Definition
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According to the World Anti-Doping Agency (WADA) Code, doping is defined as the occurrence of one or more of the following antidoping rule violations:
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Presence of a prohibited substance or its metabolites or markers in an athlete’s bodily specimen
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Use or attempted use of a prohibited substance or prohibited method
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Refusing, or failing without compelling justification, to submit to sample collection after notification, as authorized in applicable antidoping rules, or otherwise evading sample collection
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Violation of applicable requirements regarding athlete availability for out-of-competition testing, including failure to provide required information on whereabouts and missing tests that are declared based on reasonable rules
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Tampering, or attempting to tamper, with any part of doping control
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Possession or use of prohibited substances and methods
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Trafficking of any prohibited substance or method
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Administration or attempted administration of a prohibited substance or method to any athlete or assisting, encouraging, aiding, abetting, covering up, or any other type of complicity involving an antidoping rule violation or any attempted violation
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Scope of the Problem
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1964: Drug testing began at the Olympics
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Substance or method shall be considered for inclusion on the prohibited list if the WADA determines that a substance meets any two of the following three criteria ( Box 26.1 ):
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Medical or other scientific evidence, pharmacologic effect, or experience that a substance or method has potential to enhance or enhances sports performance
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Medical or other scientific evidence, pharmacologic effect, or experience that use of a substance or method represents actual or potential health risk to the athlete
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The WADA’s determination that use of a substance or method violates the spirit of the sport
Anabolic Agents
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Anabolic Androgenic Steroids (AAS)
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Exogenous
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Endogenous
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Other Anabolic Agents (e.g., clenbuterol, zeranol, and zilpaterol)
Hormones and Related Substances
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Erythropoietin (EPO)
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Growth Hormone (hGH), Insulin-like Growth Factors (e.g., IGF-1), Mechano Growth Factors (MGFs)
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Gonadotrophins (LH, hCG) (prohibited in males only)
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Insulin
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Corticotrophins
Beta 2 Agonists
Agents With Antiestrogenic Activity
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Aromatase inhibitors
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Estrogen receptor modulators
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Other antiestrogenic substances
Diuretics and Other Masking Agents
Stimulants
Narcotics
Cannabinoids
Glucocorticosteroids
WADA , World Anti-Doping Agency.
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A substance or method shall also be included on the prohibited list if the WADA determines that there is medical or other scientific evidence, pharmacologic effect, or experience that the substance or method has the potential to mask use of other prohibited substances and prohibited methods.
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1968: Formal drug testing adopted for the Summer and Winter Olympic Games; drug testing has been used at every Olympiad thereafter.
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1985: The NCAA began a series of quadrennial surveys that documented substance abuse, use, and abuse patterns by intercollegiate athletes. The methodology changed significantly in 1997, and the number of participating schools and subjects increased. The eighth iteration in 2012 measured substance-use patterns in 20,474 male and female athletes ( Table 26.1 ). Periodic surveys are necessary to assess patterns of use of recreational and ergogenic substances.
TABLE 26.1
Drug
Percentage (%) of Athletes Using
2005
2012
Anabolic steroids
1.2
0.4
Spit tobacco
16.3
17.4
Alcohol
76.9
83.2
Ephedrine
2.5
0.9
Amphetamines
4.1
3.7
Marijuana
20.3
22.6
Cocaine
2.1
1.8
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Following a series of doping scandals, the International Olympic Committee convened the World Conference on Doping and Sport in February 1999 that led to creation of the WADA. The WADA was charged with developing standards and a consistent, worldwide doping-control program. In addition, each country founded its own antidoping agency (e.g., United States Anti-Doping Agency [USADA]) to ensure compliance. The WADA is composed of and equally funded by sports movement and governments of the world. Fig. 26.1 demonstrates the numerous worldwide tests conducted by WADA-accredited laboratories.
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2003: Investigation into Bay Area Lab Co-Operative (BALCO) revealed a sophisticated conspiracy involving professional athletes as well as US and international Olympic athletes. In addition to developing designer anabolic steroids, BALCO records were used to discipline athletes based on “nonanalytical” positives, i.e., athletes were suspended based on doping records rather than an adverse analytical finding during drug tests. Use of nonanalytical positives and forensic investigations has increased since 2003 as another antidoping tool.
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Sports Pharmacology
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Classifies drugs according to their reason for use rather than chemical structure, mechanism of action, or pharmacologic effects—a drug is classified as ergogenic, recreational, or therapeutic depending on the primary reason for use, which can influence prevention, identification, and treatment
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Ergogenic drugs are substances consumed specifically to increase performance.
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Nonperformance (“recreational”) use of drugs by athletes for same reasons as nonathletes and carries the risk of addiction
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Therapeutic drugs are taken to treat an underlying condition.
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The Physician’s Role
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The relationship between physicians and drugs in sports is often complicated and has a long historical legacy.
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Since the ancient Greek Olympics, athletes have sought out physicians to provide performance aids.
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2012 NCAA Study: 20.9% of anabolic steroid users named an athletic staff member as a source of drugs.
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Physicians play a central role in use and abuse of drugs by athletes.
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Physicians are asked to provide education, act as medical directors or medical review officers for drug testing, and provide therapeutic use exemptions (TUEs). It is imperative that physicians who serve as team physicians are familiar with performance-enhancing drugs (PEDs) used by athletes and also with procedures used to determine positive test results.
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Important to remember that a majority of high-profile doping scandals could not have been possible without active participation of physicians
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Role of National Olympic Committees (NOCs) and National Governing Bodies (NGBs)
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Historical evidence of systematic doping of athletes sanctioned by either NOCs or NGBs exists.
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East German swimmers admitted to systematic doping in the 1970s that was sanctioned by their NOC.
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Discovery of widespread use of blood doping by US cyclists participating in the 1984 Summer Olympic Games
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Recent evidence that systematic doping took place under aegis of the Russian Sports Federation uncovered in a recent WADA investigation
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Anabolic-Androgenic Steroids (AAS)
Definition: Testosterone or testosterone-like synthetic drugs that result in both anabolic and androgenic effects, e.g., increase protein synthesis (anabolism) and enhance the development of male secondary sexual characteristics (androgenic)
Prevalence:
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Since 1988, surveys have sought to assess usage rates in athletes and nonathletes with conflicting results; however, it is clear that use of AAS is no longer confined to athletes participating in organized sports but is also prevalent in the general population for nonathletic enhancement.
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2014: Monitoring the Future study reported that 1.5% of 12 th graders used AAS in the previous 12 months. Since 1989, this rate has ranged between 1% and 2.5%.
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2012: An NCAA survey revealed that 0.4% (declined from 1.2% in 2005) of male and female athletes had used AAS in the past 12 months. Additional data from NCAA surveys are presented in Tables 26.2 and 26.3 .
TABLE 26.2
Response Category
Percentage (%)
2012
Before age 14
17
Ages 14–15
8
Ages 16–17
25
Ages 18–20
42
Ages 21+
8
TABLE 26.3
Reason
Percentage (%)
To improve athletic performance
47
For sports-related injury
28
For non-sports-related injury or illness
23
To prevent injury
2
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The androgenization program developed by the former German Democratic Republic provided anecdotal information supporting the efficacy of AAS as well as its adverse effects.
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Current estimates indicate there are as many as 3 million AAS users in the US and that 2.7%–2.9% of young American adults have taken AAS at least once in their lives. A 2014 global epidemiologic study highlighted the widespread AAS public health issue when it reported a global lifetime prevalence rate of 3.3% (6.4% in males and 1.6% in females).
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Recent estimates are that 1.5 million teenagers have tried AAS and that teenage girls may be the fastest-growing demographic for use of AAS.
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Mechanism of action:
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AAS are bound by cytoplasmic proteins and transported to the nucleus. Activation of DNA-dependent RNA polymerase results in the production of messenger RNA for protein synthesis.
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Muscle size increases in users of AAS through hypertrophy and formation of new muscle fibers. According to a study conducted by Kadi et al., muscle biopsies suggested that use of AAS enhances activation of satellite cells and contributes to muscle fiber growth.
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In addition, AAS may have anticatabolic effects by attenuating effects of cortisol. Haupt proposed that AAS displace cortisol from receptors, allowing an athlete to train at a higher level; he also suggested that AAS increase motivation through heightened aggressiveness.
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In vivo studies of athletes and anabolic steroids:
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Numerous studies of anabolic steroid use by male athletes have produced conflicting results. Certain studies have supported improvement in strength, whereas others have found no significant improvement in strength. The American College of Sports Medicine’s official position statement as well as many other systematic reviews support the following position on AAS:
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Use of steroids by athletes is contrary to rules and ethical principles of athletic competition.
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With adequate diet, AAS can contribute to increase in body weight and lean mass.
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Gains in muscular strength achieved through steroid use at doses beyond those utilized in clinical medicine improve performance and seem to increase aerobic power or capacity for muscular exercise, giving an unfair advantage to those who are willing to risk potential side effects to achieve gains in athletic performance.
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Steroids have been associated with adverse side effects in therapeutic trials and in limited studies on athletes.
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A study conducted by Bhasin et al. in 1996 demonstrated an increase in fat-free mass and muscle size and strength in weight lifters who used weekly injections of 600 mg testosterone enanthate for 10 weeks. This was the first study to demonstrate that supraphysiologic doses of testosterone in trained weight lifters, combined with resistance training, increases strength.
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Designer steroids: Chemical alternations are made to existing synthetic AAS in order to avoid detection by drug testing.
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Norbolethone
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Originally documented 30 years ago; isolated in two urine samples from a female athlete in 2002 who later received a lifetime ban
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Never commercially marketed because of possible toxic effects in animal studies and/or reports of menstrual irregularities
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Anabolic activity 20 times higher than its androgenic activity, thus very attractive to athletes looking to gain a competitive edge
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Tetrahydrogestrinone (THG)
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Unlike norbolethone, THG is a new chemical entity and would have remained undetectable if a syringe containing it had not been anonymously sent to the USADA in 2003.
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Closely related to gestrinone, a progestin, and to trenbolone, a veterinary androgen
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Limited information regarding the safety and anabolic effects of THG; has been found to be a potent androgen
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Several Olympics laboratories have reported positive results for THG.
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Several other designer AAS have appeared as increasing sophistication of drug testing continues.
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Over-the-counter steroids:
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The 1994 Dietary Supplement and Health Act made supplements available over the counter, including testosterone (androstenedione, androstenediol, dehydroepiandrosterone [DHEA] and nandrolone precursors [19-norandrostenedione, 19-norandrostenediol]).
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Athletes use these short-acting compounds to increase muscle mass despite lack of definitive studies on the benefits and adverse effects.
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Some of these have been found to increase testosterone and nandrolone metabolites; assumed to have similar profile to AAS
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Governmental regulations:
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1990 Anabolic Steroid Control Act: AAS were added to Schedule III of the Controlled Substances Act.
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2004 Anabolic Steroid Control Act: added steroid precursors such as androstenedione to the list of controlled substances; DHEA was not included in the Act and is still legally available as a dietary supplement despite being banned by several sports organizations; also increased penalties for trafficking
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Designer Anabolic Steroid Control Act of 2014: further defined designer AAS and increased penalties
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Potential therapeutic uses : True medical indications for AAS probably account for <3 million prescriptions/year. Indications include refractory anemias, hereditary angioedema, palliation therapy in advanced breast carcinoma, replacement therapy in hypogonadal males, and muscle-wasting states associated with HIV infection. Moreover, AAS may be useful in patients with constitutional delay of growth (as adjunct to growth hormone [GH] therapy) and osteoporosis and has potential use as a male contraceptive. A major marketing effort by pharmaceutical companies and “antiaging” clinics has increased the number of prescriptions for testosterone amid liberalization of diagnosis of hypogonadism. The Endocrine Society published guidelines for legitimate prescription of testosterone in men with androgen deficiency. Recent position statement published by American Association of Clinical Endocrinologists and American College of Endocrinology reinforces these principles.
Dosage: Doses taken by athletes may be 10–40-times higher than the therapeutic dose . Athletes frequently use combinations of anabolic steroids ( stacking ) or cycling in a pyramidal fashion to achieve maximum effect.
Adverse reactions:
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Gastrointestinal: hepatocellular dysfunction, peliosis hepatis, and case reports of hepatocellular carcinoma. Hepatic effects are more severe when 17-alpha-alkylated compounds are consumed orally. Serum liver function tests should be performed in athletes with suspected history of AAS use.
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Cardiovascular: increase in total cholesterol and low-density lipoprotein (LDL) cholesterol; decrease in high-density lipoprotein (HDL) cholesterol; hypertension; thrombotic risks; compartment syndromes; reported cases of myocardial infarction, atrial fibrillation and cerebrovascular accident
The Food and Drug Administration (FDA) has released a warning to reflect potentially increased risks of myocardial infarction and stroke with testosterone use. However, while retrospective reports have suggested that testosterone therapy increases cardiovascular risk, randomized controlled trials have been insufficiently powered to evaluate the risk of cardiovascular events in men who have undergone testosterone replacement therapy.
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Psychological effects : changes in libido, mood swings, aggressive behavior, exacerbation of underlying mental illness, addiction to the appearance when on AAS, and suicide attempts; dependence pattern with opioid medications as well as conduct disorder has been reported. Pope and Katz interviewed 41 bodybuilders and football players who had used AAS and found that according to DSM III-R criteria, nine (22%) athletes displayed full affective syndrome and five (12%) exhibited psychotic symptoms in association with AAS use. However, a well-designed study by Bahrke et al. of current AAS users, previous users, and nonusers demonstrated that although perceived or actual psychological changes may occur, they were not demonstrated on several standardized inventories.
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Male reproductive effects : oligospermia, azoospermia, decreased testicular size, and gynecomastia; case of adenocarcinoma of prostate has also been reported. In addition, a case of a young male using high doses of oral turinabol suggested a potential causal relationship to intratesticular leiomyosarcoma.
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Female reproductive effects: reduced luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone; menstrual irregularities; male-pattern alopecia; hirsutism; clitoromegaly; and deepening of voice: the latter three are probably irreversible
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Youths: irreversible and premature closure of the epiphyses; several highly publicized cases of suicide in high school athletes related to steroid use (e.g., Taylor Hooton)
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Additional drug use: AAS users are likely to use other drugs. A 2007 study conducted by Elliot evaluating high school female students revealed that AAS users were more likely to use alcohol, cigarettes, marijuana, and cocaine. In 2009, Ip conducted the Anabolic 500 survey demonstrating that AAS-dependent users were significantly more likely to report heroin use within past 12 months and endorse a history of physical and sexual abuse.
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Miscellaneous:
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Spontaneous tendon rupture
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Increase in sebaceous glands and acne
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Infectious complications, including HIV (due to sharing of contaminated needles), hepatitis B and C, and intramuscular abscess
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A case report described bilateral deltoid myositis ossificans in a patient who repeatedly injected anabolic steroids in his bilateral deltoids in the past.
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Worsening of tic symptoms in patients with Tourette’s syndrome
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Suppression of humoral immunity and immunoglobulin levels
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Anecdotal reports of an association with compartment syndromes following trauma and/or surgical procedures
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Side effects: documented in a secret AAS program for elite athletes sponsored by German Democratic Republic: liver damage, gynecomastia, polycystic ovarian syndrome, arrested body growth, and three deaths
Prevention: programs designed to reduce AAS use have been developed (e.g., by Goldberg and the ATLAS program for use at the high school level)
Detection: The presence of aforementioned adverse effects should arouse clinical suspicion. Drug testing (discussed later) can detect AAS with a high degree of accuracy.
Growth Factors
Human Growth Hormone (hGH)
Definition: polypeptide hormone composed of 191 amino acids with a molecular weight of 21,500 and contains several different isoforms, the predominant ones being a 22-kD isomer and approximately 10% 20 kD; typically, 5–10 mg stored in the anterior pituitary
Men have a production rate of 0.4–1.0 mg/day. Production of recombinant human growth hormone (rhGH) in 1980s dramatically increased potential supply. As opposed to natural GH, rhGH contains only the 22-kD isomer.
Prevalence: With growing effectiveness of gas chromatography and mass spectrometry in detecting AAS and testosterone, numerous athletes have turned to hGH; estimating prevalence is difficult but thought to be widely used by various professional athletes.
Mechanism: hGH stimulates the production of various markers, most prominent being insulin-like growth factor (IGF-1) or somatomedin-C. Although there is some debate regarding whether substances such as liver-produced IGF-1 are markers or mediators, hGH exerts most of its effects through receptors at target cells. There is limited evidence that commercially available IGF-1 products have any ability to increase IGF-1 levels or strength; it is also clear that while certain controlled, albeit limited studies, on hGH have revealed increases in IGF-1 and changes in lean body mass, none have definitively demonstrated increases in strength or athletic performance with hGH alone.
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Function: Administration of hGH to GH-deficient children results in positive nitrogen balance and stimulation of skeletal and soft tissue growth.
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Metabolic effects: GH reduces glucose and protein metabolism and has a net anti-insulin effect by inhibiting cellular uptake of glucose. In addition, it stimulates mobilization of lipids from adipose tissue and greatly increases protein synthesis in hypophysectomized animals.
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Effects on muscle: Several studies have reported conflicting data regarding effects of hGH on muscle. Goldberg conducted animal experiments and concluded that hGH increased the basal metabolic rate of protein synthesis; however, the effect was determined by the amount of muscular work. It is difficult to predict the ability of hGH in increasing contractile elements and improving performance of normal muscle in normal humans. hGH studies conducted by Deyssig revealed that while there may be increases in IGF-1 and changes in lean body mass, there is no definitive demonstration of increases in strength or athletic performance. Studies have demonstrated increases in muscle mass in settings of current or past use of AAS.
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According to a previous study, hGH treatment in adults with acquired GH deficiency increased lean body mass, decreased fat mass, and increased basal metabolic rate, inferring that hGH can regulate body composition through anabolic and lipolytic actions.
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Therapeutic uses: The FDA, under USC 33(e), has established guidelines for the legitimate use of hGH; it cannot be used “off-label” ( Table 26.4 ). The FDA has established the use of the GH stimulation test to diagnose adult GH deficiency. Low serum IGF-1 levels alone are not considered evidence of GH deficiency.
TABLE 26.4
Children, Poor Growth Due to
Turner’s syndrome
Prader–Willi syndrome
Chronic renal insufficiency
hGH Insufficiency/deficiency
Children born small for gestational age who fail to manifest/catch-up growth by 2 years of age
Idiopathic Short Stature or growth failure associated with short stature homeobox gene (SHOX) deficiency
Noonan syndrome
Adults
Wasting syndrome of HIV/AIDS
hGH deficiency
Short bowel syndrome
Dosage: FDA-approved dosage is 0.003–0.004 mg/kg/day via subcutaneous injection, although other governing bodies recommend 0.15–0.3 mg/day regardless of body weight.
Adverse reactions:
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Acromegaly is a potentially serious side effect of megadoses of hGH. It is estimated that acromegalic patients with hGH concentrations of 5–30 ng/mL have production rates of 1.5–9 mg/day. As little as a two-fold increase in recommended dose may result in acromegaly, which leaves a narrow therapeutic window . With athletes consuming hGH up to 20 mg/day, the risk of acromegaly is significant. Complications of acromegaly include diabetes, arthritis, myopathies, and characteristic coarsening of the bones of face, hands, and feet.
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In general, the incidence of side effects with the use of physiologic replacement doses in GH-deficient patients is low. Reported adverse reactions include intracranial hypertension, hyperglycemia, and glycosuria. However, in 2012, the FDA reported that a long-term epidemiologic French study, SAGhE, demonstrated a 30% increased risk of death when using rhGH. Data suggested mortality was associated with bone tumors and cardiovascular events (primarily subarachnoid or intracerebral hemorrhage). The risk was higher when higher than normal doses were prescribed. The FDA maintained that when appropriately used, benefits outweigh risks.
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Adult patients using hGH have reported fluid retention, arthralgia, myalgia, gynecomastia, hypoesthesia, and paresthesia (e.g., carpal tunnel syndrome via median nerve edema).
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Use of hGH by “antiaging” clinics without establishing GH deficiency constitutes illegal prescribing .
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Use of hGH derived from cadaveric pituitary glands can result in Creutzfeldt–Jakob disease. Although use of synthetic hGH obviates this issue, athletes often obtain substances from black-market sources, which thus increases the risk of this catastrophic neurologic disorder.
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Detection : Banned by the WADA with two established serum methods of detection
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Isoform Test : Immunoassays used to estimate the amounts of various GH isomers in serum. Although a majority of circulating GH is 20 and 22 kD, several other isomers naturally exist. When rhGH (22 kD) is administered, natural production of all GH isomers is suppressed; thus, the ratio of 22- to non-22-kD isomers will increase, indicating use of synthetic GH. The isoform test can detect the use of hGH for up to 72 hours, and there have been several positive tests worldwide. Recent research has established decision limits for this test, which has been upheld by the Court of Arbitration for Sport (CAS). The current detection threshold is 1.45 for males and 1.8 for females.
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Biomarker Test : It measures the serum markers IGF-1 (from liver) and procollagen type III (P-III-NP from bone) that can discriminate hGH users from nonusers up to 2 weeks after use. The test was first used at the 2012 London Olympic Games and revealed positive tests in two Russian Paralympian weight lifters who admitted use. This test should be available worldwide in 2016.
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IGF-1
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hGH stimulates the production of IGF-1 by the liver.
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Limited evidence that commercially available IGF-1 products have any ability to increase IGF-1 levels or strength
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Limited controlled studies on rhGH have revealed increases in IGF-1 and changes in lean body mass, but none has definitively demonstrated increases in strength or athletic performance.
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Supplements containing deer antler velvet extract have been advertised to contain IGF-1. Although these products contain IGF-1, research has demonstrated that human IGF-1 was added after production, and thus, it is illegal.
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Adverse effects related to IGF-1 use include hypoglycemia, decreased hGH secretion, carbohydrate oxidation preferentially over lipids, interference in insulin–glucagon axis, and an association with carcinoma of prostate, colon, and lung.
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Mechano growth factors are a new form of IGF-1 produced in response to mechanical loads and have been described by Goldspink.
Growth Hormone-Releasing Peptides (GHRPs)
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Synthetic peptides with a small fraction of GH that are potent stimuli for GH secretion
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GH peaks in 15–30 minutes and returns to baseline in 2–3 hours.
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Ghrelin analogs GHRP 1,2,4,5,6, and Ipamorelin
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Oral, intravenous, and nasal routes with metabolites detectable for 20 hours by liquid chromatography–mass spectrometry (LC-MS).
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Multiple positives in professional and Olympic sports
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Has been detected in nutritional supplements; not legally available but can be purchased on the Internet for “research purposes”
Insulin
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Physicians are trained to view insulin as a solely therapeutic drug, but increasing anecdotal information associates AAS use with insulin; a study by Parkinson and Evans revealed that 25% of AAS users also used insulin.
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Speculated that insulin might enhance strength through its inhibitory functions (deters lipolysis, glycolysis, gluconeogenesis, proteolysis, and ketogenesis); when combined with an anabolic agent such as hGH or AAS, the protein-sparing effects of insulin produce larger anabolic results and significantly increase lean body mass
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Risks of insulin use in normoglycemic athletes include lethal hypoglycemia, lipodystrophy, lipoatrophy, insulin allergy/resistance, and production of insulin autoantibodies.
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Insulin prohibited by the WADA, but no approved test for detection