State-of-the-art clinical results of growth hormone secretagogues, sarm and antagonists

Introduction: The term growth hormone secretagogues (GHS) encompasses compounds that were developed to increase growth release of growth hormone (GH). GHSs include growth hormone receptor secretagogue agonists (GHS-R), whose natural ligand is ghrelin, and growth hormone releasing hormone (GHRH) agonists, to which GHRH binds as a native ligand. In the context of selective androgen receptor modulators (SARM), the presence of a Toll-IL-1 receptor domain (TIR) predicts a role for SARMs in innate immunity. SARMs are an emerging class of therapies aimed at cachexia, sarcopenia and hypogonadism or treatment of stress urinary incontinence, osteoporosis, breast cancer and Duchenne muscular dystrophy. Objective: To present the state-of-the-art scientific evidence in humans on the use of growth hormone secretagogues, SARM and antagonists. Methods: Experimental and clinical studies were included (case reports, retrospective, prospective, randomized studies and systematic review) with qualitative and/or quantitative analysis. For further specifications, the description “Clinical Trail” for refinement was added during the research, following the rules of the systematic reviewPRISMA. Of 384 articles, a total of 80 articles were evaluated in full and 58 were included and discussed in this study. Results and conclusion: Several clinical trials have been conducted and completed to assess the safety and efficacy of GHS for the diagnosis and / or treatment of GH deficiency. Over the past two decades, scientists' efforts have focused on the discovery and biological characterization of new tissue-specific SARM to promote the beneficial effects of androgens with greatly reduced undesirable side effects. In this regard, numerous studies with SARM of different structures have been reported. Despite evidenced clinical and preclinical studies, no SARM has yet received full clinical approval.

Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.