Hsieh Wen-Tsong
CASE
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Tony is a good defensive lineman on a college football team and wants to do everything he can to increase his chances of being drafted into the National Football League (NFL). His older brother Ron has been encouraging him to use growth hormone. Ron claims it has helped him in his bodybuilding work; he tells Tony that since the substance cannot be detected, Tony need not worry. Tony would never use anabolic steroids, because he knows that not only are they easily detected, but that serious long-term consequences are associated with their use. Since he has not heard anything bad about growth hormone, he decides to try it. You discover several months later that he has been using growth hormone. What do you tell him?
CASE
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Tony is a good defensive lineman on a college football team and wants to do everything he can to increase his chances of being drafted into the National Football League (NFL). His older brother Ron has been encouraging him to use growth hormone. Ron claims it has helped him in his bodybuilding work; he tells Tony that since the substance cannot be detected, Tony need not worry. Tony would never use anabolic steroids, because he knows that not only are they easily detected, but that serious long-term consequences are associated with their use. Since he has not heard anything bad about growth hormone, he decides to try it. You discover several months later that he has been using growth hormone. What do you tell him?
COMMENT
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Even if there were no long-term health consequences (and there are!), Tony first needs to realize how serious an error in judgment he has made. Growth hormone is a peptide hormone and, as such, is banned by the NCAA. (National Collegiate Athletic Association) Association ) And even without this restriction, it is illegal to use a prescription drug outside of an appropriate medical need. Tony has broken the law. Unfortunately, these legal issues do not seem to deter overzealous athletes' from using drugs they believe will enhance performance. If that reasoning doesn't work with Tony, explain that although growth hormone may have helped his older brother in bodybuilding or body composition, it does not enhance athletic performance. Tony is risking it all for, no good reason whatsoever.
Introduction •
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How far have we come considering that the 1996 Atlanta Olympics were nicknamed the "Growth Hormone Games"? With better detection of anabolic steroids, many athletes quit using the steroids and began substituting GH, thinking that similar improvements in performance would occur. Abuse of agents like GH and erythropoietin (see chapter 9), because they are endogenous hormones, is very difficult for athletic officials to detect. The low number of positive tests for peptide hor-mones is likely a function of the inability to reliably detect abuse of these substances, and should not be misinterpreted as an accurate reflection of the prevalence of their use.
Endocrinology of HGH •
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In order to understand the rationale of human growth hormone replacement vs Secretagogue augmentation The hypothalamus is the primitive site of the brain that sends either stimulating or inhibiting hormones to the pituitary. Growth hormone stimulating hormone (GHRH) tells the pituitary gland to secrete more growth hormone (GH). On the other side, Growth Hormone Inhibiting Hormone (GHIH = Somatostatin) tells the pituitary gland to stop producing more GH.
Endocrinology of HGH •
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Once the pituitary receives the positive stimulating signal it then secretes GH which in turn stimulates the liver to produce IGF-1 (Insulin-like growth factor 1) . IGF-1 is also a more stable compound unlike true GH which has up to 5 spurts a day - the largest being just before sleep. If we were to measure GH directly it might show as too low or too high just because of the timing. Measuring IGF-1 circumvents this problem because of its more constant blood levels. Interestingly, both have distinct biochemical properties. Once the IGF-1 levels are high enough, a feedback message is sent back to the pituitary and the hypothalamus to modulate further GH secretion. This is accomplished by secreting more Somatostatin which then slows down GH production.
Regulation of growth hormone (GH) secretion in man.
Growth hormone deficiency in adults
Physiologic Effects of Growth Hormone •
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Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to tak e up and accumulate circulating lipids. Indirect effects are mediated primarily by a insulin-lik e growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.
Effects on Growth •
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Growth is a very complex process, and requires the coordinated action of several hormones. The major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth. Growth hormone does seem to have a direct effect on bone growth in stimulating differentiation of chondrocytes. IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
Metabolic Effects •
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Protein metabolism: In general, growth hormone stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins. Fat metabolism: Growth hormone enhances the utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes. Carbohydrate metabolism: Growth hormone is one of a battery of hormones that serves to maintain blood glucose within a normal range. Growth hormone is often said to have anti-insulin activity, because it supresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver. Somewhat paradoxically, administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemia.
Control of Growth Hormone Secretion •
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Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone. Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. Somatostatin inhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration. Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates secretion of growth hormone.
Disease States •
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Giantism is the result of excessive growth hormone secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes. One of the most famous giants was a man named Robert Wadlow. He weighed 8.5 pounds at birth, but by 5 years of age was 105 pounds and 5 feet 4 inches tall. Robert reached an adult weight of 490 pounds and 8 feet 11 inches in height. He died at age 22.
Disease States •
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Acromegaly results from excessive secretion of growth hormone in adults. The onset of this disorder is typically insideous. Clinically, an overgrowth of bone and connective tissue leads to a change in appearance that might be described as having "coarse features". The excessive growth hormone and IGF-I also lead to metabolic derangements, including glucose intolerance.
Somatrem and Somatropin •
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Growth hormone-specifically, human growth hormone (hGH), since the amino acid structure of GH differs among different speciesis an anabolic hormone that affects all body systems and is important in muscle growth. The endogenous hormone is composed of 191 amino acids. It is secreted from the anterior pituitary at a rate of 0.4-1.0 mg/ day in adult males, with higher rates in adolescents and females Originally, pharmaceutical companies produced GH injection from the pituitary glands of cadavers.
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The use of human cadavers for GH was discontinued in 1984 when this source was linked to the development of a viral disease known as Creutzfeldt-Jakob disease. In 1985, the first bioengineered version of hGH, somatrem (Protropin), was approved for use, although the endogenous hormone itself had been originally isolated in 1956 and its structure identified in 1972. In 1987, another recombinant product, somatropin, was released. Somatrem contains 191 amino acids, while somatropin contains 192. Several manu-facturers produce somatropin, and, as a result, it has been assigned multiple trade names in the United States: Genotropin, Humatrope, Norditropin, Nutropin, Serostim.
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Although hGH has a very limited use in clinical medicine, it is reportedly the most highly sought drug among athletes Because athletes believe hGH has anabolic properties, and because urine testing is an unreliable screen for hGH abuse, the use of hGH by athletes is on the rise (Mottram 1999). There are reports that athletes spend up to $30,000 per year to obtain hGH and use it in amounts 20-fold higher than recommended doses, but, unfortunately, the substance they receive in return may not even be hGH (Smith and Perry 1992). Since the legal distribution of hGH is tightly controlled, what is available on the black market may actually be human chorionic gonadotropin (HCG) or, in some cases, anabolic steroids. Other drugs and hormones can affect the production of endogenous hGH (see table 6.1). In addition to the interest in GH because of its use (abuse) by athletes, there is increasing interest in the role of GH in the elderly, specifically with regard to muscle strength, bone density, and body composition The clinical medicine uses of GH have been recently reviewed by Tritos and Mantzoros (1998). Other authors have reviewed the topic of GH in sports.
Table 6.1 Pharmacologic and Physiologic Agents That Affect hGH Production Stimulate output Bromocriptine Clonidine Corticotropin (ACTH) Estrogen Glucagon Levodopa Propranolol Vasopressin
Suppress output Beta-2 receptor agonists (i.e., isoproterenol) Corticosteroids Cyproheptadine Imipramine Octreotide Phenothiazines Phentolamine Progesterone
How Exercise Affects the Action of Growth Hormone •
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It is known, how-ever, that exercise stimulates endogenous hGH output acutely. This has been reported in both males and females, and after both resistance exercise and aerobic exercise, such as treadmill running (Bunt et al. 1986). There is some evidence (see figure 6.2) that hGH output is related to intensity of resistance exercise. Obesity (Kana ley et al. 1999) and advanced age (Zaccaria et al. 1999) attenuate exercise-induced increases in GH output, although GH levels have been documented to increase substantially in elderly men immediately after resistance exercise . Women who take oral contraceptives have an increased response (Bernardes and Radomski 1998).
Figure 6.1 Alteration of growth hormone concentrations before, during, and after resistive exercise. Results are corrected for plasma volume change. Values are mean + SEM; n = 8. * = P < 0.05 compared with -10 value. BP = bench press; LP = leg press; LE = leg extension; LC = leg curl.Adapted from Kraemer et a1. 1992.
How Growth Hormone Affects Exercisers •
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Growth hormone really works quite differently than anabolic steroids do: GH causes hyperplasia (i.e., increased cell number), whereas ana-bolic steroids tend to cause hypertrophy of some tissues. Growth hormone facilitates the transport of amino acids across the cell membrane, which results in increased amounts of RNA, ulti-mately leading to increased protein synthesis. The effects of GH on skeletal muscle are thought to be mediated through the effects of insulin like growth factor (IGF-l) activity (Kraemer et al. 1992). While many of the effects of anabolic steroids wear off after use is discontinued, with GH the effects persist. When endogenous GH levels are excessive, a condition known as acromegaly results. Acromegaly is associated with left ventricular hypertrophy and a diminished exercise capacity.
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In contrast to the data that indicate widespread use of GH by athletes, data regarding the effects of hGH on the physiology of exercisers and athletes are somewhat limited. Administration of GH has been shown to decrease body fat and produce significant increases in fat-free mass in weightlifters (1988), healthy normal subjects, elderly subjects, and GH-deficient subjects Oorgensen et al. 1996). Other investigators have found that body composition changes during weight training with hGH are not different from changes during weight training without hGH. Although the physiologic effect of GH is anabolic, Yarasheski and colleagues reported that a 14-day regimen of GH did not augment muscle protein synthesis in 7 power athletes currently enrolled in a weight-training program (Yarasheski et al. 1993), and 16 weeks of GH did not augment improvements in bone mineral density related to weighttraining in elderly subjects. Cuneo and colleagues showed that exogenous hGH improved VO2max (oxygen uptake) measured via cycle ergometry, but they studied GH-deficient subjects, not athletes.
Table 6.2 FFW, % Fat, and FFW/FW in Subjects Before and After Six Weeks Treatment With Placebo and Met-hGH During Weight Training
* Significant difference between pre- and posttest means (p < 0.05) Values are means + SE; n = 8 subjects. FFW = fat-free weight; % fat = percent body fat; FFW /FW = ratio of fat-free weight to fat weight; met-hGH = methionyl-human growth hormone.
How Growth Hormone Affects Exercise Performance •
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Administration of GH to individuals who produce inadequate endog-enous quantities has been associated with an improvement in exercise performance; however, GH does not appear to be ergogenic in subjects who are not GH-deficient. A human's lack of endogenous hGH pro-duces a condition known in clinical medicine as dwarfism, and supple-mentary hGH corrects the diminished growth rate in people having this condition. In GH-deficient adults, muscle mass, muscle strength, and exercise performance have all been shown to improve after hGH supplementation. Cuneo and colleagues showed that hGH im-proved muscle strength in hip flexors in GH-deficient adults but not in any of the other eight muscle groups tested, and they concluded that these patients may have a proximal myopathy. Thus, data obtained in GH -deficient subjects should not be extrapolated to subjects who are not GH-deficient.
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When non-GH-deficient subjects are studied, regardless of their level of fitness, the combination of GH plus weight training does not produce further improvements in muscle strength over weight training alone. This has been documented in male power athletes and healthy untrained males. When elderly subjects were studied, GH was not shown to improve muscle strength regardless of whether GH and weight training began simultaneously or if, instead, GH was added after several months of weight training had already occurred (Taaffe et al. 1994). Even when GH was given to elderly subjects in the absence of weight training, no improvements in muscle strength were seen (Papadakis et al. 1996). To summarize, while GH produces a generalized anabolic action on many tissues of the body, its actual anabolic and lipolytic actions in adults depend on the preexisting state of GH output and amount of body fat. Regardless of its physiologic actions and effects on body composi-tion, GH does not augment improvements in muscle strength more than the response from weight training alone.
Table 6.3 Effect of Growth Hormone on Muscle Strength Response to Resistance Exercise Exercise + placebo Exercise
Exercise + GH
Delta
% change
Delta
% change
Shoulder press
5.3 + 0.5
53 + 6
6.5 + 0.9
60 + 10
Bench press
6.1 + 0.7
43 + 6
6.2 + 1.3
43 + 11
Deltoids
4.4 + 0.5
47 + 7
4.5 + 0.4
50 + 6
Bicep curl
4.4 + 0.3
36 + 3
4.2 + 0.6
33 + 4
Latissimus
6.5 + 0.4
59 + 5
6.3 + 0.5
60 + 8
Flys
6.5 + 0.4
73 + 8
6.4 + 0.5
66 + 10
Knee extension
9.7 + 0.9
63 + 10
8.8 + 1.2
65 + 16
Leg press
4.9 + 0.7
26 + 4
4.8 + 0.5
34 + 5
Knee flexion
4.1 + 0.4
47 + 8
5.0 + 0.8
71 + 17
Average
5.8 + 0.6
50 + 4.8
5.9 + 0.5
54 + 4.7
Values are means + SE. Final strength score greater (p < 0.01) than initial for all exercises in both groups. Delta scores represent absolute increase in number of 4.5 kg weights lifted. Average and individual delta and % change scores were not different between groups.
Avoiding Potential Complications •
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Whereas androgenic-anabolic steroids (AASs) stimulate the growth of only muscle, hGH stimulates the growth of all tissues, including internal organs. Even more worrisome, while some of the effects of AASs are reversible, the effects of long-term administration of hGH are not. Acromegaly is a syndrome affecting many organ systems as a result of overproduction of endogenous hGH. The disease affects the skeleton, soft tissues, heart, glucose metabolism, and sexual function, and it can cause hypertension. Acromegaly is irreversible, and individuals with the condition typically die by the sixth decade of life. Further, acromegalies have been shown to develop left ventricular hypertrophy and have a diminished exercise capacity.
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Although the effects of long-term, exogenous hGH are not clear, it seems likely that many of these same consequences would occur. In several studies of non-GH-deficient subjects, carpal tunnel syndrome and pain and edema of the fingers were reported in several subjects in the active drug group. Individuals with acromegaly are noted to have thick hands and fingers. Is carpal tunnel syndrome a warning that anatomical changes similar to acromegaly are occurring? Even without the health consequences associated with the use of hGH, athletes risk disqualification and, worse, arrest for illicitly using a prescription-only drug. Further, since hGH is administered only by injection, sharing needles is still another risk-and another reason to avoid abusing this drug.
NCAA •
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and USOC Status Since it is a peptide hormone, hGH (or GH from any animal source) is banned by both the NCAA and the USOC. In his book Drugs, Sport, and Politics (1991) Robert Voy, MD and former chief medical officer for the USOC, has summarized many of the issues of hGH abuse by athletes and what should be done to stop the overuse. IOC Banned Drugs 2004 2005
