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INTRODUCTION
Growth hormone secretagogues (GHS) are an expanding class of peptide and non-peptide molecules which stimulate the pituitary gland to secrete growth hormone (GH) through their own specific receptor (1). They act at both the hypothalamus and pituitary gland and thus their efficacy requires these structures to be intact. The effects of GHS are modulated by GH-releasing hormone (GHRH) and somatostatin but GHS do not act via these hormones or via other agents which can effect GH secretion such as thyrotrophin-releasing hormone (TRH).
GHS in healthy subjects have been found to stimulate not only GH secretion but also secretion of ACTH (and thus cortisol) and prolactin. Clearly, this raises the concern that increased cortisol concentrations could counteract the anabolic effects of elevated GH concentrations.
The use of GHS, as an alternative anabolic therapy to exogenous GH, can only be anticipated to be successful in conditions in which GH has been shown to be efficacious. To date these include patients undergoing some forms of surgery (2), patients taking glucocorticoids (3), patients with burns (4), the acquired immuno-deficiency syndrome (AIDS) (5,6), renal failure (7,8) and chronic obstructive airways disease (9). These conditions are chronic and an ideal anabolic agent should be active orally — the more recently developed GHS, such as MK-677, fit this criterion. Studies of GHS in catabolic states have predominantly involved single injections which can either provide data that these agents are active in the conditions studied or illustrate GH physiology in catabolism. Long-term studies will be required to determine whether acute efficacy can be translated into longterm anabolic benefits. As with the early trials of GH treatment, small metabolic studies must be followed by longer-term clinical studies with clinically relevant end-points such as length of hospital stay, functional performance or mortality. The results of published studies are discussed below according to catabolic state (Table 1).
Table 1. Summary of published studies of the effects of GHS in catabolic conditions
Condition Secretagogue Dose Route GH secretion ACTH secretion Prolactin secretion IGF-Iconc. IGFBP-3conc. Cortisolconc. Refs. Diet-induced catabolism MK-677 25 mg Oral ↑↑↑ NT ↑ ↑ ↑ ↑ (12)* Hexarelin 1 μg/kg IV ↑↑↑ NT NT NT NT NT (13) Anorexia Hexarelin 1 μg/kg IV ↑↑↑ Critical illness GHRH 1 μg/kg IV ↑ NT ↔/↑ ↔ NT ↑ (14) GHRP-2 1 μg/kg IV ↑↑/↑↑↑ ↑ ↔ ↑ GHRH + GHRP-2 As above IV ↑↑↑↑↑↑ ↔/↑ ↔ ↑ GHRH 1 μg/kg/hr IVI ↑ NT ↑ ↔/↑ NT ↔ GHRP-2 1 μg/kg/hr IVI ↑↑ ↔/↑ ↑ ↑ ↔ (15,16,30) GHRH + GHRP-2 As above IVI ↑↑↑↑ ↔/↑ ↑↑ ↑ ↔ Renal failure Hexarelin 1 μg/kg IV ↑↑ ↑ ↔ NT NT ↑ (17,18) 2 μg/kg IV ↑↑↑ ↑ ↔ ↑ Short-term exogenous L 692,429 0.2 mg/kg IV ↑↑ NT ↑ NT NT ↔ (21) glucocorticoids 0.75 mg/kg IV ↑↑↑ ↑↑ ↔ Long-term exogenous GHRH 100 μg IV ↔ NT NT NT NT NT (22) glucocorticoids Hexarelin 100 μg IV ↑↑ GHRH + Hexarelin As above IV ↑↑↑↑ GHRH 100 μg IV NT NT ↔ NT NT (23) GHRP-6 1 μg/kg IV ↑↑ GHRH + GHRP-6 As above IV ↑↑↑↑↑ Cushing’s — pituitary GHRH 100 μg IV ↔ NT NT ↔ NT NT (23) GHRP-6 1 μg/kg IV ↔/↑ GHRH + GHRP-6 As above IV ↑/↑↑ GHRH 100 μg IV ↔/↑ NT NT NT NT NT (19) GHRP-6 100 μg IV ↑ GHRH + GHRP-6 As above IV ↑/↑↑ Hexarelin 2 μg/kg IV ↑↑ ↑↑↑ NT NT NT ↑↑ (20) Cushing’s — adrenal or Hexarelin 2 μg/kg IV ↑↑ ↔ ↔ ectopic Hyperthyroidism GHRH 100 μg IV ↔/↑ NT NT NT NT NT (25) GHRP-6 1 μg/kg IV ↑↑↑ GHRH + GHRP-6 As above IV ↑↑↑
* The paper found different effects of MK-677 on days 1 and 7 of treatment; these are elaborated in the text, ↑, increased; ↓, decreased; ↔ unchanged; NT, not tested.
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Growth Hormone Secretagogues
GH secretagogues are peptides or nonpeptidic agents that act to release GH from the pituitary. There is evidence that they are being used by athletes as an indirect method for GH doping. Secretagogues include GHRH and its analogues, ghrelin analogues (known as GH-releasing peptides) or GHS (GH secretagogues in a narrower sense), and amino acids (e.g., arginine or ornithine). GH secretagogues have short-lived effects and provide a relatively weak boost in GH exposure compared with what can be achieved by direct GH administration.123 Nevertheless, GH secretagogues may be attractive to athletes who want to avoid detection because the GH released is endogenous and therefore not detectable by the GH isoform test.123
Currently there is no published method to detect use of these GHRH analogues, but because they differ structurally from native GHRH, unequivocal detection methods should be feasible if sufficient sensitivity can be achieved.123
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Abstract
Growth hormone secretagogues (GHSs) are a family of synthetic peptidyl and nonpeptidyl molecules that bind specific receptors (GHS-Rs) in the hypothalamus and pituitary with stimulatory effect on somatotrope secretion. Over the last 40 years, many nonnatural GHSs, with different oral bioavailability, have been synthesized in order to treat GH deficiency. Although GHS-R had been designated as an orphan receptor specific for synthetic GHSs, in 1999 Kojima et al. isolated, from the enteroendocrine cells in the stomach, the first natural bioactive ligand for this receptor, named ghrelin.
Ghrelin, a 28-amino acid peptide, is multifunctional and it exerts several endocrine and nonendocrine activities. It has a strong GH-releasing effect through which it has been used as a provocative test for the diagnosis of GH deficiency and as an anabolic treatment of cachexia. The stimulatory effect of ghrelin on ACTH and PRL secretion is even more pronounced than other GHSs, and it has been studied in healthy individuals and in pathological conditions (Cushing׳s disease and prolactinoma). Ghrelin also regulates the hypothalamus–pituitary–gonadal (HPG) axis acting both at the central and at the peripheral level in a gender-different manner: it has an inhibitory effect on LH, but not on FSH, pulsatility in men while it suppresses gonadotropin secretion in women.
Besides these endocrine effects, ghrelin is also endowed with metabolic functions: it is the first known peripheral hormone to display strong orexigenic effects through its action on the hypothalamic appetite-regulating pathways. Moreover, a ghrelin infusion has been shown to increase glucose levels in healthy subjects and to inhibit insulin secretion. Thus, it has been hypothesized a potential therapeutic role of ghrelin blockade in glucose intolerance/diabetes and in obesity. Furthermore, some bariatric surgery procedures could decrease ghrelin secretion resulting in inhibition of appetite and improvement of glycemic metabolism and remission of diabetes.
Finally, emerging evidences have revealed ghrelin function on the cardiovascular system and in regulating several processes related to cancer progression, especially in tumor cell proliferation.
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1 Introduction
The growth hormone secretagogue receptor (GHSR) was discovered in 1996 as the target of some synthetic molecules that induce the secretion of growth hormone (GH), named growth hormone secretagogues (Howard et al., 1996). The first endogenous ligand for GHSR was discovered in 1999 and termed ghrelin, which is a stomach-derived octanoylated peptide that potently stimulates growth hormone secretion in rodents and humans (Kojima et al., 1999; Takaya et al., 2000). Soon after, ghrelin was also shown to increase food intake (Nakazato et al., 2001; Tschöp et al., 2000; Wren et al., 2001). Further studies revealed that ghrelin displays a variety of metabolic, neuroendocrine and autonomic effects. The detection of GHSR expression in the pituitary and in some specific brain areas provided the neuroanatomical basis for a better understanding of such roles of GHSR (Guan et al., 1997; Mitchell et al., 2001; Zigman et al., 2006). Notably, those seminal neuroanatomical studies in rodents showed that GHSR is also expressed in brain targets that control complex animal’s functions such as learning, the capability to process information regarding the pleasurable (hedonic) and incentive (motivational) aspects of some stimuli (rewards) or the actions to seek and obtain such rewards. Thus, two intriguing possibilities emerged from these observations. First, the expression of GHSR in brain areas without immediate access to circulating ghrelin suggested that this receptor could display some ligand-independent actions, which were further discovered and included constitutive activity and allosteric modulation of other receptors. Second, GHSR emerged as a molecular candidate by which “hunger” could enhance some reward-related behaviors towards obtaining not only food but also other rewarding stimuli (e.g. drugs of abuse). In line with this possibility, many independent studies have shown that GHSR activity enhances not only the consumption of rewards but also the assignment of a rewarding value, the learning processes involved, and the further motivation to obtain such rewards. This review describes the evidence indicating that GHSR acts via ligand-dependent and ligand-independent manners, and discusses the putative molecular mechanisms and neuronal circuits by which GHSR could enhance reward-related behaviors towards different stimuli.
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GROWTH HORMONE SECRETAGOGUES ARE CENTRALLY ACTIVE COMPOUNDS
In the early 1980s C.Y. Bowers and colleagues identified the first member of a class of synthetic growth hormone (GH)-releasing compounds, GH-releasing peptide-6 (GHRP-6), whose actions were potent and selective for GH secretion (4). Direct GH-releasing activity at the pituitary level was observed in vitro, providing evidence for a direct pituitary action (4) and the GH-releasing mechanism was clearly different to that of GHRH (5,6). That GHRP-6 may also affect the hypothalamic regulation of GH secretion was first suggested by Clark and Robinson (7). They proposed that part of the GH-releasing mechanism of GHRP-6 is likely to include increased GHRH release, since the GHRP-6-induced GH response was attenuated in rats passively immunized with GHRH antiserum. Furthermore they suggested that GHRP-6 may alter somatostatin secretion, since it disrupted the cyclic changes in GH release following regular injections of GHRH (a response which has been attributed to cyclic changes in somatostatin secretion) (8). Certainly, it emerged that the GH-releasing actions of GH secretagogues could not be explained solely by a pituitary action since, when administered together, GHRP-6 and GHRH had merely additive effects on GH secretion in vitro (in pituitary perfusion experiments and in cell culture) but produced an enormous synergistic effect in vivo (9). Rather it was suggested that the central actions of GHRP-6 may include the release of an unknown hypothalamic-releasing factor (a “U-factor”) into the portal blood; according to this hypothesis, the U-factor would act together with GHRH to stimulate GH secretion from the pituitary (9).
The first direct evidence that the GH secretagogues are centrally active compounds was provided by studies demonstrating increased activity of a sub-population of cells in the hypothalamic arcuate nucleus (6). In this study and in subsequent studies, cells activated following systemic GH secretagogue injection were detected using two complementary approaches: (1) by the immunocytochemical detection of Fos protein (the product of the immediate early gene, c-fos, which is expressed in many neuronal systems following activation) and (2) by changes in electrical activity of arcuate neurones recorded in anaesthetised rats (6,10).
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From the First Growth Hormone Secretagogues to the Endogenous One, Ghrelin
Growth hormone secretagogues (GHSs) are a family of synthetic peptidyl and nonpeptidyl molecules that bind specific receptors (GHS-Rs) in the hypothalamus and pituitary with potent stimulatory effect on somatotrope secretion. Interestingly, the activity of GHSs is not fully specific for GH release; in fact, after acute administration they also possess a weak prolactin (PRL-), adrenocorticotropin hormone (ACTH-) and cortisol-releasing effect, but they have also been reported to be able to influence food intake and sleep patterns (Ghigo et al., 1998). However, over the last 30 years, relevant scientific research has been focused on identifying synthetic GHSs in order to treat GH deficiency. The first GHSs were nonnatural synthetic peptides (also known as GH-releasing peptides, GHRP) endowed with a potent GH-releasing action. Invented in 1977 as met-enkephalin derivatives, they were devoid of any opioid activity and they did not affect the release of pituitary hormones (Bowers et al., 1977; Ghigo et al., 1998). The GHS family includes peptidyl analogues, such as GHRP-1, GHRP-2, GHRP-6, hexarelin (Bowers et al., 1993), and nonpeptidyl molecules. A series of hexarelin analogues that contain one or several unnatural amino acids have been synthesized (Vodnik et al., 2016). The peptidyl analogues possess strong GH-releasing activity, but they have the disadvantage of having an oral bioavailability of less than 1% with a short-lasting effect (Ghigo et al., 1998). In the nineties, research at Merck & Co. led to the synthesis of an orally active nonpeptidyl molecule, MK-0677 also known as spiroindoline, one of the most potent peptidomimetic GHSs (Patchett et al., 1995). MK-0677 shows an oral bioavailability of more than 60% and seems endowed with a long-lasting effect (Copinschi et al., 1996). GHSs bind to specific sites in the rat forebrain and other brain regions, although the greatest density of binding sites is the hypothalamus and pituitary gland. GHS-R was in fact initially cloned in 1996 from pig pituitaries (Howard et al., 1996). It is expressed in humans as two isoforms from the same gene on chromosome 3q26.2: GHS-R type 1a and GHS-R type 1b. GHS-R type 1a is a G protein-coupled receptor, composed of 366 amino acids with seven transmembrane regions and a molecular mass of approximately 41 kD, while GHS-R type 1b is a splice variant of type 1a made up of a truncated polypeptide of 289 amino acids with five transmembrane domains and a molecular mass of approximately 32 kDa (Laviano et al., 2012). Whereas GHS-R type 1a binds both peptidyl and nonpeptidyl GHSs, GHS-R type 1b does not bind GHSs and its functional role is unknown. It has been hypothesized that the latter receptor would play a critical role in modulating the activity of GHS-R type 1a by forming hetero-dimeric complexes which attenuates trafficking of the active variant to cell surface (Laviano et al., 2012; Chan and Cheng, 2004). The GHS-R1a is expressed predominantly in the anterior pituitary gland and in the hypothalamus, but also in extrahypothalamic areas of the central nervous system (ventral tegmental area, nucleus accumbens, hippocampus, and amygdala), in multiple peripheral endocrine (pancreatic islets, adrenal gland, thyroid) and nonendocrine organs and in different neoplastic tissues (Gnanapavan et al., 2002).
Although GHS-R had been designated as an orphan receptor specific for the synthetic GHS molecules, in 1999 Kojima et al. isolated and characterized a natural bioactive ligand for this receptor, named ghrelin. The name ghrelin derives from the word “ghre,” the Proto-Indo-European root of the word “grow” (Kojima et al., 1999). It derives from the 117 amino acid precursor “preproghrelin” encoded by the gene GHRL located on chromosome 3p25–26, with five exons and four introns. Mature ghrelin consists of 28 amino acid residues, mainly produced from the enteroendocrine (X/A like) cells in the stomach wall (oxyntic mucosa), but lower levels of expression have been found in several other peripheral tissue, such as the gastrointestinal tract, adrenal gland, thyroid, breast, ovary, placenta, fallopian tube, testis, prostate, liver, gallbladder, fat tissue, human lymphocytes, spleen, kidney, lung, skeletal muscle, myocardium, vein, and skin (Date et al., 2000; Kojima et al., 2001; Gnanapavan et al., 2002; Ghelardoni et al., 2006). Ghrelin is also produced by neurons in several areas of the central nervous system, particularly in the nucleus arcuatus of the hypothalamus and in a group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei (Kojima et al., 1999; Korbonits et al., 2001; Cowley et al., 2003; Kojima and Kangawa, 2005). Ghrelin is the first peptide isolated from natural sources in which the hydroxyl group of its third serine residue (namely, serine 3) is acylated by n-octanoic acid, catalyzed by ghrelin-O-acyltransferase (GOAT). The acylation of the N-terminal tetra-peptide is critical for the peptide to be able to cross the blood–brain barrier and is essential for binding GHS-R type 1a and for endocrine actions (Banks et al., 2002; Lorenzi et al., 2009). This special feature is conserved across species (Muccioli et al., 2007). Ghrelin circulates in two major forms, acylated ghrelin (AG) and nonacylated ghrelin (UAG), which is the most abundant and stable form. UAG does not bind GHS-R type 1a and is devoid of typical AG endocrine activities. Nevertheless, UAG is an active peptide sharing some of the activities of AG, either enhancing or opposing AG. In fact, UAG has been demonstrated to have opposite effects on glucose and insulin metabolism in healthy humans (Benso et al., 2012). Moreover, several studies have shown that UAG exhibits biological activities on cell proliferation and binds to cell membranes of cardiomyocytes, adipocytes, prostatic, and skeletal muscle cells (Cassoni et al., 2001; Baldanzi et al., 2002; Muccioli et al., 2004; Filigheddu et al., 2007). These effects are likely mediated through different GHS-R subtypes or completely different receptor families (Cassoni et al., 2001; Baldanzi et al., 2002; Ghigo et al., 2005; Giovambattista et al., 2008).
It is possible that ghrelin is not the sole natural GHS-R ligand and that GHS-R type 1a is one of a group of receptors for such ligands. Indeed, GHS-R is also bound by other molecules, such as Des-Gln14-ghrelin, which is a gastric homologue of ghrelin, with the exception that one glutamine is missing, and which has the same biological activities as ghrelin; adenosine, which binds but does not activate the receptor; and cortistatin, which is a neuropeptide that is homologous to somatostatin and is unable to recognize GHS-R type 1a. Moreover, there is strong evidence suggesting the existence of additional receptor subtypes. Specific binding sites for peptidyl GHS only, with very low binding affinity for ghrelin and nonpeptidyl GHS, have been shown in a wide range of nonendocrine peripheral human tissues.
The regulation of ghrelin secretion is still largely unknown, but it has already been shown that circulating ghrelin levels are increased in fasting states and declined 60–120 min after meals (Tschöp et al., 2001; Cummings et al., 2001), suggesting that ghrelin may act as an initiation signal for food intake (Ariyasu et al., 2001; Tschöp et al., 2001; Cummings et al., 2001; Klok et al., 2007; Lorenzi et al., 2009). A diurnal and nocturnal rhythmicity of ghrelin levels in humans has also been observed by some (Cummings et al., 2001; Koutkia et al., 2004), but not by other authors (Barkan et al., 2003). In addition, ghrelin levels seem to be influenced by age, gender, BMI, GH, glucose, and insulin (Ariyasu et al., 2001; Tschöp et al., 2001; Cummings et al., 2001; Barkan et al., 2003; Klok et al., 2007). Notably, leptin has also been suggested to have influence on circulating ghrelin levels. In fact, it has been hypothesized that the satiety-inducing effects of leptin include the suppression of ghrelin secretion. In agreement with the critical influence of nutrition on ghrelin secretion, circulating ghrelin levels are increased in anorexia and cachexia but reduced in obesity (Yildiz et al., 2004).
A comprehensive summary of ghrelin actions in vivo is provided in Table 1.
Table 1. In vivo endocrine and nonendocrine ghrelin actions
Site of action Acylated ghrelin actions Hypothalamus ↑ GHRH secretion ↑ CRH secretion ↓ GnRH pulse generator ↑ Food intake (via NPY) and appetite Pituitary ↑ GH secretion ↑ ACTH secretion ↑ PRL secretion ↓ LH in men/↓ FSH and LH in women ↓↔ TSH Pancreas ↓ Insulin secretion (spontaneous and glucose stimulated) ↑ Glucose levels ↑ Glycogenolysis ↑ Glucagone secretion Adipose tissue ↑ Lipogenesis Cardiovascular system ↑ Cardiac output ↑ Cardiac contractility ↓ Systemic vascular resistances ↑ Vasodilation Gastrointestinal system ↑ Gastric emptying ↑ Gastric acid secretion ↑ Gastric motility ↑ Intestinal motility Liver ↑ IGF-I
In the following paragraphs we will discuss the main endocrine and nonendocrine ghrelin activities.
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Abstract
Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G-protein-coupled receptor highly expressed in the hypothalamus and pituitary. Using an orphan receptor strategy with a stable cell line expressing GHS-R, we purified endogenous ligands for GHS-R from rat and human stomach and named it “ghrelin,” after a word root (ghre) in Proto-Indo-European languages meaning “grow.” Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The main active form of rat ghrelin is 28-amino acid peptides with n-octanoyl modification. In rat stomach, a second type of ghrelin peptide was purified, identified as des-Gln14-ghrelin. With the exception of the deletion of Gln14, des-Gln14-ghrelin is identical to ghrelin, retaining the n-octanoic acid modification. Des-Gln14-ghrelin is encoded by an mRNA created by alternative splicing of the ghrelin gene. As in the rat, the major active form of human ghrelin is a 28-amino acid peptide with an n-octanoylated Ser3. However, in human stomach, several minor forms of human ghrelin peptides have been isolated. These can be classified into four groups by the type of acylation observed at Ser3 and into two groups by the amino acids in length. The discovery of ghrelin indicates that the release of GH from the pituitary and appetite stimulation might be regulated by ghrelin derived from the stomach.
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Publisher Summary
This chapter reviews the structure, distribution, and physiological functions of ghrelin. Growth hormone secretagogues (GHSs) are synthetic stimulate the release of growth hormone from the pituitary. They act through a G-protein-coupled receptor (GHS-R). In the chapter an endogenous ligand for GHS-R “ghrelin,” from rat stomach is purified using a reverse pharmacology paradigm with a stable cell line expressing GHS-R. Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in bullfrog a threonine, is modified by a fatty acid and this modification is essential for the activity of ghrelin. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by the hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Taking into account all these activities, ghrelin plays important roles for maintaining growth hormone release and energy homeostasis in vertebrates.
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4.15.2.3 Growth Hormone Secretagogues
During studies of the opioid control of GH secretion several analogs of met-enkephalin were found to be potent GH secretagogues. Among them were GHRP-6 (GH-releasing peptide-6) and hexarelin (His-D2MeTRP-Ala-Trp-DPhe-Lys-NH2) (Laron, 1995). They act via a receptor unrelated to that of GHRH (Howard et al., 1996). The potent biologic action of the GHRPs (GHS) and the identification of a specific receptor suggested the existence of a natural ligand (Laron et al., 1995; Korbonits et al., 1999; Laron, 2003).
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GH secretagogues
GHSs act at the ghrelin receptor (also called growth hormone secretagogue receptor) in the hypothalamus to promote the release of GH [10]. While these receptors are found in the brain, they are also found in the liver, skeletal tissue, and heart. For the purposes of GH release, interaction between secretagogues and the receptor occurs in the brain. GHSs are not inherently growth promoting; many result in the ultimate increased production or secretion of IGF-1 [11], which acts at target tissues to promote growth and anabolism [12]. GH use, often through the actions of IGF-1, is purported to
-
increase lean body mass [13], -
decrease fat mass [14], -
increase exercise capacity [14], anaerobic energy [15], and maximum oxygen uptake [16], -
enhance muscle strength [17], -
improve linear growth [18], and -
improve recovery time [19].
Figure 1 provides a summary of the activity of the GH/IGF-1 axis.
Figure 1. GH/IGF-1 axis and purported effects after the use of a GH/IGF-1–stimulating drug. Shown are the site of action, purported downstream effects, and examples of drugs in the classes of growth hormone secretagogues (GHSs), growth hormone–releasing hormones (GHRHs), growth hormone–releasing peptides (GHRPs), growth hormone segments (denoted by truncated GH shapes), and insulin-like growth factor-1 (IGF-1) variants (denoted by star shape). Also shown are the sites of action for both endogenous and exogenously administered growth hormone (GH) and IGF-1. Negative feedback of GH and IGF-1 at the hypothalamus and pituitary is shown by the dotted line.
Analytical evidence of the performance-enhancing capabilities of GH, or the growth-promoting effects in healthy adult individuals, is weak. However, GH and other growth factors remain prohibited in sports because of the potential for performance enhancement [20], the adverse health effects that supraphysiological levels of GH may cause [21], and its use (with the sole intention of gaining a competitive edge) violating the spirit of sport.
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