Sports Pharmacology: Ergogenic Drugs In Sport
There is no room for second place. There is only one place in my game, and that’s first place. VINCE LOMBARDI
In this day and age, it is common for athletes to be scrutinized for using prohibited performance-enhancing drugs and methods. Our society places a high value on winning and rewards athletes who perform well. As a result, competitors are often motivated to do “whatever it takes” to perform at a higher level and thus improve in their sport. The word ergogenic is derived from the Greek éaargon , to work, and gennan , to produce, and literally means “increasing the ability to do work.” Athletes have sought ways to improve their performance for thousands of years. Athletes at the first Greek Olympics ate substances that they thought would give them a competitive advantage, including dried figs, mushrooms, large amounts of meat, and strychnine (a known poison). These ancient Greek athletes were willing to risk taking a potentially deadly substance in the hope of winning. History does repeat itself, because this trend continues today and has escalated to incomprehensible levels. The ensuing battle to weed out athletes who engage in unfair practices is a challenge to organizations that believe in the concepts of “an even playing field” and fairness in sport.
The desire to win at all costs was confirmed by a poll of Olympic athletes conducted by Mirkin in the 1980s. The question was, “If you could take a pill that would guarantee you the Olympic gold medal but would kill you within a year, would you take it?” The shocking result was that more than 50% of the athletes would take the pill.
Goldman subsequently conducted a modified poll in the 1990s and asked 198 aspiring Olympians, all elite athletes, two questions:
- 1.
If you were offered a banned performance-enhancing substance that guaranteed that you would win an Olympic medal, and you could not be caught, would you take it?
- 2.
If you were guaranteed that you would not be caught, would you take a banned performance-enhancing drug that would allow you to win every competition for the next 5 years but would then cause you to die from the side effects of the substance?
Of 198 athletes, 195 answered yes to the first question, and in response to the second question, more than 50% of the athletes said they would take the substance.
The results of these two polls reveal that a high percentage of athletes are willing to use substances that are potentially fatal if they believe those substances will help them win. Athletes want to win now and may not consider or even be concerned about the future consequences of taking a performance-enhancing substance.
Testosterone: Historical Perspectives
In the 1950s it was discovered that Olympic weight lifters were gaining immense strength by injecting testosterone, a male hormone. An American physician, John Bosley Ziegler, saw the potential benefits, and in an effort to minimize the adverse androgenic effects that the weight lifters were experiencing, he developed the derivative, methandrostenolone. Although it was initially considered a superior ergogenic drug compared with testosterone, it had its own adverse effects related to its potent androgenic properties. Since then many scientists have attempted and failed to develop a pure anabolic agent without androgenic features. To underscore the important point that derivatives of testosterone have anabolic and androgenic properties, we categorize all ergogenic derivatives of testosterone in this chapter as anabolic-androgenic steroids (AASs). Hundreds of ergogenic variants of testosterone are now being used by athletes.
One of the first scientists to promote the ergogenic properties of testosterone was the prominent French physiologist Brown-Séquard. Although largely remembered in the medical world today for his description of a spinal cord syndrome, Brown-Séquard played an important role in the history of AASs. In June 1889, at the Société de Biologie meeting in Paris, the 72-year-old Brown-Séquard announced he had found a “rejuvenating compound” that had reversed many of his physical and mental ailments related to aging. He reported that he had injected himself with a liquid extract made from the testicles of dogs and guinea pigs and that these injections had dramatically increased his strength, improved his mental acumen, relieved his constipation, and increased the arc of his urinary stream. Brown-Séquard’s findings were viewed with disdain, yet he had made an important discovery with enormous implications for the medical and athletic worlds. Brown-Séquard’s discovery of the positive properties of the testicular extract was based on the earlier work of Berthold, who had proposed that the implantation of testicles in the abdomen of roosters reversed the effects of castration.
Scientists continued the work of these two scientists, and several important discoveries were made that contributed to a better understanding of the properties of the testicular hormone. The Dutch scientist David and his colleagues first isolated testosterone in 1935. Soon thereafter, German scientists published an article describing the synthesis of testosterone from cholesterol. Subsequently, physicians and veterinarians started using testosterone and its intermediaries clinically, and testosterone was first used medically in humans to help chronically ill patients recover muscle mass. Testosterone was found to have positive effects on almost every organ of the body, and 60 years after Brown-Séquard announced his discovery, testosterone was promoted once again as a rejuvenation compound. Consequently, in 1939 Boje suggested that male sex hormones might improve athletic performance. Finally, after a racehorse dramatically improved its performance following injections of testosterone in 1941, human competitors who were looking for an advantage during competition started experimenting with testosterone use.
The first systematic use of testosterone in sports was by Soviet Olympic athletes in the 1950s, and by the 1960s, use of AASs was increasingly prevalent. During that time, no sanctions against the use of ergogenic drugs existed, and many athletes believed that it was necessary to use drugs to be able to compete with their competitors. By the 1968 Olympics, the use of AASs was pervasive across various disciplines of sport, including both strength and aerobic events. New drugs claiming to have superior anabolic qualities were being marketed openly, and male athletes from other sports such as American football soon began taking AASs in large numbers either knowingly or allegedly as “vitamins.” It was estimated that 40% to 90% of professional football players were using AASs by the 1980s, and soon thereafter, college football players followed the lead of the professionals.
Female athletes began experimenting with the drugs to improve their own performance abilities. Before long, it was discovered that women who took AASs experienced increased muscular strength. In addition, the androgenic properties of AASs also induced masculinization effects, including deepening of the voice, amplification of body hair, loss of breast tissue, and clitoral enlargement. Masculinization of female athletes from the Soviet Bloc nations was so dramatic that gender tests and chromosomal analyses were performed at the 1967 European Championships to ensure that male athletes were not masquerading as female athletes.
Women in Western nations have been suspected of using ergogenic drugs. Florence Griffith Joyner became one of the most famous athletes in the world when she reappeared on the world stage after coming out of semiretirement and achieved tremendous success at the 1988 Olympic Games. Joyner had progressed from a good runner to a world champion whose record in the 100-meter run was unsurpassed for 10 years. Her muscular physique, combined with her newfound athletic success, led to speculation that her athletic superiority was a result of the use of performance-enhancing drugs—a charge she vehemently denied. Joyner instead insisted that her athletic prowess was the result of a relentless training program supervised by her husband, Olympian Al Joyner. When Florence Griffith Joyner died in her sleep at the young age of 38 years, speculation that her death may have been related to adverse effects from taking ergogenic drugs was rampant. To date, it has not been verified that Joyner either used ergogenic aids or that her death was related to the use of drugs.
Many young athletes apparently believe that using ergogenic drugs is a worthwhile risk. A study by Buckley and colleagues in 1988 revealed that 6.6% of 12th graders had used anabolic steroids. An alarming finding was that 30% of users were nonathletes who were using ergogenic drugs to improve their appearance rather than their athletic performance. Evidence indicates that ergogenic drug abuse commences in middle school. In the National Institute of Drug Abuse 2006 Monitoring the Future study, in which drug abuse among adolescents in middle school and high school was surveyed, evidence was found that 2.7% of high school male students had taken AASs at least once in their lives. Furthermore, ergogenic drug use is not limited to young men; alarmingly, Yesalis and Bahrke found that the percentage of 14- to 18-year-old girls using anabolic steroids has almost doubled in 7 years, and many women consider ergogenic drugs an effective means of obtaining athletic scholarships to college.
When a Danish cyclist died at the 1960 Olympics after ingesting a combination of nicotinic acid and amphetamines, concerns were raised regarding both fairness and safety, and a plan of action to address these issues was formulated. One of the first steps was to define the problem, and in 1963, the Council of Europe established a definition of doping as “the administration or use of substances in any form alien to the body or of physiological substances in abnormal amounts and with abnormal methods by healthy persons with the exclusive aim of attaining an artificial and unfair increase in performance in competition.”
Anabolic-Androgenic Steroids
Physiologic Considerations
The three main steroids in the human body are androgens, estrogens, and corticosteroids. The androgens are responsible for the development of male characteristics, whereas the estrogens express female characteristics. Corticosteroids—both glucocorticoids and mineralocorticoids—are responsible for a wide variety of essential body functions involving the immune, cardiovascular, metabolic, and hemostatic systems.
Females produce small amounts of androgens in the ovary and adrenal gland, and males produce small amounts of estrogen, but it is the production of androgens that makes males “masculine” and the production of estrogen that makes females “feminine.” The most abundant androgen in males is testosterone, which is produced primarily in the testes. In many target cells in the body, testosterone is reduced at the 5α position to dihydrotestosterone, which serves as the intracellular mediator of the actions of testosterone. Dihydrotestosterone has a greater affinity for androgen receptors compared with testosterone and is thus the more stable and potent androgen. Precursors in the metabolic pathway to testosterone, dehydroepiandrosterone (DHEA) and androstenedione, bind weakly to the androgen receptors and are known as weak androgens. Other weak androgens that are metabolites of testosterone include etiocholanolone and androsterone. Although they are weak, these androgens can induce significant anabolic effects.
In males, testosterone production peaks at three distinct phases of life. The first peak occurs during the fetal period, in the second trimester, and directs male fetal development. Subsequently, a smaller surge occurs during the first year of life and the largest surge occurs during puberty, resulting in several visible changes. Androgens cause laryngeal enlargement, thus deepening the voice; genital maturity; spermatogenesis in the testicles; and bone and muscle growth, with a relative decrease in body fat. The skin becomes thicker and oilier, and body hair on the face and in the axilla and groin grows to adult levels.
On the cellular level, testosterone, or its more active metabolite, dihydrotestosterone, works by binding to an intracellular androgen receptor in the cytoplasm. The steroid–androgen receptor complex is transported to the nucleus, where it attaches to a specific hormone regulatory complex on nuclear chromosomes. Here the complex stimulates the synthesis of specific ribonucleic acids and proteins. The ribonucleic acid compounds are transported through the bloodstream to act on target organs to stimulate spermatogenesis, effect sexual differentiation, and increase protein synthesis in muscle tissues. The androgenic message is received and processed in all organs that have androgenic receptors.
The metabolism of testosterone and its products occurs rapidly in the liver. Oral testosterone is absorbed immediately and metabolized so rapidly that it becomes ineffective. Scientists have therefore developed methods of altering the basic structure of the molecule to delay its metabolism and increase its half-life in the plasma. Alkylation at the 17α position with a methyl or ethyl group allows oral agents to be degraded slowly. Similarly, esterification of the 17β position allows parenteral agents to resist degradation. Testosterone esters, such as cypionate and enanthate esters, are more potent than testosterone. These compounds must be injected intramuscularly, usually at 1- to 3-week intervals. Newer preparations of testosterone can be administered transdermally. These preparations were originally applied to the scrotum, but new transdermal patches and creams can be applied to other parts of the body.
In addition to promoting muscle development, androgens cause the skin to become unusually oily, which can lead to acne, increase body hair, and induce male pattern baldness, with hairline recession and thinning and loss of central scalp hair. The skin effects are crucial clues for physicians who suspect anabolic steroid use. The extent of the acne can be profound, and the back is often significantly affected. Lastly, the distinctive odor caused by the effects of anabolic steroids on the sebaceous glands is inimitable.
Athletic Performance Considerations
Despite the perceptions of athletes, scientific data regarding the effects of anabolic steroids on athletic performance are varied. When used at therapeutic doses, neither strength nor performance gains are expected, because in a homeostatic state, hormonal levels are maintained within a narrow window. After a therapeutic dose of a hormone is administered, the body halts its own endogenous hormone production to maintain constant levels. Athletes who are cognizant of this fact have taken doses 50 to 100 times the therapeutic dose, which shuts down endogenous production of AAS. But does taking such high doses improve athletic performance?
In the world of athletics, several popular theories foster steroid abuse. The first theory is that “In combination with training, AASs increase lean body mass and decrease body fat.” Early studies that evaluated this theory showed equivocal results. More recent studies have shown an increase in body weight and lean body mass but showed no significant decrease in the percentage of body fat.
Another theory suggests that “AASs increase muscle strength.” Early studies in which mostly low-dose AASs were evaluated were inconclusive. Later, in 1996, Bhasin and colleagues studied the effect of supraphysiologic doses of testosterone on healthy men, which was the first prospective randomized study that looked at the effect of “super dosing” of AAS. In this study of 43 healthy men, the group that received steroids had definite increases of strength and muscle size compared with the placebo group. Notably, no significant adverse effects were observed in the steroid group; however, the study had limitations, including a short term (6 weeks) and inadequate follow-up. Significantly, however, this study was the first to provide scientific evidence for the theory that athletes believed for decades—that steroids do work, especially at the amplified doses that are popular in athletics. Other investigations have shown distinct advantages for muscle, with both expansion in cross-sectional diameter and proliferation of new fibers. The upper regions of the body are more susceptible to gains from AASs because of the relatively larger number of androgen receptors in these areas. AASs, however, do not appear to improve athletic endurance.
AASs work on several different levels in the body. Not only do they stimulate protein synthesis, but they also stimulate the production of growth hormone (GH), a potent ergogenic agent. Furthermore, AASs display some anticatabolic features because they delay the effects of cortisol, a stress hormone. Cortisol is released in response to physical and psychological stress and causes protein degradation and muscle atrophy. Testosterone slows this catabolism by displacing the corticosteroids from receptor sites. Additionally, AASs may increase oxygen uptake, increase cardiac output, and increase stroke volume. Lastly, they may improve athletic performance by increasing aggressive behavior. However, the data on the relationship between testosterone levels and aggressive behavior is inconclusive.
Adverse Effects
The use of anabolic steroids may result in several less than desirable side effects. Oily skin, acne, small testicles, gynecomastia, and changes in hair patterns are the most common. Small doses of androgens increase sebaceous gland secretions, leading to the changes in the skin and acne. Enlargement of the male breast (gynecomastia) is characterized by the presence of firm glandular tissue and is usually associated with increased production of estrogens or decreased levels of androgens. The specific pathophysiology of gynecomastia in men taking AASs remains unclear. One theory suggests that the body homeostatically shuts down production of endogenous androgens. Once the user stops using AASs, an increase occurs in the relative level of estrogens, leading to the development of breast tissue. Gynecomastia is irreversible once levels of androgens return to normal. A means of off-setting the estrogen-related adverse effects of AASs is to take an antiestrogenic drug such as clomiphene citrate (Clomid). Clomid blocks the effects of increased estrogen in persons using AASs by binding and thus blocking estrogen receptors.
Small testicles often also develop in men who use AASs. The testicles atrophy and shrink, which is a response to the homeostatic effect triggered from high exogenous AASs. Often the testicles remain smaller after discontinuation of the AAS. Other adverse effects on the male reproductive system include oligospermia (a decreased number of sperm) and azoospermia (the absence of sperm). Moreover, taking exogenous AASs not only decreases levels of endogenous testosterone but also decreases circulation of follicle-stimulating hormone and luteinizing hormone, which can lead to male infertility. Testosterone-dependent prostate enlargement and accelerated growth of prostate cancer have been documented. Women who take AASs experience virilization effects, including deepening of the voice, an increased amount of body hair, loss of breast tissue, and enlargement of the clitoris. Irregularities in the menstrual cycle, as well as infertility or early menopause, may result, and many of these adverse effects in women are irreversible.
Musculoskeletal
The musculoskeletal system may be affected adversely, especially in prepubertal athletes who take AASs. Although bone growth is stimulated immediately after the use of AASs, growth plates of long bones may close prematurely. The resultant short stature is permanent. Disproportionate changes in the muscle-tendon unit muscle strength (greater) than tendon strength (lesser) increases susceptibility for tendon rupture.
Cardiovascular
Numerous adverse changes occur in the heart of a person who takes AASs. Androgens are modulators of serum lipoprotein, thus increasing plasma levels of low-density lipoproteins (bad lipids) and decreasing levels of high-density lipoproteins (good lipids). Oral and synthetic AASs have more pronounced negative effects on lipid metabolism than do injectable AASs or natural AASs. Regardless, an altered lipid pattern may lead to atherosclerotic heart disease. Conspicuously, male and female AAS users show similar adverse changes in lipid metabolism.
Animal studies have suggested that AASs may cause myocardial damage. A study that investigated the relationship among resistance training, anabolic steroid use, and left ventricular function in elite bodybuilders showed concentric left ventricular hypertrophy. However, no effect on cardiac function was observed, which suggests that the heart may enlarge as a physiologic adaptation to the intensive training potentiated by use of AASs. In a set of bodybuilding twins, one twin used AASs for more than 15 years, whereas the other twin abstained. No significant difference in cardiac function was found between the twins. However, noteworthy changes in cardiac function after AAS use have been reported in other cases, such as myocardial infarction and death of young athletes. These case reports are no doubt worrisome, yet do not provide scientific “proof” that AAS use directly led to myocardial infarction or death. Nevertheless, cardiac pathology was evident upon postmortem examination in more than one third of 34 persons (aged 20 to 45 years) who had used AASs and died as a result of accidents, suicides, and homicides. Alarmingly, cardiac abnormalities may not resolve after use of AASs is stopped. A study of former AAS users showed that many years after discontinuing use of AASs, strength athletes showed persistent left ventricular hypertrophy compared with strength athletes who had not used AASs.
Hepatic
Most AAS metabolism occurs in the liver, which is thus prone to liver damage. Athletes with preexisting liver dysfunction are at greatest risk for androgen-induced damage. Temporary liver disturbances are common in athletes who use oral androgens, although function appears to return to normal after discontinuation of the drugs. Several investigators believe that AAS-induced hepatotoxicity is overstated, attributing resultant transaminitis to skeletal rather than to liver damage. A study of the effect of AASs on rats showed definite cellular damage to hepatocytes, yet long-term studies on the effect of AASs on the liver in human subjects have not been conducted, and until we have scientific data, hepatotoxicity should remain a potential concern.
Hepatotoxicity may manifest as peliosis hepatis, that is, the formation of blood-filled cysts in the liver. Enlarged liver cells block venous and lymphatic flow, producing cholestasis, necrosis, and peliosis cysts, which can rupture and may be life threatening. In contrast to most adverse effects of AASs, peliosis hepatitis does not appear to be dose related and can occur at any time after starting AAS use. Pathogenesis is perhaps via AAS-mediated hepatocyte hyperplasia.
Lastly, although no definite evidence exists to support a causal relationship between hepatocellular carcinoma and steroid abuse, multiple reports have been made of the development of hepatocellular carcinoma after AAS use.
Psychiatric
The most commonly associated psychiatric effect of AASs is an increase in aggressive behaviors, although only a few well-conducted prospective, randomized studies confirm this observation. In fact, most studies using therapeutic doses of exogenous testosterone showed no adverse effects, and a short-term study of supratherapeutic dosing of AASs in athletes revealed no significant psychiatric effects. However, some studies reported positive effects on mood. In Brown-Séquard’s 19th-century study of the self-administration of testicular substrates, one of the reported positive effects was improvement in mood, which was accompanied by an enhancement of his physical stature. Subsequently, benefits of AASs on mood and other psychiatric maladies were further evaluated by physicians following the advent of synthetic testosterone derivatives in the 1930s. AASs were being researched during their use to treat a variety of conditions ranging from depression to psychoses, and although results were varied, some small studies revealed an increase in aggression, which was thought to be linked to other personality disorders such as antisocial, borderline, and histrionic personalities.
Additional studies suggest an association with AAS use and psychiatric disturbances. A study of 41 athletes using supratherapeutic doses of AASs for an average of 45 weeks revealed that 34% experienced symptoms of major mood disorders such as severe depression or mania. AAS users are also more likely to abuse alcohol, tobacco, and illicit drugs, and data suggest that AAS users tend to meet criteria for substance dependence disorder more commonly than do nonusers.
Lastly, disorders of body image have also been reported after use of AASs. Many weight lifters who may appear muscular when compared with the average athlete consider themselves small or weak. This dysmorphic disorder is similar to that of women with anorexia nervosa who, despite being very thin when compared with the average woman, erroneously perceive themselves as fat.
Steroid Supplements
In 1994, the U.S. Congress passed a pivotal act affecting all persons involved in the care of athletes—the Dietary Supplement Health and Education Act. This law permits numerous substances to be sold without prior approval from the U.S. Food and Drug Administration (FDA), as long as they are sold as dietary supplements and not as “drugs.”
The Dietary Supplement Health and Education Act also established a formal definition of a dietary supplement using several criteria. A dietary supplement is a product (other than tobacco) that is intended to enhance the diet. It bears or contains one or a combination of dietary ingredients, such as a vitamin, mineral, herb, or other botanical product. Products have included approved new drugs, certified antibiotics, or licensed biologic agents that were marketed as dietary supplements or food before approval, verification, or licensure. The products are not recommended for use as a conventional meal or diet and are labeled as a dietary supplement. Subsequent to this bill’s passage, several synthetic AASs have become commercially available as dietary supplements, and as such they do not have to pass the safety requirements of the FDA and are not held to strict quality control standards. Claims regarding their effectiveness need not be substantiated by scientific proof as long as a disclaimer is listed on the product. Two dietary supplements that are used widely and purchased legally by athletes are DHEA and androstenedione.
Dehydroepiandrosterone
DHEA is a naturally occurring hormone produced in the adrenal glands of the human body. Its synthetic form, isolated from soy and wild yams, is marketed as a supplement and has become popular for its antiaging properties, fat-burning properties, and enhancement of muscle mass, strength, and energy. DHEA is a weak androgen, but it is the most abundant steroid in the body and is a precursor of testosterone, estrogen, progesterone, and corticosterone. Levels are high in the prenatal period and in puberty and gradually decrease as individuals age. Some studies performed on patients older than 50 years (when DHEA levels have dropped significantly) showed beneficial results after DHEA supplementation. Conversely, other studies have revealed inconsistent improvements in strength.
Many athletes use DHEA for its androgenic and anticatabolic effects. Unfortunately, DHEA is a precursor for several other hormones, including estrogen, which results in feminization. Athletes attempt to combat this outcome by using Clomid, an antiestrogenic drug, while taking DHEA. Little evidence exists to support claims for DHEA, either as a potent anabolic agent or as an antiaging drug. Furthermore, no studies of the long-term effects of taking DHEA have been published, particularly regarding the large doses used by athletes.
Androstenedione
As with DHEA, androstenedione is a dietary supplement. Originally touted as the “secret weapon of the East Germans,” androstenedione was first used in the 1970s, and its reputation as an effective anabolic agent encouraged worldwide use. In March 2004, the U.S. Department of Health and Human Services announced that the FDA had asked manufacturers to stop distribution of androstenedione. By October 2004, President Bush signed into law the Anabolic Steroid Control Act, which added androstenedione to the list of banned, nonprescription, steroid-based drugs. Currently, Major League Baseball, the National Football League, the Olympics, and the National Collegiate Athletics Association (NCAA) prohibit its use. Androstenedione received tremendous exposure in the media during the 1998 baseball season when St. Louis Cardinals slugger Mark McGuire was discovered to be using the supplement, albeit legally, after which sales of androstenedione rose dramatically.
Androstenedione is a potent AAS produced endogenously in the adrenal glands and gonads. In the liver, androstenedione is metabolized to testosterone, and akin to DHEA, during transformation it can be converted to testosterone and estrogen. As a result, a male athlete taking androstenedione can have elevated estrogen levels, as noted in several studies. Male subjects taking androstenedione experienced elevated estradiol levels equal to the estradiol levels seen in women during the follicular phase of the menstrual cycle, when levels are at their highest. Additionally, as a testosterone precursor, it can decrease high-density lipoprotein cholesterol and enhance cardiac risk. Priapism has been described in an otherwise healthy young man using androstenedione who had no other precipitating factors, and other concerns such as prostatic enlargement and cancer exist. Notably, significant ergogenic improvement after androstenedione supplementation is unproven in the medical literature.
Doping
Historical Perspectives
The word doping originates from the Dutch word dop, an opium mixture used to enhance the racing capacity of horses. In 1967, the International Olympic Committee (IOC) published a medical code that included a list of banned drugs to “protect the health of athletes and to ensure respect for the ethical concepts implicit in Fair Play, the Olympic Spirit, and medical practice.” From this committee, the World Anti-Doping Agency (WADA) was established in 1999. Through its affiliation with various international, national, and private governing bodies, WADA has helped to establish strategies to tackle organized trafficking and doping schemes that thwart detection. It also publishes an annual listing of banned substances, which is an invaluable resource for athletes and medical providers.
Erythropoietin
WADA defines blood doping as “the misuse of certain techniques and/or substances to increase one’s red blood cell mass.” Bonsdorff and Jalavisto were the first to discover the blood-stimulating hormone erythropoietin (EPO). The subsequent description of its molecular structure has served as a base for the development of recombinant human EPO (rhEPO). The first experiments of enhanced red blood cell mass and exercise showed that blood transfusion decreases submaximal heart rate for several weeks, predicting performance enhancement. Subsequent studies showed a 17% increase in the time to exhaustion among male athletes after 6 weeks of EPO administration.
As EPO became more commercially available through the production of rhEPO, its use among athletes as an ergogenic aid increased, which heightened negative media attention. The IOC eventually banned blood transfusion for the 1988 Olympics. In 1990, EPO was added to the IOC list of prohibited substances and has been on WADA’s prohibited list since the organization’s inception.
Physiology
Central to the physiology of peak athletic performance is the bodily transport of oxygen by erythrocytes. EPO is a hormone that stimulates the production of 2.5 × 10 11 erythrocytes per day, each of which has a life span of approximately 120 days.
In response to hypoxia, 90% of EPO is produced in the peritubular renal cells, with the remainder being produced in the liver and brain. EPO has a half life of approximately 6 hours, maintaining its presence in circulation for 1 to 3 days.
Testing
WADA publishes an annual summary of prohibited substances and doping methods. Commonly referred to as the Prohibited List, it comprises a total of 10 different classes of banned substances (S0–S9), three different groups of prohibited methods (M1–M3), and two classes of drugs (P1 and P2) that are banned from selected sports only. Analogous to many substances on this list, traceability of EPO abuse has been a complex issue; testing is laborious and time consuming, and the results are frequently challenged by athletes. Testing is expensive, and the inception of new ergogenic aids and novel masking agents have made detection of illegal doping a challenge. Furthermore, negative ramifications of the positive results of a drug test mandate precise sampling and accurate and updated testing protocols. Fortunately, research has fostered novel analyses and improved techniques for detection that helps WADA in its attempts to maintain a fair “playing field.”
Detection of rhEPO includes both indirect approaches via measurement of markers of enhanced erythropoiesis in addition to direct detection of recombinant isoforms. In the 1990s, the International Cycling Union introduced random blood tests to detect abnormalities in biologic parameters as a screening test for subsequent urinary detection of rhEPO. Although this technique was successful in preventing heavy use of rhEPO, it could not distinguish athletes with naturally elevated blood parameters. Therefore, in 2007, individual reference ranges were introduced in the form of “biologic transport,” or the method of tracking each athlete’s own blood numbers, known as the Athlete Biologic Passport hematologic evaluation. Markers that are currently tracked include hematocrit, hemoglobin, red blood cell count, reticulocyte percentage, reticulocyte number, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration, among others. Blood results are then processed by a model that identifies any abnormal blood parameters compared with the athlete’s individual baseline. These operating guidelines, in accordance with the WADA code, were implemented in 2009.
Additional models have since been used, including recent advances in electrophoresis techniques, such as isoelectric separation, Western blot analysis, antibody detection, and mass spectrometry, to help distinguish between physiologic EPO versus rhEPO. Although our current understanding and knowledge are limited, ongoing research will develop innovative testing methods, help decrease false-positive results, and improve sensitivity of contemporary testing measures. What is clear, however, is that the combination of an athlete’s biologic passport (based on individual profiling) and urine tests targeting rhEPO has undoubtedly made it more challenging for athletes to compete illegally.
Adverse Effects
For some athletes, the benefits of using performance-enhancing agents clearly outweigh the risks. EPO and its synthetic analogs are known to increase red blood cell mass. Accordingly, physiologic benefits include normalization of cardiac output, enhanced exercise tolerance, reduced fatigue, and subjective quality of life improvement. Erythropoietin excess has been associated with hazardous adverse effects including amplified blood viscosity, which in turn can lead to headache, hypertension, stroke, congestive heart failure, venous thromboses, pulmonary emboli, encephalopathy, and tissue hypoxia. Some reports have indicated that rhEPO administration leading to excessive erythropoiesis may result in reduced thickness of cortical bone and theoretically increase fracture risk. Lastly, intuitively EPO should benefit endurance athletes in whom aerobic performance is crucial, yet controlled studies to determine the efficacy and safety of EPO are lacking.
Creatine
Historical Perspectives
One of the most popular supplements currently used by athletes, creatine is a nitrogenous compound synthesized in the body; it is also absorbed by the body from fish and meats. In 1992, creatine was manufactured as a supplement to potentially improve muscular performance. Shortly thereafter, it was touted as a supplement that delayed fatigue and enhanced athletic performance.
Physiology
Creatine has a fundamental role in the structure and function of adenosine triphosphate, the body’s prime energy source. It is synthesized, largely in the liver, from amino acids and subsequently is transported to skeletal muscles, the heart, and the brain, where it is absorbed into the cells. Intracellularly, creatine is phosphorylated into creatine phosphate, and in this state it serves as an energy substrate that contributes to the resynthesis of adenosine triphosphate for energy. Creatine is also proposed to buffer lactic acid produced during exercise. Lactic acid is a byproduct of intense exercise caused by the accumulation of H+ molecules, and in excess it limits exercise. Creatine binds these molecules, delays fatigue, and lengthens exercise duration. Creatine may also help athletic performance by promoting protein synthesis, thereby increasing muscle mass, a process believed to occur by the synthesis of the myosin heavy chain in skeletal muscles. Lastly, when combined with high-carbohydrate diets, creatine may enhance glycogen stores, which could be advantageous during long-duration, high-intensity exercise.
Creatine may benefit athletes who engage in sports that emphasize short bursts of intense anaerobic activity, such as football, soccer, lacrosse, hockey, basketball, and powerlifting. Short-term creatine supplementation has been shown to enhance the ability to maintain muscular forces during jumping, intense cycling, and weight lifting. It is important to note, however, that not all athletes appear to benefit from creatine supplementation. At the outset, it was thought that athletes involved in aerobic sports do not appear to benefit from creatine supplementation, but it may have positive effects on endurance activities. Regardless of the sport, it appears that some athletes are “responders” and other athletes are “nonresponders” to creatine supplementation. It is estimated that about 30% of athletes are “nonresponders” because they already possess a maximal amount of creatine that can be stored by muscle cells. Unfortunately, muscle creatine content is measured only by muscle biopsy, making it necessary for an athlete to use the supplement on a “trial and error” basis.
Early studies emphasized the importance of loading creatine. Athletes would use large doses (20 g per day of creatine for 5 days) before reaching a maintenance dose (2 g/day). More recent evidence has shown that loading is unnecessary and that a low-dose regimen of 3 g per day is just as effective, although it may take longer to glean benefits.
Adverse Effects
An increase in body mass of up to 2 kg occurs frequently and is believed to be the result of an increase in water in the body. According to some recommendations, creatine should not be consumed either before or during intense exercise. Case reports of gastrointestinal distress (diarrhea) are common, but a direct cause and effect relationship has not been defined. Concerns regarding nephrotoxicity have been raised, but in healthy persons without a previous history of renal disorder, creatine supplementation does not seem to negatively affect renal function if athletes adhere to recommended dosing.
The use of creatine in athletes is thus popular, because it is considered a legal means of improving performance. Despite findings of a few controversial studies, supplementation with creatine can increase fat-free mass and strength. Creatine may also be of benefit to athletes who engage in high-intensity sprints or endurance training, but the benefits seem to diminish with prolonged exercise.
Growth Hormone
Historical Perspectives
One of the most popular ergogenic drugs used by athletes, human GH was discovered in the 1920s when researchers noted that after an injection of ox pituitary glands, normal rats grew abnormally large. Animal breeders later used these injections to increase muscle mass and decrease body fat in their breeds. In the 1950s, GH extracted from the brains of cadavers from Africa and Asia was administered to children whose growth was stunted by absence of GH. Thousands of short-statured children were successfully treated with human GH. However, as a result of treatment with cadaver extracts, Creutzfeldt-Jakob disease developed in many children. This disease causes progressive dementia, loss of muscle control, and death. By the early 1990s, the FDA had stopped distribution of GH, yet there was a need to treat children who had short stature that was induced by low levels of human GH. The Genentech Company used recombinant deoxyribonucleic acid technology to manufacture a biosynthetic GH, somatrem (Protropin), enabling GH to be safely provided to children in need. However, the use of human GH as a supplement is universally illegal.
GH affects almost every cell in the body. Because human GH levels dip with advancing age, it has been endorsed as an antiaging agent. Human GH secretion can be stimulated throughout life by either sleep or exercise, and thus combining exercise with rest may be beneficial. Currently, long-term studies on the effectiveness of human GH are lacking.
Mechanism of Action
Human GH is a polypeptide that is produced and stored in the anterior pituitary gland. Its secretion is high during puberty, and it continues to be secreted throughout a person’s lifetime. Secretion occurs daily in a pulsatile fashion, with the highest levels observed shortly after the onset of sleep. Human GH works in two ways. First, by binding on target cells, it exerts its effects on adipocytes, which, in turn, break down triglycerides and prevent lipid accumulation. Second, after reaching the liver, human GH is rapidly converted into insulin-like growth factor-1 and thus exerts its growth-promoting effects throughout the body.
Athletes have used human GH and insulin-like growth factor–1 as ergogenic supplements. Human GH is an appealing supplement for athletes because it stimulates protein metabolism by stimulating amino acid uptake. It is also a potent regulator of carbohydrate metabolism by decreasing insulin sensitivity and cellular uptake of glucose. In addition, human GH stimulates the catabolism of lipids, making free fatty acids available for quick energy use and sparing muscle glycogen. Finally, human GH stimulates bone growth, which is crucial for growth in prepubertal youths.
Adverse Effects
Most notably, excess GH may cause problems with bone growth in adults. In adults, growth plates have fused but continue to enlarge in the presence of high levels of GH, resulting in dysmorphic, acromegalic features, particularly of the face, hands, and feet. Other problems include a predisposition to diabetes (attributed to decreased insulin sensitivity), cardiomyopathy, and congestive heart failure. Correlations have been noted between human GH and the enlargement of intracranial lesions, amplification of intracranial hypertension, and leukemia in patients treated with recombinant human GH.
No scientific studies have been conducted that show improved athletic performance with use of human GH. Nevertheless, human GH has been used widely by athletes. Limitations of human GH include poor quality (because much of it is supplied from international sources), exorbitant cost (about $1000 per month), and availability only in the parenteral form (which increases risk of infection). Nonetheless, human GH is used frequently, especially because few solid testing methods exist, aside from a few tests performed within a few days of dosing. Previously, an “isoform test” used to detect the presence of synthetic HGH was effective for detection of use within 12 to 72 hours of ingestion. A recent test called the “biomarker test,” which evaluates the presence of chemicals produced by the body after human GH use, may be used alone or in conjunction with the isoform test. The U.S. Anti-Doping Agency and the United Kingdom Anti-Doping Agency had proposed testing with use of this method at the 2012 London Olympics, curtailing the confidence of athletes that they could escape detection.
Caffeine
Historical Perspectives
Caffeine is the most widely used legal ergogenic drug, with billions of people using this drug annually. It is commonly ingested in liquid forms but is also available in tablets. Typical doses of between 5 and 10 mg/kg are ingested 1 hour prior to athletic contests. The United States Olympic Committee had previously classified caffeine as a restricted agent, allowing no more than 12 µg/mL in urine. However, because of highly variable excretion rates, this restriction has been eliminated. Caffeine is not included on the 2012 Prohibited List of substances and has not appeared on the list since 2004. The drug is part of WADA’s monitoring program, which includes substances not prohibited in sport, yet monitored to detect misuse in sport. Since 2010, caffeine use among athletes has increased, although no global indications of misuse have been detected.
Mechanism of Action
Historically, caffeine has been used to enhance physical and mental performance. Ergogenic effects are mediated both centrally and peripherally. Once in the bloodstream, caffeine is rapidly absorbed, leading to the stimulation of excitatory neurotransmitters. Centrally, caffeine increases perception of physical effort and improves neural activation of muscle transport. Peripherally, caffeine leads to the release of free fatty acids from adipose tissue, sparing muscle glycogen and maintaining blood glucose levels. It also stimulates potassium transport into tissue, maintains muscle cell membrane excitability, and decreases muscle cell reaction time after neural stimulus while reducing muscle fatigue. Good evidence indicates that caffeine ingestion enhances endurance while providing performance enhancement. Beneficial effects occur when modest doses of ~1 to 3 mg × kg −1 are taken 1 hour prior to exercise without noticeable dose dependency, although higher doses (>6 to 9 mg × kg −1 ) tend to induce adverse effects.
Adverse Effects
The most common adverse effects include anxiety, restlessness, panic attacks, gastritis, reflux, and heart palpitations. Chronic users may experience withdrawal manifested by headache and fatigue, especially after abrupt discontinuation. Acute caffeine intake is known to increase urinary loss of fluid, although a recent review has proposed that there is little evidence that the drug affects overall fluid status. Doses of caffeine within the ergogenic range do not alter sweat rates, urinary losses, or indices of hydration status.
Studies on the effects of caffeine and athletic performance have focused on endurance sports. In long-distance cycling competitions, time to exhaustion at maximum oxygen uptake was significantly improved. In another cycling study, a 7% increase in distance covered in 2 hours was noted. Evidence also shows that caffeine can enhance performance in sustained, high-intensity activities. In one study, 1500-meter swim time was significantly improved in trained athletes. Currently, little evidence exists regarding the effect of caffeine on anaerobic activities, power, and strength enhancement. One study noted improvement in one-repetition-maximum bench press after short-term caffeine supplementation, but no improvement was found in Wingate, leg extension, and total volume of weight lifted during an endurance test. A great need exists to educate athletes regarding the responsible intake of caffeine to appropriately balance and maximize benefits without placing themselves at jeopardy for adverse effects.
Summary
For centuries, athletes have been willing to risk death in an attempt to improve their ability to compete in sports. What can persons entrusted with the health of athletes do to protect athletes from themselves? The first step is “meaningful education” as reflected by the important tenet in medicine—“you only recognize what you know.” Most medical personnel receive very little education about doping and ergogenic aids during their schooling. To stay abreast with the practices of athletes, lifelong learning is essential. Health care professionals should be able to communicate openly with athletes regarding the health risks and legality of ergogenic aids and the importance of healthy nutrition and honest training as a viable and preferred alternative for promoting athletic superiority. Second, the medical community should conduct scientific controlled studies on athletes who are using ergogenic drugs. Obviously, such studies would be difficult to conduct because many of these drugs are illegal, many ergogenic drugs have significant adverse effects, and research oversight committees often are reluctant to approve studies using drugs with known or suspected adverse effects. Third, effective drug testing and stringent penalties for athletes, coaches, teams, and nations who use banned substances are imperative.
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