with blood vessels, such as promoting angiogenesis and inhibiting vascular calcification (VC), has gained significant attention. This article reviews the effects of GHRH and its analogues on blood vessels.

GHRH in diabetes and metabolism.

Despite over a century of insulin therapy and recent advances in glucose monitoring, diabetes and its complications remain a significant burden. Current medications are not durable, with symptoms often returning after treatment ends, and responses vary between patients. Additionally, the effectiveness of many medications diminishes over time, highlighting the need for alternative approaches. Maintaining β-cell mass and promoting β-cell regeneration offer more curable treatments, while cell replacement therapies could be an option if regeneration is not feasible. For both strategies, enhancing β-cell survival is crucial. Growth hormone-releasing hormone (GHRH) was originally discovered for its ability to stimulate the production and release of growth hormone (GH) from the pituitary. Beyond the hypothalamus, GHRH is produced in peripheral tissues, with its receptor, GHRHR, expressed in tissues such as the pituitary, pancreas, adipose tissue, intestine, and liver. Several studies have shown that GHRH and its analogs enhance the survival of insulin-producing pancreatic β-cells both in vitro and in animal models. These beneficial effects strongly support the potential of GHRH agonists and antagonists for the clinical treatment of human metabolic diseases or for enhancing β-cell survival in cells used for transplantation. In the current review, we will discuss the roles of hypothalamic and extrahypothalamic GHRH in metabolism in physiological and pathological contexts, along with the underlying mechanisms. Furthermore, we will discuss the potential beneficial effects of GHRH analogs for the treatment of metabolic diseases.

Regulatory Effects of Copper on Ghrelin Secretion in Rat Fundic Glands.

Copper (Cu) is an effective additive in feed for promoting growth. Growth dan axis comprising growth hormone (GH), somatostatin (SS) and GH-releasing hormone (GHRH), with ghrelin regulating their release. The growth-promoting effects of Cu are closely related to ghrelin, but the specific mechanism behind the relationship remains unknown. We investigated the adjustment of ghrelin synthesis and secretion by Cu. Sprague-Dawley rats were fed basal diets with an addition of 0, 120 or 240 mg/kg Cu sulfate for 28 day to establish a growth-promoting model. Signalling molecules relevant to ghrelin synthesis and secretion were detected and mechanistically explored using enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction and Western blot analysis. The 120 mg/kg supplement improved growth performance; significantly increased the serum levels of ghrelin, ghrelin O-acyltransferase (GOAT), acylated ghrelin (AG), GH, and reactive oxygen species (ROS) and decreased those of SS; significantly increased the mRNA and protein expression of ghrelin, GOAT, ghrelin receptor (GHS-R1α), and activator protein 1 (AP-1); increased the phosphorylation ratio of JNK and p38 MAPK; and inhibited the mRNA and protein expression of SS and SS receptor subtype 2 (SSTR2) in gastric fundic gland tissues. Thus, Cu may affect gastric ghrelin synthesis at the transcriptional level by activating the JNK/p38 MAPK pathway through increased ROS levels and regulating the activation of the downstream redox-sensitive transcription factor AP-1. SS plays a crucial determinant role in ghrelin regulation via intragastric Cu. Cu promotes GOAT activity and ghrelin secretion by inhibiting SS secretion, affecting AG levels, and promoting ghrelin acylation through ghrelin/GOAT/GHS-R1α system, modulating ghrelin secretion.

Growth hormone-releasing hormone and its analogues in health and disease.

Growth hormone-releasing hormone (GHRH) and its ability to stimulate the production and release of growth hormone from the pituitary were discovered more than four decades ago. Since then, this hormone has been studied extensively and research into its functions is still ongoing. GHRH has multifaceted roles beyond the originally identified functions that encompass a variety of direct extrapituitary effects. In this Review, we illustrate the different biological activities of GHRH, covering the effects of GHRH agonists and antagonists in physiological and pathological contexts, along with the underlying mechanisms. GHRH and GHRH analogues have been implicated in cell growth, wound healing, cell death, inflammation, immune functions, mood disorders, feeding behaviour, neuroprotection, diabetes mellitus and obesity, as well as cardiovascular, lung and neurodegenerative diseases and some cancers. The positive effects observed in preclinical models in vitro and in vivo strongly support the potential use of GHRH agonists and antagonists as clinical therapeutics.

GHRH and the prostate.

In the late 1960s and early 1970s, hypothalamic regulatory hormones were isolated, characterized and sequenced. Later, it was demonstrated hypothalamic and ectopic production of growth hormone-releasing hormone (GHRH) in normal and tumor tissues, of both humans and animals. Pituitary-type GHRH receptors (pGHRH-R) had been demonstrated to be expressed predominantly in the anterior pituitary gland but also found in other somatic cells, and significantly present in various human cancers; in addition, the expression of splice variants (SVs) of GHRH receptor (GHRH-R) has been found not only in the pituitary but in extrapituitary tissues, including human neoplasms. In relation to the prostate, besides the pGHRH-R, it has been detected the presence of truncated splice variants of GHRH-R (SV1-SV4) in normal human prostate and human prostate cancer (PCa) specimens; lastly, a novel SV of GHRH-R has been detected in human PCa. Signaling pathways activated by GHRH include AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR and JAK2/STAT3, which are involved in processes such as cell survival, proliferation and cytokine secretion. The neuropeptide GHRH can also transactivate the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2. Thus, GHRH-Rs have become drug targets for several types of clinical conditions, including prostate-related conditions such as prostatitis, benign hyperplasia and cancer. Over the last fifty years, the development of GHRH-R receptor antagonists has been unstoppable, improving their potency, stability and affinity for the receptor. The last series of GHRH-R antagonists, AVR, exhibits superior anticancer and anti-inflammatory activities in both in vivo and in vitro assays.