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

more »

... re 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 review-PRISMA. 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. Abstract content goes here | This a preprint and has not been peer reviewed. Data may be preliminary. which GHRH binds as a native ligand [1] . Several GHS was developed to treat or diagnose GH deficiency, namely, growth retardation, gastrointestinal dysfunction, and changes in body composition, in parallel to extensive research to identify GHRH, GHS-R, and ghrelin [1]. Ghrelin is a polypeptide containing 28 amino acids that are mainly synthesized in the stomach. Its activity stimulates GH secretion and appetite, resulting in net body weight gain [1] . From a historical angle, growth hormone-releasing peptides (GHRPs) were found before the discovery of ghrelin and the ghrelin receptor. Subsequently, GHSs, that is, ghrelin peptide mimetics, were developed. It was only later that the GHS type 1 receptor (GHS-R1a) was discovered. Finally, ghrelin was successfully isolated as a natural GHS-R1a ligand from stomach substrates in 1999. This context triggered the development of ghrelin receptor agonists, GHRPs, and GHSs; some of which have reached tests in clinical trials [2] [3] [4] [5] . A wide range of ghrelin receptor agonist indications has been evaluated including growth retardation, gastrointestinal dysfunction, and altered body composition; some of which have received approval from the Food and Drug Administration (FDA) [6] [7] [8] [9] . The present study focused on the history of research and the pharmacology of ghrelin receptor agonists [10] [11] [12] [13] . Publicly released clinical trials on GHSs will be discussed in this regard [14] [15] [16] [17] [18] . Also, 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, but SARM is very different from other TIR proteins mammalian cytosolic MyD88, Mal, TRIF and TRAM, as it is not necessary to signal downstream of Toll-Like (TLR) receptors [45] . Mammalian SARM was first described in 2006 as an inhibitor of TLR signaling. Another important role for SARM is in mediating cell death [45] . Also, a recent advance reveals that SARM is enzymes that degrade NAD + and this activity is necessary for SARM to perform axonal destruction of neurons [45] . Since SARM is the only protein in the TIR domain that exhibits this activity, this suggests that at some point in the early evolution the functions of the other TIR proteins diverged [45] . In this context, 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 [46] . Since their initial scientific reports in 1998 [46], SARMs with a variety of chemical supports and pharmacological profiles have been discovered to facilitate the selective activation of androgen receptor (RA) tissues. RA is a member of the steroid receptor family of ligand-activated transcription factors, which are crucial to the organogenesis, physiology, and pathology of many tissues and are activated by comprehensive ligands such as natural hormones, peptides, synthetic molecules or hormones from growth [46] . The ability of SARMs to promote muscle and bone growth and strength, inhibit the growth of breast cancer and shrink the prostate in animals and humans is a problem based on many parameters, such as differences in the conformation of RA, expression of the enzyme metabolizer of RA and steroids between tissue recruitment, co-activator, and co-repressor [47, 48] . The present work aimed to present the State-of-the-Art of 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. Initially, keywords were determined by searching the DeCS tool (Descriptors in Health Sciences, BIREME base) and then verified and validated by the MeSH system (Medical Subject Headings, the US National Library of Medicine) to achieve a consistent search. MeSH Terms The main descriptors (MeSH Terms) used were "Growth hormone secretagogues, Peptides, SARM, Antagonists and Human Studies". For further specifications, the description "Clinical Trail" for refinement was