ANABOLIC AGENTS

SPORTS PHARMACOLOGY

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ANABOLIC AGENTS James E. Sturmi, MD, and Douglas J. Diorio, MD

Athletes of all types continuously strive for competitive advantages. Today’s society encourages winning above sportsmanship and fair play. Unfortunately, the desire to ”win at all costs” has fostered an unprecedented demand for ergogenic drugs. A recent poll” of 198 current or aspiring US Olympians proposed two scenarios: Athletes were asked whether they would take a banned performance-enhancing substance if they were guaranteed to win and not get caught . . . 98% said, ”yes”!! In the second scenario, the athletes were asked if they would take the same undetectable substance if it would contribute to winning every competition for 5 years, then result in death . . . more than 50% still said, ”yes”!!! This poll, although limited by sample size and the type of athlete surveyed, is quite illustrative. The epidemic use of performance-enhancing drugs reflects the coercion pressure felt by many athletes at many levels. Athletes are, by their very nature, competitive. As opponents begin to use drugs to improve their performance, so will previously “clean” athletes. A culture of underground chemists, suppliers, detection-avoidance advisors, and ”better than ever” but less detectable substances has thus gained acceptance among athletes. Like it or not, this trend is not likely to change. The use of ergogenic substances is now common among age groups and sports that were previously untainted. This article reviews four current anabolic agents: dehydroepiandrosterone, anabolic-androgenic steroids, human growth hormone, and insulinlike growth factor. A summary of basic chemistry and physiology,

From the Department of Family Medicine, Division of Sports Medicine, and the Ohio State University Athletic Department, Ohio State University, Columbus, Ohio

CLINICS IN SPORTS MEDICINE VOLUME 17 NUMBER 2 APRIL 1998

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effects and function, performance effects, clinical and athletic uses, side effects, cost, and availability is presented.

DEHYDROEPIANDROSTERONE Basic Chemistry and Physiology Dehydroepiandrosterone (DHEA) is a hormone produced by the zona reticularis cells of the adrenal glands. It was first identified in 1934 and serves as a precursor to the endogenous production of both androgens and estrogens in DHEA and DHEA sulfate (DHEA-S) both circulate in the blood bound mostly to albumin and are easily interconverted. Both are physiologically active and can be converted peripherally to androstenedione, testosterone, and dihydrotestosterone. In addition, DHEA and DHEA-S can be aromatized to estrogens.62Factors that influence these conversions are not well established. Serum levels of DHEA and DHEA-S have been shown to decline with age to less than 20% of young adult levels by the Sth to gth decades, thus prompting its promotion as the “fountain of youth.”13,45 In one large French study, DHEA levels were found to be 30% to 50% higher in men.13Natural sources of DHEA include wild yams.7

Effects and Function The exact mechanism by which DHEA exerts its effect on the human body is not well known. As precursors to anabolic-androgenic sex hormones, the effects of natural and supplemented DHEA are presumed to be those of testosterone analogues: stimulation and maintenance of protein anabolism (growth) of most body tissues and development and maintenance of secondary sexual characteristics. DHEA has been shown to stimulate human osteoblasts in vitro, although not as effectively as dihydrotestoster~ne.~~ Other possible effects are discussed further under anabolic steroids. The degree of anabolic/androgenic effect on different individuals and different tissues is subject to many variables, including the specific hormone, age, gender, training, nutrition, genetics, and other factors. In addition to possible effects noted above, DHEA may also increase levels of bioavailable insulinlike growth factor 1 (IGF-1),which has been shown to facilitate the passage of glucose and other body fuels into the intracellular compartment. IGF-1 is presented in detail later. Finally, it has been suggested that DHEA might have a direct stimulatory effect on neurotransmitter re~ept0rs.l~

Clinical Uses Some theoretic uses of DHEA include attenuation of the effects of aging and maintenance of bone mass. Whether DHEA can stimulate

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osteoblasts in vivo remains to be proven. This certainly raises the possibility that declining DHEA levels with aging may contribute to agerelated losses in bone density. If such an effect could be shown, supplementation of DHEA in patients with osteoporosis or Paget's disease might prove beneficial. In Berr and associates13 study of older patients in France, DHEA levels declined with age and were lower in women with functional limitations, confinement, depressive symptoms, dyspnea, and usage of some medications. The same study reported similar correlations in men without statistical significance. The authors also reported an inverse relationship between levels of DHEA and short-term m0rta1ity.I~Another study showed significantly lower levels of DHEA in patients with Alzheimer's and cerebrovascular dementia versus age-matched controls but no differences in patients between the two types of dementia.lo5 Further prospective, controlled studies are needed to delineate possible causal relationships and clinical applicability of these findings. Athletic Uses

The number of athletes who supplement with DHEA is unknown. Since it was banned by the Food and Drug Administration in 1996, DHEA has been scrutinized carefully but is still readily available as a nutritional supplement. Although its effects on strength and performance in athletes remain unstudied and unproven, the theoretic benefits are probably attractive to many athletes. Its effect on young, healthy individuals (i.e., those with higher baseline DHEA levels) has not been studied. In older adults, two studies have shown significant increases in androgenic steroid plasma levels and subjective improvements in physical and psychological well-being with supplements of 50 mg/day" and 100 mg/day.lo8Assuming most athletes believe in the "if one is good, 10 are better '' philosophy, it is logical to assume that supplementation with 150 to 1000 mg/day or more would not be unusual. The cost for such a regimen would range from $0.67 to $1.34 per day7 Side Effects

Users of DHEA report few adverse effects. Most of them are secondary to androgen excess. These are discussed under anabolic-androgenic steroids later. It is also very possible that athletes may combine DHEA with other supplements or ergogenic aids. Notably irreversible side effects include virilization in women (hair loss, clitoromegaly, hirsutism, voice-deepening) and gynecomastia in men.' Long-term adverse effects are yet to be determined. Armsey and Green7 propose that unopposed prolonged estrogen and testosterone may increase the risk of uterine and prostate cancers, respectively. A recent review of published literature on the possible relationship

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between DHEA and coronary heart disease (CHD) risk concluded that there is either a neutral or favorable effect of testosterone and DHEA on CHD in males? A subsequent Japanese study showed a positive correlation between high density lipoprotein cholesterol (HDL-C) and DHEA levels and a negative correlation with low density lipoprotein cholesterol (LDL-C).jr3A larger, prospective study with control of other cardiac risk factors would be very helpful in determining what, if any, relationship exists between DHEA, human lipid profiles, and CHD risk. Until further studies are completed, DHEA should be considered unproven. Legal and Ethical Issues

DHEA is yet another agent in a long line of substances ingested to enhance performance. Despite its status as a ”nutritional supplement,” it may function as an anabolic-androgenic agent in some people. DHEA is not currently tested for; however, its testosteronergic qualities could conceivably alter a urine drug screen testosterone: epitestosterone ratio. This could place the using athlete at risk for disqualification. Unfortunately, the threat of such sanctions probably have little deterrent effect on potential users. ANABOLIC-ANDROGENIC STEROIDS Basic Chemistry and Physiology

Anabolic-androgenic steroids (AAS) are natural and synthetic compounds that are structurally similar to cholesterol. Testosterone, the ”prototype” steroid, is the human male gonadotrophic hormone. All other AAS are structurally derived from it, either naturally or synthetically. Testosterone is secreted primarily by the Leydig cells of the testis (95%) under the influence of leutenizing hormone (LH) from pituitary gland. Follicle-stimulating hormone (FSH) may augment this secretion via up-regulation of LH receptors on Leydig cells. Both FSH and LH secretions are controlled by gonadotropin-releasing hormone (GnRH) from the hypothalamus. Testosterone production and exogenous administration both inhibit further production of GnRH, FSH, and LH.46 The balance of endogenous testosterone comes from the adrenal cortex or testicular conversion from androstenedione.%,61 The human testes and adrenals, under normal circumstances, secrete 4 to 10 mg of testosterone and 1 to 2 mg of androstenedione per day in a cyclical fashion. Women secrete 0.04 to 0.12 mg testosterone and 2 to 4 mg androstenedione per day from their ovaries and adrenals.46,92 The daily production of androgens can be negatively affected by physical stress, emotional stress, alcohol consumption, and marijuana use. The natural effects of testosterone and its analogues on the body include both anabolic and androgenic effects. Anabolic effects occur in

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nonreproductive tissues and include an increase in muscle mass; acceleration of bone growth before epiphyseal closure in adolescents; increase in bone density; increase in heart, liver, and kidney size; stimulation of erythropoiesis; laryngeal enlargement and vocal cord thickening; decrease in body fat; and the development of sexual drive and potency.46, 57, 85, 92, lol These effects are seen in both men and women. Androgenic effects are those that reflect the development of sexual characteristics and reproductive ability in males: spermatogenesis; changes in genital size and function; axillary, facial, and pubic hair.46,85, 92 Significant energy has been spent in trying to develop ”designer steroids” with minimal androgenic and greater anabolic effects. Such a task, however, has proved quite formidable and is probably physiologically impossible. At the cellular level, steroid hormones readily pass through the cell wall of the target tissue, bind with specific steroid receptors, move to the nucleus where they attach to nuclear chromatin, and stimulate specific messenger RNA by transcription. Ribosomal translation then results in new proteins that mediate the hormone’s This nature and quantities of proteins produced will vary based on the type of tissue and its sensitivity to the hormone. There also appears to be a significant anticatabolic effect from AAS. It has been reported that AAS directly block or displace cortisol from 85 This prevents cortisol, which glucocorticoid receptors within the is secreted in response to the physical stress of intense and frequent workouts, from exerting its catabolic effect within the tissue. The potential benefit of this is obvious: more rapid recovery time resulting in longer or more intense training sessions. HaupP7 has suggested that this effect may actually be the most significant mechanism by which athletes gain competitive advantages from AAS.47 Another mechanism by which AAS are thought to work involves the central nervous system. Changes in the CNS from AAS may have a direct effect on the neural control of muscle work or perhaps an indirect effect from stimulated aggression leading to increased workout intensity.60Finally, the placebo effect has been demonstrated in one small study of athletes on methandrostenolone.6 It is likely that each of these mechanisms contributes to the clinical effects seen in athletes on AAS. Pharmacology

In unmodified form, testosterone is rapidly cleared by the liver. Active metabolites of testosterone include dihydrotestosterone, androstanolone, estradiol, androsterone, androstenedione, and others.” Modification of the testosterone molecule is designed to prevent its metabolic degradation and therefore prolong or enhance its tissue effects. There are more than 1000 different testosterone derivatives that have been prepared, some to minimize androgenic side effects and many to avoid detection on urine drug screening.”,85 Alkylation of testosterone at the 17-alpha-hydroxy position results in oral preparations that are quite

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active and retard hepatic degradation.@,85 Esterification of testosterone at the 17-beta-hydroxy position increases the lipophilic properties of the androgen and slows its absorption. Longer carbon chains in the ester result in increased lipid solubility and therefore even longer absorption and clearance times.85Some common oral and injectable AAS are listed in Table 1. Each has its own characteristic efficacy and side effect profile. The individual's response to each drug or combination of drugs is quite variable, and often guided by a "coach or self-defined "expert" in ergogenic aids."

Clinical Uses AAS have relatively few therapeutic uses. They were developed for the treatment of refractory anemias, hereditary angioedema, osteoporosis, certain types of breast cancer, and cachexia associated with trauma, bums, or terminal illness. Their most practical clinical use is congenital hypogonadism. In most cases, testosterone or one of its analogues is prescribed in physiologic replacement doses, 2 to 10 m g / d a ~ .83~ ~ ,

Athletic Uses For many years, the medical community contended that AAS simply did not work. Athletes' personal experiences and observations suggested otherwise. As the use of AAS became widespread during the 1970s and

Table 1. COMMON ORAL AND INJECTABLE ANABOLIC-ANDROGENIC STEROIDS Trade Name(s) Oral

Injectable

Dianabol Dianabol Anavar Androyd Androl Winstrol Maxibolin Metandren Oreton methyl Halotestin Deca-durabolin

Durabolin Delatestryl Depo-testosterone Bolfortan Oreton Primabolin-depot Data from references 43, 57, and 85.

Chemical Name(s) Methandrostenolone Methandienone Oxandronone Oxymethalone Oxymethalone Stanozolol Ethylestrenol Methyltestosterone Fluoxymesterone Nandrolone decanoate Nandrolone phenylproprionate Testosterone enanthate Testosterone cypionate Testosterone nicotinate Testosterone proprionate Methenolone enanthate

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1980s,lo9the scientific community was forced to look at the ovemhelming anecdotal and observational evidence that AAS: Increase strength Increase weight Increase aggressiveness Allow faster recovery time from repetitive, high-intensity workouts Enhance performance These are clearly the reasons why athletes use AAS. Each has been debated and studied extensively with variable results. Elashoff and colleagues35published a critical analysis of the literature to determine whether or not AAS contributed to strength gains and concluded that they ”may slightly enhance muscle strength in previously trained athletes.” Several recent reviews suggest that previously inconsistent studies were affected by lack of dietary and other controls, inadequate doses of AAS, variability in research design, lack of blinded observation, 47* 57, 60, 83* 85, ll1 and other significant methodological To further debate and study this fundamental issue would waste valuable resources. The American College of Sports Medicine, though discouraging their use, acknowledges the following: “AAS, in the presence of an adequate diet, can contribute to increases in body weight, often in the lean mass compartment” and ”the gains in muscular strength achieved through high-intensity exercise and proper diet can be increased by the use of AAS in some individuals.” It is generally accepted that adequate protein intake and high-intensity strength training in previously trained individuals are required for these gains to be 60, Several other variables may impact the clinical effects reali~ed.4~. of AAS supplementation: training intensity and experience, diet, drug dosage(s), duration of drug use, number of drugs used, and individual variables (genetics). Although AAS stimulate erythropoiesis, scientific evidence supporting increased aerobic capacity and improved endurance is limited and inconclusive. Despite some evidence that indirect measurement of VO, max may be enhanced in males on AAS, the direct effect of AAS on aerobic capacity and endurance has not been determined. The American College of Sports Medicine states the following: ”anabolic-androgenic steroids have no positive effects on aerobic perf~rmance.”~ With a large number of endurance athletes currently using AAS, this represents an area of great interest and potential further research.60,l I 2 Athletes commonly use AAS over 6- to 12-week ”cycles.” During these periods, the athletes use an average of five different AAS, both oral and injectable, at the same time.lo1This process is referred to as ”stacking.” The rationale for stacking is to theoretically activate multiple steroid receptor sites, although there is no scientific basis for this practice. Another common practice is overlapping cycles/drugs to avoid “plateauing,” developing tolerance to a particular drug. Many athletes actively cycle in the off-season to avoid detection. Dosages used during

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cycles may approach 40 to 100 or more times the medical replacement dosages!85, The highest dosages have been reported in bodybuild93, Steroids are also often combined with other types of drugs ing.92* including the following: Human growth hormone (hGH)-for synergistic anabolic effects Human chorionic gonadotropin-to block testicular effects Stimulants-for increased workout intensity and drive Diuretics-to counteract water retention and promote the "ripped" look Anti-estrogens (e.g., Tamoxifen)-to block gynecomastia Anti-acne medications-to counteract the severe acne in some users It is clear that such combinations and practices present a very real challenge to the physicians responsible for the care of athletes. Despite the development of a strong underground infrastructure, deadly combinations of these drugs do occur.15,95, 114 Although rare, the risks of adverse events are probably greatest in those athletes who use multiple substances at once and combine them with other self-destructive behaviors.15, 21,94,95, 113 The history of AAS abuse dates back many years. Comprehensive reviews are available for the motivated reader.&* Eastern Bloc Olympians (powerlifters) were probably the earliest consistent users in the early 1950s. As subjective and objective evidence of its effectiveness became apparent, AAS use spread rapidly throughout Olympic strength sports, the National Football League, and into other sports and levels of competition. The International Olympic Committee (IOC) banned AAS use in 1975 and first started urine drug testing in 1976. The National Collegiate Athletic Association (NCAA) started testing in 1986 and now has a comprehensive program for its member institutions. There is evidence of AAS use in high school football players as early as 1959 and widespread use into other sports by the late 1980s. The use of AAS by adolescents has sparked public interest and awareness. It is now generally accepted that the use of AAS is a significant and rapidly accelerating problem, particularly among adolescents.21,lol, Surveys show that AAS use patterns (incidence, demographics, age at first use, etc.) vary by sport, level of competition, and perceived risk of retribution. Several recent original studies and quality review articles are available for the interested reader.21, 29, 44, sa, 66, 79, lol, lo4, A brief summary of pertinent facts includes the following: More than 1,000,000 Americans, 250,000 of them adolescents, either use or have used AAS.lol Five percent to 11% of high school males and 0.5% to 2.5% of females have used AAS.lol, More than half of these students initiate use before their 16th birthday.lol

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More than one third of high school users are not active in school sports.104 Adolescent AAS users appear to be at risk for prolonged, heavy use.'O' Four percent of seventh graders in one study had used AAS.79 Most high school users are "not afraid" of AAS side effects/ health risks.lM There is a strong correlation between AAS and other drug use.79,96,104 Approximately 5% to 14% of NCAA athletes have used AAS.66,110 AAS use in college athletes is rising in women and Division I1 and I11 athletes.% AAS use among community weight trainers is approximately 15%." AAS use in elite and professional athletes; bodybuilders may be 30% to 75%.'*, 29, 57, 64 These facts underscore the importance of a thorough understanding and heightened awareness of AAS for all health professionals. Strength athletes (football, wrestling, powerlifting, sprinting, field events) probably use higher doses and expect slightly different results than endurance athletes (distance running, swimming, cycling). It is also very likely that adolescent users, particularly young males, aim for changes in physique and subsequent improved self-esteem as primary goals of use.'04 Side Effects

The physical side effects of AAS use have been historically over85 Fortunately, most of them are minor and reversible stated (Table 2).41,60, following cessation of use. Irreversible side effects, such as gynecomastia, can be surgically corrected.*O Long-term side effects are not well established, and prospective, controlled studies to assess relative health risks among users are methodologically impossible. Perhaps greater overall risks are associated with use of multiple substances, association with other high-risk behaviors, and the psychiatric/psychologic manifestations of AAS use. A comprehensive review of side effects and scrutiny of their scientific validity is beyond the scope of this article. The interested reader is encouraged to pursue reviews by FriedlQ 41 and Stone and Wright.92 Areas where further research may provide valuable information include 53 thromrelative risks of myocardial infarction? 49 myocardial bogenic CVA,37and tumorgenesis. Legal and Ethical Issues

The abuse of AAS is forbidden by major medical and athletic organi~ations.~, 5, 12, Many sports administrative bodies (National Foot-

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Table 2. SIDE EFFECTS OF ANABOLIC-ANDROGENIC STEROIDS Genitourinary Males Azoospermia Oligospermia Decreased testicular size Females Menstrual irregularities Clitoromegaly Masculinization Both Infertility Libido changes Decreased FSH, LH, GRH, testosterone Decreased sex-hormone binding globulin Increased estradiol > gynecomastia Gastrointestinal Hepatocellular insufficiency (increased LFTS) Cholestatic jaundice Peliosis hepatis Hepatocellular adenoma Hepatocellular carcinoma Cardiovascular Decreased HDL cholesterol Decreased apolipoprotein A-1 Elevated blood pressure; hypertension Myocardial changes

Endocrine Hypothyroidism Glucose intolerance Hyperinsulinism Hematologic Erythrocytosis Reduced serum immunoglobulins Reduced natural killer cells Hemostasis > thrombogenesis Dermatologic Acne Alopecia Musculoskeletal Premature physeal closure Collagen dysplasia > ? tendon weakness Psychiatric/psychological Mania, hypornania Major depression Aggression Mood swings Addiction

Data from references 6-10, 16,18,19,27, 37,3941,50,59,60,69,71,77,78,82,87,92,97,

98,112.and 113.

ball League, National Basketball Association) and individual universities also have deterrence/detection programs. Each has its own strengths and weaknesses. Unannounced random urine testing using strict chainof-custody protocols is required for results to withstand legal challenges (which has become all too common). Gas chromatography/mass spectroscopy is the current ”gold standard” technique for sample assay of AAS. Its sensitivity and specificity is greater than 99%. As the use of AAS spread during the 1980s, concerns about side effects and purity also escalated. This resulted in passage of the Anabolic Steroids Control Act of 1990, which made it a felony to possess or distribute AAS for nonmedical purposes. Detection of AAS abuse depends on timing, dosage, and properties of substances used. Legal and deterrence efforts continue to be met with resistance from athletes.

INSULINLIKE GROWTH FACTOR Basic Chemistry and Physiology

IGF-I is a single-chain 70 amino acid polypeptide that is indirectly responsible for most of the growth-promoting effects of hGH. Most IGF

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is produced in the liver although most tissues in the body are able to make IGF. IGF acts via multiple mechanism^.^^ Human growth hormone is the primary stimulus for IGF release and can trigger an increase in IGF levels 3 to 6 hours after endogenous secretion. Peak levels of IGF are found 16 to 28 hours after GH is secreted. Several IGF binding proteins have been identified, and each alters the bioavailability of IGF in a unique fashion. IGF is responsible for most growth-promoting effects of hGH. After binding to an IGF receptor, IGF will stimulate protein synthesis, which results in a positive nitrogen balance; increase glucose uptake; increase amino acid uptake; and inhibit apoptosis (programmed cell death). These functions have been shown to occur in many cell lines including fibroblasts, smooth and skeletal muscle cells, keratinocytes, neuronal cells, chondrocytes, osteoblasts, hematopoietic cells, epithelial cells, and 31*91 many cancer cell lines.24* Many factors regulate the production of IGF. Exercise has been shown to increase hGH levels, but its effect on circulating IGF has not been completely established. Some studies show a transient increase in IGF during exercise,2O. 89 whereas others demonstrate no such effect.56,67 Measured IGF levels 24 hours after exercise show no significant delayed 56 Hepatic secretion of IGF may not respond to exercise increases.20* owing to inadequate hGH stimulation. Other factors, such as hypoglycemia, may inhibit IGF production. Finally, IGF may be stimulated in specific tissues and exert its effect locally." Nutritional status can also influence the release of IGF in most tissues. Low IGF levels are found in malnourished individuals and may not respond to hGH stimulation, particularly in the presence of protein 67,99 Other factors cause tissue-specific IGF release. Thyroiddepletion.31* stimulating hormone stimulates IGF release in thyroid tissue, whereas parathyroid hormone stimulates IGF in cartilage. Follicle-stimulating hormone causes IGF production in ovarian granulosa and testicular Sertoli cells, whereas estrogen causes IGF production in the uterus. IGF is also present in the brain and stimulates cellular proliferation during 31 IGF has a negative feedback on the production of times of hGH and growth hormone-releasing hormone. Many other factors regulate IGF on the tissue-specific level, most of which are not completely understood. Effects and Function

IGF is essential for neonatal and postnatal development. In addition to its primary role as mediator of hGH function, IGF's independent actions include reduction of protein degradation and stimulation of cell proliferation.86Chondrocyte extracellular matrix proteins, such as collagen and ground-substance proteoglycans, are stimulated by IGF. Progesterone secretion in ovarian cells, testosterone secretion in Leydig cells, and ACTH receptor production are also promoted by IGF. Animal

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studies suggest that IGF supplementationpartially reverses the catabolic effects of glucocorticoids, nutritional deprivation, and acute ischemic renal failure.31*42 Finally, IGF plays a role in regulating renal function by increasing glomerular filtration rate and renal plasma flow in humans." In contrast to growth hormone, IGF does not have hepatocyte or adipocyte receptors. IGF does, however, enhance lipolysis indirectly via insulin suppression and may also increase the basal metabolic rate.= Insulin suppression results in enhanced lipid oxidation, reduced protein oxidation, and an increased availability of free fatty acids as fuel. Furthermore, IGF has been shown to improve lipid profiles in both healthy and nonhealthy subjects by reducing triglycerides, very low density lipoproteins, low density lipoproteins, and lipoprotein A.Q 51 Finally, IGF may also be linked to tumorgenesis. Increased number of IGF receptors have been found in tumors of the lung, breast, and in Wilms' tumor of the kidney31 Side Effects

Exogenous administration of IGF administration may predispose the individual to the clinical syndrome of acromegaly. In addition to musculoskeletal changes (discussed in the section on "Growth Hormone," later), organomegaly of the spleen, kidney, and thymus may occur although this has not established in humans.", 31 An IGF-using individual with significant adenoidal hypertrophy requiring adenoidectomy has been d e ~ c r i b e dOther . ~ ~ side effects that have been reported include headache, snoring, jaw pain, dyspnea, myalgias, back pain, and edema of the hands, face, and forearm.5l A common side effect of IGF is hypoglycemia. Like insulin, IGF causes a shift of glucose into cells thus lowering plasma glucose. Insulin receptors can also bind IGF but with much less affinity than insulin. Overall, insulin is 10 times more potent at inducing hypoglycemia than IGF. When exogenous IGF is given, it is readily available to all tissues because of increased bioavailability and 42, 51 Other potential risks include hepacan cause severe hypogly~emia.~~, titis and HIV from needle sharing. The risk of antibody formation to IGF is also a possibility. Clinical Uses

Food and Drug Administration-approved clinical uses of IGF-I include Larontype dwarfism and type A insulin resistance syndrome. In Larontype dwarfism, growth hormone receptors are nonresponsive to GH but do respond to IGF with longitudinal bone growth and weight gain.42,51 Type A insulin resistance syndrome is a rare condition that is treated with IGF in Japan.42, 51 Other possible clinical applications of IGF include increasing stroke volume,34growth hormone deficiency in children who have developed an antibody to the recombinant GH42;

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reduced insulin levels and glucose tolerance in noninsulin-dependent diabetics51; and some cases of resistant insulin-dependent diabetes.42,51 By enhancing renal plasma flow and glomerular filtration rate, IGF may prevent or delay the need for hemodialysis. Investigational uses include severe catabolic states (including AIDS), treatment of osteoporosis, ath42, 51 erosclerosis, neuropathies, and o~teoarthritis.~~, Athletic Use

Injectable recombinant IGF shares many effects with human growth hormone (hGH): increased protein synthesis, decreased protein catabolism, and enhanced lipolysis. These potential benefits are particularly attractive to elite athletes. Like hGH, IGF is not detectable with current screening methods which further supports its abuse potential. Athletes may stimulate endogenous IGF indirectly via abuse of hGH. Like hGH, use of exogenous recombinant IGF requires intramuscular injections. Because IGF is one of the newest performance enhancing agents, very little is known about its abuse patterns, availability, cost, and long-term side effects. A general lack of knowledge also exists among athletes, including those who use it. In one survey of 189 bodybuilders and weight-lifters with previous ergogenic drug use, 85% had heard of IGF and 14% had used it. Thirty-seven percent of the IGF users could not answer simple general questions about IGF.74The cost of IGF is similar to GH ($3,000 per month or more), and counterfeit products are a significant problem. Like growth hormone, IGF does not promote virilization, which makes it attractive to female athletes. There are no studies that have determined the effects of IGF on strength, aerobic capacity, body mass, or performance in athletes. HUMAN GROWTH HORMONE Basic Chemistry and Physiology

hGH is a single-chain polypeptide composed of 191 amino acids. It is produced by somatotrophic cells in the anterior pituitary. After release from the pituitary, it is bound to a carrier protein in the blood. This carrier protein is specific for hGH and is part of the receptor mechanism that allows hGH to bind to tissues.@Growth hormone acts on different tissues to create protein anabolism, carbohydrate tolerance, lipolysis, natriuresis, and bone and connective tissue turnover.’06Growth hormone also causes the release of IGF from the liver and other tissues. The plasma half-life of hGH is 17 to 45 minutes and it is metabolized in the liver.65 The pulsatile release of growth hormone is controlled by many factors including diet, exercise, nutrition, stress, drugs, and feedback mechanisms. The largest release occurs approximately 1 to 2 hours after

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the onset of sleep.68,93 The hypothalamus produces growth hormonereleasing hormone and somatotropin release-inhibiting hormone, which regulate the release of hGH.26Negative feedback on the hypothalamus and pituitary occurs when blood levels of hGH or IGF increase. Other factors that suppress hGH release include hyperglycemia and hypothermia. Multiple pharmacologic agents can increase or decrease hGH and are listed in Table 3. Many stimuli can increase growth hormone secretion. Several studies have demonstrated that exercise increases the hGH level in the bl00d.l~~ 26, 56* 65, 91, lo6 This effect continues into the later decades of life despite natural declines in hGH with advancing Exercise intensity is directly proportional to the quantity of hGH released. It has also been demonstrated that conditioned individuals performing identical exercise will secrete less hGH than matched unfit individuals. A glucose load will blunt the hGH release in individuals during equal exercise pro-

Table 3. CONDITIONS, HORMONES, AND MEDICATIONS THAT AFFECT HUMAN GROWTH HORMONE Conditions That Stimulate GH Release

Physiological Exercise Sleep Hypoglycemia Stress (physical, psychological) Hyperthermia Hormones and neurotransmitters Amino acids Arginine, lysine, ornithine GHRH Glucagon Estrogen Vasopressin Medications Epinephrine Propranolol Levodopa Clonidine Serotonin Bromocriptine Acetylcholine Galanin Substance P Neurotensin VI P/P HI Pathologic Acromegaly/gigantism Starvation/anorexia nervosa Diabetes

Conditions That Inhibit GH Release

Hyperglycemia Elevated free fatty acids Hypothermia

SRIH, GH, IGF Progesterone Glucocorticoids Phentolamine lsoproterenol Methysergide Cyproheptadine Atropine Theophylline Chlorpromazine lmipramine

Hypothyroidism Hyperthyroidism

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grams. Obesity also blunts hGH release.65The amino acids 1-arginine, 1lysine, and ornithine have been shown to increase endogenous growth 65, 93 hormone, although their mechanism of action is not well under~tood.4~,

Effects and Function

hGH is essential for neonatal development, postnatal growth, and development of many tissues. Growth hormone decreases protein catabolism and increases protein synthesis, cellular uptake of amino acids, and lipolysis.lo6Many of these functions are mediated via stimulation of IGF release from the liver and other target organs. The effects of hGH on bone and muscle growth reflect both direct and indirect (IGF-mediated) mechanisms. One significant example of this is the differentiation of prechondrocytes into chondrocytes2l In human muscle cells, hGH causes nitrogen retention and an increase in messenger RNA, which augments synthesis of collagen. Intracellular fat catabolism is also under the influence of hGH and produces free fatty acids. Free fatty acids are then available as an immediate energy source, preventing the need for tissue catabolism and sparing muscle glycogen.91,Io6 Growth hormone’s effects on insulin are antagonistic: less cellular uptake of insulin and decreased tissue sensitivity. This ultimately results in increased insulin p r o d u ~ t i o n .lo6 ~ ~The , amount of adipose tissue is thereby lowered although hepatic fat is increased. Growth hormone affects the electrolyte balance by acting on the renal tubules. Potassium, magnesium, and phosphorus resorption are increased by hGH, whereas Io6 enhanced calcium excretion results in hypercalc~ria.~~, It is well documented that hGH supplementation increases muscle size and some strength in hGH-deficient individuals.’06 In ”normal” (nondeficient)subjects, the effects of hGH supplementation are less clear. Studies demonstrate an increase in muscle size but not strength after hGH supplementation in normal 65 One clinical example of this principle is growth hormone-induced acromegaly, in which muscles are hypertrophic and show increased collagen but no increase in contractile tissue.32,65, 102, 106 Growth hormone may increase lean body mass in some athletes, particularly those with increased fat mass. Its effect on bodybuilders with little fat mass has been unimpressive, suggesting that lipolysis may be the dominant mechanism of this effect.23Both human and animal studies support the lack of strength gains in nondeficient subjects on 65, Io2, Io6 In contrast to work-induced muscle hGH s~pplementation.~~, growth, hGH-induced muscle growth requires insulin as a cofactor and results from translation of existing RNA. This may explain why hGH seems to increase size but not necessarily strength in nondeficient individual~.~~ The effect of excess growth hormone on growth depends on the age of the individual. In preadolescence, excess hGH causes gigantism as a

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result of overstimulation of open physes. In adults, hGH excess results in the clinical syndrome of acromegaly. This is characterized by overgrown skull bones causing a distinctive protruding jaw and frontal bone. Thickened fingers and coarse facial features reflect soft-tissue proliferation. Medical complications include diabetes, hypertension, coronary heart disease, cardiomyopathy, congestive heart failure, peripheral neuropathy, impotence, amenorrhea, and osteoporosis. Acromegalic muscles become hypertrophied but do not demonstrate increased strength. In fact, the myopathy of acromegaly is associated with muscle weakness and fatigue.47,65,102 The mortality rate from acromegaly is high with cardiac failure being the major cause of death.

Side Effects

Exogenous hGH administration exposes the individual to the clinical syndrome of acromegaly. Another organ system commonly affected is the skin. Growth hormone has been associated with changes in skin texture76and abnormal growth of melanocytic nevi.”, 76 Adverse effects on lipid profiles have also been reported. A study by Zuliani and associate^"^ concluded that hGH, both with and without anabolic steroid administration over a 6-week period, decreased HDL-cholesterol and apolipoprotein A-1. Both of these conditions predispose patients to coronary heart disease. The risk of contracting hepatitis or HIV from sharing injection needles is also a possibility. Peripheral edema and carpal tunnel syndrome have also been reported.32Creutzfeld-Jakob disease has previously been associated with cadaver hGH, which is no longer produced for clinical use.65It may still be on the black market. Information on the long-term risks of hGH abuse is lacking. Risks of tumorgenesis and autoimmunity deserve further study. The recent death of a popular professional football player and his admitted heavy use of hGH (and other substances, including AAS) raise healthy questions about its possible long-term adverse effects.

Clinical Use

hGH is currently being used to treat hGH-deficient children. Many studies document the benefit of hGH replacement in children with short stature, Turner‘s syndrome, constitutional delay, intrauterine growth retardation, and glucocorticoid-induced growth arrest.%Other potential uses may include catabolic states, such as sepsis, malnutrition, burns, renal failure, and major illness or surgery? These clinical uses are very similar to those associated with anabolic-androgenic steroids.

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Athletic Use

Potential benefits of hGH abuse in athletes are obvious. Despite its unproven effects, increased lean body mass, shorter recovery times between workouts, possible strength gains, and performance enhancement are reasons for use. Growth hormone is also not detectable with current drug screening. For these reasons, hGH is very popular among athletes despite its cost.'l Endogenous hGH secretion may be manipulated by medications, such as clonidine, levodopa, and vasopressin. These substances may stimulate hGH release by a direct action on the pituitary or indirectly via growth hormone releasing hormone (GHRH) stimulation.26,65 The amino acids arginine, ornithine, lysine, and tryptophan are also used to increase hGH.25,26, 47, 65, lo2 Amino acid supplements are part of the lucrative supplement industry and are easily accessible in nutrition stores. Several internet sites also aggressively market these products via large advertisements complete with references and testimonials from doctors, pharmacists, and athletes. The cost of such products varies, but $60 to $200 a month are reasonable estimates. Commonly recommended doses may not increase hGH release.58Arginine must be taken in very high doses (250 mg/kg) to affect hGH. Manufacturer's recommended supplementation dosages (e.g., 2.4 g/day arginine and lysine) may be 65 inadequate to increase hGH in healthy male weight-lifter~.~~, Exogenous hGH administration requires intramuscular injection of recombinant hGH, often in 6- to 12-week "cycles" and often in conjunction with AAS.", loo Despite voluntarily production limits and postmarket surveillance to track legitimate use, the opportunity for mass production exists and hGH is accessible on the black market.25 Approximate costs of hGH are driven by market forces, but $3,000 per month is probably a conservative cost estimate.88The abuse of hGH may be combined with anabolic-androgenic steroids. Survey-reported reasons for use include increasing muscle growth and strength, decreasing protein breakdown, increasing tendon strength, and decreasing workout recovery time.", 81 The purity of hGH, like that of AAS, may be very poor. Drug Enforcement Agency sources project that 30% to 50% or more of hGH and AAS products sold are phony.25,88,101 Abuse of hGH may be increasing at many competitive levels and in recreational athletics.65, A readily available underground ergogenic user's guide states: (about hGH) "It is the best drug for permanent muscle gains. . . . People who use it can expect to gain 30 to 40 lbs of muscle in 10 weeks. . . . This is the only drug that can remedy bad genetics as it will make anybody grow . . . we LOVE the In a recent survey of 224 suburban high school boys, 5% reported past or present use of hGH. Although it is very likely that the students thought they were using hGH and bought placebo, over half of them also admitted using steroids. Another concern was that sources/suppliers included coaches and peers; and knowledge about side effects was very limited.81Finally, the popularity of hGH is not limited to male athletes. Because hGH is not androgenic, female users do not experience the

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virilization side effects commonly associated with AAS, and their use is probably increasing. hGH was probably the most popular banned substance at the 1996 Atlanta games for sprinters and strength athletes. Some athletes even called the Atlanta Olympics the "Growth Hormone Games.""

FINAL THOUGHTS The use of drugs continues to plague the athletic world, with more products, detection avoidance techniques, and evidence of their efficacy than ever before. The clear pattern of increased overall use, younger users, and higher dosages raises some very difficult ethical and practical questions for athletes, parents, and health professionals.

Is the use of drugs in sports fair? What role do coaches, administrators, trainers, and physicians have? Do education and enforcement methods really work? What can any of us do to "level the field" and remove the pressure to cheat? These are significant challenges indeed. Each of us must seriously consider these questions before we can expect reasonable progress to be made. Team physicians have a unique opportunity to maintain the highest standards of fair play, particularly among children and adolescents.

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