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Human growth hormone
Overview
Human growth hormone (HGH) is one of the hormones regulating human growth. It is secreted from the somatotrope cells of the anterior pituitary. In turn, it stimulates release of insulinlike growth factor-1. These hormones cause a net increase in lipolysis and protein anabolism.17 Exercise stimulates the release of growth hormone.18 When endogenous growth hormone levels are too high and unregulated, acromegaly occurs, causing increased height, body weight, muscle mass, and bone mass, especially in the hands, feet, jaw, and skull. HGH is increasing in popularity as an ergogenic aid, including popularity among adolescents, where one study found that 5% of teens reported using HGH.19 It is often used in combination with AAS as a means of “stacking” multiple ergogenic aids. Its use as an ergogenic aid began in the 1980s and has remained popular due, in part, to a lack of reliable tests for detection of use.17
Preparations and dosages
•
Recombinant HGH (injectable)17 •
Cadaveric HGH (injectable), which is available in Europe and on the black market.
○
Root cause of some cases of Creutzfeldt-Jacob disease •
HGH secretagogues, used to increase endogenous growth hormone production, are available as the injectable subcutaneous peptides hexarelin and ipamorelin. Oral forms (MK-0677 and NNC 26-0703) are in development.20
Physiologic and performance effects
Athletes use HGH because it is thought that it will improve healing and increase muscle mass, muscle strength, and body size.17 Data support that HGH does the following21:
•
Increases lean body mass but not body weight or fat mass •
Increases basal metabolic rate •
Increases heart rate •
Shows no benefit in exercising respiratory exchange ratio or energy expenditure, bicycling speed, power output, or Vo2Max •
Changes body composition but no performance benefit •
Shows no benefit in muscle strength, power, or workload capacity18,22
Use of HGH continues despite a lack of published research. Like many substances discussed in this article, HGH is studied at different doses than athletes use when they are looking for a performance advantage.
Adverse effects are listed in (Table 4).
Table 4. Adverse effects of human growth hormone use
Soft tissue edema Irreversible facial, jaw, and skull bone growth Impaired glucose tolerance and diabetes mellitus Fatigue Coarsened facial features Hyperlipidemia Arthralgias Carpal tunnel syndrome Cardiomyopathy Muscle weakness Erectile dysfunction Death
Data from Stacy JJ, Terrell TR, Armsey TD. Ergogenic aids: human growth hormone. Curr Sports Med Rep 2004;3(4):229–233; and Pipe A. Effects of growth hormone on athletic performance: a review. Clin J Sport Med 2009;19(1):75–6.
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Introduction
Human growth hormone (GH) is a 191-amino acid polypeptide secreted by the anterior pituitary lobe. Although GH is released in the general circulation, and its action on target cells is mediated by the ubiquitously expressed GH receptor (GHR), the subset of responses that is induced depends on the target tissue, the age of a person and signal dynamics (i.e. pulsatile or continuous presence of GH). These responses are mediated by a multitude of signalling pathways, the major ones being highlighted here. This complexity is mirrored by the range of genetic defects resulting in clinical growth disorders. At present, a diagnosis in a child with short stature is achieved by clinical evaluation supplemented by hormone measurements. However, the aetiological diagnosis is not always clear, and the growth disorder is labelled as ‘idiopathic’. If a clinical decision is made to treat with recombinant human (rh) GH, then this is being undertaken on an empirical basis. With the completion of the Human Genome Project and increasing use of genotyping procedures that stratify patients who superficially present the same symptoms, it might soon be feasible to test patients for a panel of suspected genetic defects, confirmation of which might result in a more rational approach to treatment decisions. This principle is now well accepted for treatment of cancers. For this scenario also to become reality for growth disorders, we need to understand the roles that these genes have in controlling growth, both at the molecular level and in genetically modified animals, and which therapies are effective in which patients. This has become an important issue in an era when both rhGH and insulin-like growth factor I (IGF-I) preparations are available for growth promotion [1].
We review here our current knowledge of GH signalling events, including observations for transgenic animals, followed by a clinical perspective of diagnosis and treatment of growth disorders, to illustrate how advances in our understanding could lead to a ‘personalized’ approach to treatment.
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URL: https://www.sciencedirect.com/science/article/pii/S1043276006002396
Overview
Human growth hormone (HGH) is one of the hormones regulating human growth. It is secreted from the somatotrope cells of the anterior pituitary. In turn, it stimulates release of insulinlike growth factor-1. These hormones cause a net increase in lipolysis and protein anabolism.17 Exercise stimulates the release of growth hormone.18 When endogenous growth hormone levels are too high and unregulated, acromegaly occurs, causing increased height, body weight, muscle mass, and bone mass, especially in the hands, feet, jaw, and skull. HGH is increasing in popularity as an ergogenic aid, including popularity among adolescents, where one study found that 5% of teens reported using HGH.19 It is often used in combination with AAS as a means of “stacking” multiple ergogenic aids. Its use as an ergogenic aid began in the 1980s and has remained popular due, in part, to a lack of reliable tests for detection of use.17
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URL: https://www.sciencedirect.com/science/article/pii/S0095454313000249
Peptide Hormones and Growth Factors
Human growth hormone
Overview
Human growth hormone (HGH) is one of the hormones regulating human growth. It is secreted from the somatotrope cells of the anterior pituitary. In turn, it stimulates release of insulinlike growth factor-1. These hormones cause a net increase in lipolysis and protein anabolism.17 Exercise stimulates the release of growth hormone.18 When endogenous growth hormone levels are too high and unregulated, acromegaly occurs, causing increased height, body weight, muscle mass, and bone mass, especially in the hands, feet, jaw, and skull. HGH is increasing in popularity as an ergogenic aid, including popularity among adolescents, where one study found that 5% of teens reported using HGH.19 It is often used in combination with AAS as a means of “stacking” multiple ergogenic aids. Its use as an ergogenic aid began in the 1980s and has remained popular due, in part, to a lack of reliable tests for detection of use.17
Preparations and dosages
•
Recombinant HGH (injectable)17 •
Cadaveric HGH (injectable), which is available in Europe and on the black market.
○
Root cause of some cases of Creutzfeldt-Jacob disease •
HGH secretagogues, used to increase endogenous growth hormone production, are available as the injectable subcutaneous peptides hexarelin and ipamorelin. Oral forms (MK-0677 and NNC 26-0703) are in development.20
Physiologic and performance effects
Athletes use HGH because it is thought that it will improve healing and increase muscle mass, muscle strength, and body size.17 Data support that HGH does the following21:
•
Increases lean body mass but not body weight or fat mass •
Increases basal metabolic rate •
Increases heart rate •
Shows no benefit in exercising respiratory exchange ratio or energy expenditure, bicycling speed, power output, or Vo2Max •
Changes body composition but no performance benefit •
Shows no benefit in muscle strength, power, or workload capacity18,22
Use of HGH continues despite a lack of published research. Like many substances discussed in this article, HGH is studied at different doses than athletes use when they are looking for a performance advantage.
Adverse effects are listed in (Table 4).
Table 4. Adverse effects of human growth hormone use
Soft tissue edema Irreversible facial, jaw, and skull bone growth Impaired glucose tolerance and diabetes mellitus Fatigue Coarsened facial features Hyperlipidemia Arthralgias Carpal tunnel syndrome Cardiomyopathy Muscle weakness Erectile dysfunction Death
Data from Stacy JJ, Terrell TR, Armsey TD. Ergogenic aids: human growth hormone. Curr Sports Med Rep 2004;3(4):229–233; and Pipe A. Effects of growth hormone on athletic performance: a review. Clin J Sport Med 2009;19(1):75–6.
Erythropoiesis stimulating agents and blood doping
Overview
Blood doping was first, or at least most famously, discovered in competitive athletics in the 1976 Olympics in Montreal, Canada.23 The rationale for this practice is a byproduct of the improved performance of athletes who live at high altitudes and train at low altitudes. The lower oxygen tension of their environment stimulates erythropoiesis and increases their red blood cell mass and therefore their oxygen-carrying capacity.
Autologous blood doping is accomplished by first removing usually 2 units of blood. The blood is then stored at −80°C. This relative anemia stimulates the body to produce enough red blood cells to return to a normal level. The stored blood is then thawed and re-infused 1 week before the event. Homologous matched blood from other donors can also be used in a similar fashion.24 The postinfusion hemoglobin should be less than 17 g/dL and the hematocrit should be less than 50%; otherwise, hyperviscosity can occur, which can result in decreased blood flow velocity as well as the other adverse effects noted in later discussion.25
Epothropoietin (EPO) is a hormone that is produced by the kidney that stimulates red blood cell production in the bone marrow. Recombinant human erythropoietin has a half-life of 20 hours when given subcutaneously but the red blood cell production that results continues for about 2 weeks. It is used medically to treat anemia that results from renal disease.26 Athletes started using EPO to get the benefits of increased red blood cell mass without the complications and challenges of blood doping. Currently, there is no method to directly test for the use of exogenous EPO that is readily available or used consistently, which also makes this substance attractive to some athletes.
Physiologic and performance effects
•
Increased red blood cell mass, hemoglobin, hematocrit, and, therefore, oxygen-carrying capacity •
Increased Vo2Max and endurance27 •
There are no data to support its use in power and anaerobic sports. •
There is no clear and predictable relationship between the level of rise in hemoglobin/hematocrit and improvement in Vo2Max, aerobic capacity, and endurance performance, which suggests that although cardiac output and oxygen delivery can be increased, there may limits at the muscle level on oxygen use.27 •
Current evidence does not support the logic that use of EPO is as effective as blood doping25
Adverse effects
•
Complications of hyperviscosity include decreased cardiac output, intravascular thrombosis, heart failure, cerebrovascular and myocardial ischemia, pulmonary embolism, deep vein thrombosis, and death. •
Other complications include infection, phlebitis, septicemia, and transfusion-associated lung injury. Mismatched blood types with homologous doping can be further complicated by hemolytic reactions, renal failure, allergic reactions, and contracted blood-borne illnesses, including hepatitis C virus, hepatitis B virus, malaria, cytomegalovirus, and human immunodeficiency virus.28 •
Decreased training and exercise capacity during the period between removal of blood and reestablishing normal red blood cell levels, and re-infusion of blood in autologous blood doping.27 •
Re-infusion of blood that contains previously used banned substances that had been stopped to avoid detection and the increased blood levels are both potential means by which athletes that are doping and cheating may be discovered.27
Hormones and metabolic modulators
AAS are the most frequently abused drug in sports and testing is now better able to detect these agents, which have led to newer methods of androgenic doping. The endogenous production of testosterone is tightly regulated by the hypothalamus-pituitary-gonadal axis via negative feedback through the concentration of testosterone and estrogen. Indirect androgen doping takes advantage of this system to increase endogenous testosterone production.29
•
Growth hormones, gonadotropins, metabolic modulators, and anti-estrogenic substances all can be classified under the concept of indirect doping and are banned. •
Chorionic gonadotropin and luteinizing hormones ultimately stimulate Leydig cells to increase the production of testosterone.29 •
Estrogen receptor blockers and anti-estrogenic substances work by causing a false sense of low estrogen levels, which in turn is a potent stimulant of gonadotropin release.29
The extent of gonadotropin and anti-estrogenic substance use is currently unknown. Multiple studies on anabolic androgenic steroids have shown that many users combine multiple substances including chorionic gonadotropin/luteinizing hormone and estrogen blockade. No scientific evidence exists that gonadotropins or anti-estrogenic substances actually have benefits on exercise or performance, but biologically plausible evidence of elevated testosterone levels has led to WADA prohibiting these substances.
Special consideration for testing must be considered. Screening for human chorionic gonadotropin is not performed in women as this invades health privacy for possible pregnancy or recent miscarriage and no evidence exists for performance enhancement in women. Furthermore, a man who tests positive must be evaluated for testicular cancer, as this will cause elevated human chorionic gonadotropin levels.
Diuretics
The use of diuretics in sports has 2 following major functions: rapid weight loss and masking illegal substances. Diuretics were first banned in 1988 and remain on the in-competition and out-of-competition prohibited substance list. Athletes who participate in sports with weight categories have used diuretics to reduce body weight transiently to compete at lower weight classes, whereas athletes using a banned substance will attempt to dilute their urine, making detection more difficult.
•
In 2010, diuretics and masking agents represented 7% of all adverse analytical findings reported by WADA laboratories. •
Diuretics were the second most commonly used nonprescription weight-loss product reported by Division I female athletes, who cited appearance enhancement as the number 1 reason for use.30
Diuretics work by increasing the volume of urinary water excretion through multiple mechanisms in the kidneys. The classes of diuretics used are thiazides, loops, carbonic anhydrase inhibitors, and mineralocorticoid receptor antagonists, with thiazides and loops accounting for nearly 70% of WADA positive tests. Special consideration must be taken for acetazolamide because it is the preferred medication for prophylaxis and treatment of acute altitude sickness.
•
Diuretics may lead to dehydration, fatigue, electrolyte imbalances, and increased susceptibility to heat illness. •
No data exist to suggest that diuretics by themselves enhance performance and are most likely to impact exercise tolerance negatively.
Plasma volume expanders and intravenous fluid hyperhydration
Dehydration is a common problem encountered during training as well as competition. To combat this issue, athletes are recommended to maintain euhydration. The use of plasma volume expanders, such as glycerol and intravenous albumin, dextran, hydroxyethyl starch, and mannitol, is banned by WADA under the section of masking agents. No studies are currently available regarding the extent of use of volume expanders, but, in 2010, WADA reported 7 adverse analytical findings of hydroxyethyl starch.
A study on the prevalence of intravenous fluid (IVF) hyperhydration before National Football League football games recently found that 75% of National Football League teams used a pregame IVF in an average of 5 to 7 athletes. Although not a prohibited practice, half of the trainers reported a history of complications, including air emboli, pulmonary edema, arterial stick, provider needle stick, peripheral edema, and player dependence on IVF before games, raising a question of player safety when no benefit of intravenous over oral hydration or rehydration has been consistently found in the literature.31
The method in which athletes hydrate before, during, and after exercise has been studied extensively. The American College of Sports Medicine published a position statement on exercise and fluid replacement in 2007 with recommendations including the following32:
•
Body weight changes can be used to calculate fluid replacement needs. •
Dehydration increases physiologic strain and perceived effort, resulting in degraded aerobic exercise performance, especially in warm to hot weather. •
Hyperhydration can be achieved by several methods, but provides equivocal benefits and has several disadvantages. •
Gylcerol is the most extensively studied plasma volume expander. A recent systematic review reported that most studies did not find a significant advantage in performance enhancement and that the documented benefits to exercise performance are inconsistent in the current scientific literature.33
β-blockers
Overview
β-Blockers are a class of drugs that acts as β-agonist receptor inhibitors. β-Receptors are part of the autonomic nervous system and are common in the cardiac, vascular, and pulmonary tissues as well as skeletal muscles. The 2 main types of β-receptors are β1 and β2. β1-Receptors are mainly found in cardiac muscle but also in the stomach and kidneys. β2-Receptors are more widespread but are found in the bronchi and bronchioles, skeletal muscle and its arterioles, adipose tissue, gastrointestinal tract and salivary gland smooth muscle, and solid organs like the brain, liver, kidneys, and pancreas. When stimulated by the binding of the catecholamines, epinephrine and norepinephrine, these receptors trigger several downstream effects.
Cardiovascular effects include increases in heart rate, mean arterial pressure, and cardiac contractility as well as muscle bed vasodilation and splanchnic vasoconstriction. Increases in respiratory rate, tidal volume, and minute ventilation as well as bronchodilation also occur. Other effects include pupillary dilation, increasing body temperature, perspiration, glycogenolysis, gluconeogenesis, lipolysis, and insulin secretion. Nervous system effects include alertness, focus, euphoria, anxiety, irritability, and tremors. Adverse effects include dyspepsia, nausea, cardiac arrhythmias, palpitations, and bronchospasm.
β-Blockers serve to inhibit all of the physiologic responses listed above to β-stimulation. In medicine, these drugs are used commonly in cardiac and neurologic conditions, including acute myocardial infarction, heart failure, hypertension, and essential tremor. In sports, athletes whose sport requires control of anxiety and tremors, like archery, shooting, gymnastics, racing, and golf, use these drugs to control performance anxiety. In 2010, the WADA banned the use of β-blockers for these and all Olympic sports.
Preparations and dosages
•
Selective β-blockers bind to β1-receptors but not β2-receptors
○
Includes atenolol, bisoprolol, metoprolol, and esmolol •
Nonselective β-blockers bind to both β1-receptors and β2-receptors
○
Includes labetalol, sotalol, propranolol, timilol, and carvedilol
Physiologic and performance effects
•
Decreased anxiety and tremor
○
May have greater benefit to participants with less experience34
Adverse effects
Significant interactions with antidepressants, oral diabetes medications, β-agonists, and other classes of antihypertensives also occur (Table 5).
Table 5. Adverse effects of β-blocker use
Decreased performance in aerobic and anaerobic sport Fluid retention, especially in extremities Impaired glucose tolerance and poor glucose control Psychomotor slowing Heart failure Fatigue and drowsiness Bradycardia Heart block Dry mouth and eyes Hypotension Erectile dysfunction Dizziness Shortness of breath Peripheral arterial disease Weight gain
Data from Jonas AP, Sickles RT, Lombardo JA. Substance abuse. Clin Sports Med 1992;11:379–401.
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2.6.3.3 Human growth hormone
Recombinant human growth hormone was found to treat in children and adults whose pituitary glands are not enough to support normal growth and development (Von Fange, McDiarmid, Mackler, & Zolotor, 2008).
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Human growth hormone (GH) is a mixture of peptides, the major physiologic and bioactive component being a 22 kDa polypeptide chain of 191 amino acids secreted by the anterior pituitary gland (Godenberg and Barkan, 2007). In man GH is secreted episodically in a pulsatile fashion. The main regulatory hormones of GH are two hypothalamic peptide hormones: GH releasing hormone (GHRH) a 44 amino-acid peptide required for the initiation of GH pulses and somatostatin an inhibitory peptide which modulates the amplitude of GH pulses. However, several brain transmitter pathways as well as sleep and several other factors seem to be involved in GH regulation, suppressing or stimulating GH release by influencing GHRH or somatostatin (Godenberg and Barkan, 2007).
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Growth hormone
Human growth hormone (GH) is an endogenous peptide secreted by the anterior pituitary gland. It functions primarily in an anabolic way, increasing amino acid uptake and protein synthesis and supporting other growth-promoting functions. Much of the basic science of GH remains unknown. Secretion of GH is regulated by several factors, including GH-releasing hormone, sleep, exercise, l-dopa, and arginine [109,110]. No studies have revealed that GH increases performance; however, it does have a repartitions effect, which decreases subcutaneous fat, making individuals appear more toned [111–114]. High levels of GH can lead to myopathic muscle changes, water retention, and carpal tunnel syndrome [110,115]. Additional risks include premature physeal closure, jaw enlargement, hypertension, and slipped femoral capital epiphysis [116,117]. Severe but rare side effects include papilledema with intracranial hypertension [118].
In an American high school study by Rickert [119], 5% of the boys reported using GH, with ten students indicating explicitly that it was for improving sports performance. The latest NCAA study found that 3.5% of athletes reported using GH in the past 12 months [120]. GH is banned by all major sporting leagues; however, no reliable test to detect use by athletes has been developed.
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2 Growth hormone
Human growth hormone (GH) is a 191 amino acid protein consisting of several isoforms. The most abundant pituitary form has a molecular weight of 22 kDa. GH is stored and secreted by the somatotrophs in the anterior pituitary gland; secretion is stimulated by ghrelin and hypothalamic GHRH (Growth Hormone Releasing Hormone) and inhibited by somatostatin in addition to negative feedback by insulin-like growth factor I (IGF-I) [14]. GH is secreted in pulses, most of which occur during sleep; however, the size and the numbers of pulses are influenced by several factors, including age, gender, acute and chronic illnesses, stress, and nutrition [14,15]. The highest levels of GH are reached in puberty. After puberty, GH levels gradually decline with age, but GH pulses are present throughout life. Women have a higher level of baseline GH and more pulses than do men [14].
GH regulates the production of insulin-like growth factor-I (IGF-I), and together, GH and IGF-I promote longitudinal growth and have important metabolic actions throughout life [14–16]. GH induces a rapid and large increase in resting energy expenditure and fat oxidation resulting in increased protein and glucose synthesis [16]. Through its protein anabolic, lipolytic and antinatriuric effects, GH increases muscle mass and bone formation, reduces fat mass and increases total body water [17,18]. GH increases the peripheral conversion of T4 to T3 and cortisol to inactive cortisone [14] and it may increase insulin resistance and lead to hyperinsulinaemia [15,16]. Intracellular GH signaling is mediated by the GH receptor, a type 1 cytokine receptor [14], a single transmembrane receptor found on most cells in the body. The extracellular GH binding domain of the receptor is also found in the circulation where it serves as a GH binding protein (GHBP) [14]. The GH molecule has two receptor binding sites that bind a preformed receptor dimer, creating a conformation change in the receptor and triggering intracellular signaling and receptor internalization [19].
The majority of circulating IGF-I is produced by the liver. While IGF-I can be bound to 6 different binding proteins, IGFBP 1 to 6, which modulate the effects of IGF-I [20], it is primarily bound to IGFBP-3 and to acid labile subunit [6] in a heterotrimeric complex. This large complex does not leave the circulation and can be regarded as a reservoir of IGF-I. The receptor for IGF-I is found in all tissues, and like the insulin receptor, it is a tyrosine kinase receptor [20]. It consists of two ligand-binding units and has a double trans-membrane and a cytoplasmic portion. Hybrid insulin/IGF-I receptors are abundant in the liver.
The circulating IGF-I level is commonly used as a biomarker for GH activity in humans. While other factors, including hormones, nutrition and state of health can also modulate IGF-I levels, serum total IGF-I is currently the best available biomarker for GH activity. Free IGF-I and bioactive IGF-I are not routinely measured and their clinical utilities still need to be defined. Calculation of the ratio between IGF-I and IGFBP 3 has been used as an indirect measurement of the free fraction of IGF-I.
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Human growth hormone (GH) is a substance that affects many metabolic processes. It is secreted from the pituitary gland under the regulation of the hypothalamus. GH affects the metabolism of lipids, carbohydrates, and proteins in the body. In past years, this hormone was collected by harvesting cadaver pituitary glands. This process carried the obvious risk of transmission of viral or prion diseases. Today recombinant human growth hormone is used for supplementation.
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Human Growth Hormone
Recombinant human growth hormone (hGH) is FDA approved for growth-hormone deficiency in children and adults (74). It has been studied in off-label use as an adjunct to IVF in women with decreased ovarian reserve and a history of poor response to gonadotropin stimulation. One proposed mechanism of action in this setting is the stimulation of hGH on the ovarian production of the insulin-like growth factor-I (IGF-1), which stimulates follicular development, E production, and oocyte maturation (75). A meta-analysis found no evidence that GH helps improves live-birth rates in women who are undergoing ovulation induction before IVF, or in the general population of women undergoing IVF. The use of GH in women considered “poor responders” did significantly increase live-birth rates. The authors caution, however, that they were unable to identify which subgroup of poor responders benefited the most from adjuvant GH and therefore recommend that further research be performed before its use is adopted in standard practice (76).
Use of hGH is associated with many precautions and side effects. Precautions include malignant transformation of nevi, hyperglycemia, hypopituitarism, papilledema, acceleration of human immunodeficiency virus replication, and malignancy. Side effects include arthralgia, headache, peripheral edema, flu-like symptoms, and hypoesthesia (74).
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