1.9 Sports endocrinology: the use and abuse of performance-enhancing hormones and drugs

The endocrine system pervades all of sports, just as it pervades all of biology and medicine. The importance of endocrine glands and their hormonal products and effects in sports is axiomatic to the endocrinologist, and the actions in athletic activity of key hormones such as adrenaline are even known to much of the lay public. The other chapters in this textbook provided a systematic review of the effects of these hormones on organ systems, including those involved in sports as well as in health and disease. This chapter will only provide brief review of endocrine physiology that is relevant to sports. Such reviews can be readily found in other publications (1) as well as in the other chapters of this book. This chapter will instead focus on the role of hormones in the international sports arena, an arena that is populated by professional athletes, aspiring athletes, and the weekend warrior public of essentially all countries.

Unlike classic endocrinology, where primarily endogenous hormones play a role in both health and disease, exogenous hormones taken supraphysiologically as well as physiologically have a major role in contemporary sports endocrinology (2). Consequently, sports endocrinology often collides with the administrative, regulatory, and legal bodies that reside at its intersection with sports events (2, 3). While systematic research will inform the basis of much of this chapter, anecdotes taken from sport can also be provocative if not informative (3). For example, consider the role of thyroid hormone replacement in the athlete who has hypothyroidism, a situation recently manifest by a pitcher in major league baseball who had surgery for thyroid cancer. Without much research support, the temptation exists to try to enhance this athlete’s performance by increasing his thyroid hormone dose before he is scheduled to pitch. At the other end of this particular spectrum is the athlete who chronically abuses androgens. Cases that also challenge the endocrinologist can fall in between these two extremes, such as glucose regulation for a diabetic footballer between games and during games and the cricketer who uses amphetamines intermittently.

While the use of hormones is at the centre of classic endocrinology, the medical periphery that is the ambit of some of sports endocrinology lurches beyond, into exercise pills and gene doping (1–4). It will become apparent that there is a paucity of controlled studies that demonstrate performance-enhancing effects of most of the agents abused by athletes (5). However, when all of the evidence is examined, exogenous androgens and perhaps growth hormone do seem to enhance athletic performance.

The central nervous system–pituitary axis and its hypothalamic pathways, as the master regulatory system of endocrine function, play an important role in sports activity (6). The onset of such activity is accompanied by an acute increase in the secretion of adrenocorticotropin (ACTH) and growth hormone. The central nervous system origin of this secretory pattern seems to be mediated through the dorsomedial hypothalamus (7). In addition to the target organ action of each of these pituitary hormones, there is also an increase in cardiorespiratory function that accompanies central activation of the sympathetic axis (7, 8). The relationship of sports and exercise and the other pituitary hormones seem lesser and on a more chronic basis if at all.

Increased secretions of endorphins, oxytocin, vasopressin, and prolactin have been reported in sports activities, but the findings have been inconsistent (9, 10). The endorphins are postulated to counter the effects of stress during exercise, an action that might be shared with oxytocin and prolactin. But there is no good evidence that exercise-related euphoria, such as the runner’s high, is associated with endogenous endorphins (11). Vasopressin acts to regulate fluid homoeostasis during exercise and sports activities, along with aldosterone and the natriuretic peptides. There is little evidence of the abuse of these hormones by athletes. However, electrolyte abnormalities can occur during sports activity. Interestingly, rather than hypernatraemia caused by excessive sweating, it is hyponatraemia induced by overhydration that is more likely to be problematic (12).

The ACTH-adrenal axis is the major regulator of responses to perturbed homoeostasis. While there are distinct regulatory pathways and actions of adrenomedullary and adrenocortical hormones, there is both remote and recent evidence of a unitary sympathoadrenal system that involves circulating levels of ACTH, corticosteroids, and catecholamines of both adrenal and peripheral origin (8). These hormones are acutely increased during sports activities, where they exert their actions on organ systems and metabolic pathways that are invoked in exercise. As will be discussed later, forms of all of them, such as ephedrine and amphetamines, are abused by athletes.

Growth hormone is well known to directly and indirectly regulate the growth and proliferation of most tissues. The exercise-related increase seen in growth hormone secretion produces the well-described metabolic effects of this hormone, which include gluconeogenesis and increased glucose metabolism, lipolysis, and increased fat metabolism, and proteolysis and increased protein metabolism. Skeletal muscle activity is nourished by these actions of growth hormone (13). In addition to these acute effects of growth hormone, there is a more chronic increase in muscle and bone mass, which is also mediated by the growth factors that are stimulated by growth hormone, notably insulin-like growth factor 1 (IGF-1) (14). In addition to growth hormone, there is evidence that IGF-1 itself is being used to enhance athletic performance, either alone, or in combination with growth hormone (13, 14).

The sports- and exercise-related actions of growth hormone have been best appreciated in growth hormone-deficient states. Exercise capacity and muscle strength are impaired in growth hormone deficiency, and physiological replacement therapy of growth hormone returns these parameters toward normal (15). Vigorous exercise regimens can magnify the growth hormone response to sports activity (16).

While administration of supraphysiological doses of growth hormone recapitulates the metabolic effects described above, there is little convincing evidence that these metabolic effects result in improved athletic performance. In fact, people with acromegaly increase their exercise capacity on successful treatment, which lowers growth hormone levels (17). Nevertheless, growth hormone abuse by athletes is widespread, and there is evidence that the administration of testosterone along with growth hormone does improve exercise performance and strength, especially in elderly subjects (5, 13). The growth hormone excess of acromegaly has only transient effects on sports activities. Andre the Giant (André René Roussimoff) was notoriously able to capitalize on these effects during a brief career as a wrestler. He chose not to be treated for his known pituitary tumour. However, he eventually succumbed to the complications of growth hormone excess that include hypertension, coronary artery disease, and diabetes mellitus (17). Malignancy is also a potential risk of growth hormone excess.

One of the most common athletic complications of pituitary function is the amenorrhoea seen in elite female athletes (18); in addition, delayed but normally progressing puberty can be seen in gymnasts (19). Since the gonadotropins do not seem to have a direct effect on exercise and sport but rather mediate their actions through their target hormones, these issues are discussed under gonadal steroids. But exercise-induced amenorrhoea is accompanied by decreases in gonadotropin-releasing hormone (GnRH) pulses from the hypothalamus and the consequent decrease in luteinizing hormone and follicle-stimulating hormone (18). A substantial number of such female athletes also have anorexia and bulimia. This can culminate in what has been termed the female athlete triad of osteoporosis, amenorrhoea, and eating disorders (18, 19).

The major effect of thyrotropin (thyroid-stimulating hormone (TSH)) in regulating the production and secretion of thyroid hormones by the thyroid gland is well known, and there is some recent evidence that TSH can have direct effects on its own (20). Although thyroid hormones are important in all metabolic pathways that underlie sports activity and exercise, most studies fail to show any remarkable changes in TSH and thyroid hormones during athletic activity, and they have has not found wide use of TSH as a drug of sports abuse (2, 3).

The skeletal system plays an obviously important supporting role in athletic activity. However, the regulation of skeletal and calcium homoeostasis by the three calcaemic hormones—parathyroid hormone (PTH), calcitonin, and vitamin D—does not seem to manifest any substantial and acute changes during sports activities (21). The same holds true for calcium and magnesium concentrations. There are, however, some chronic changes of skeletal mass that correspond to the changes in muscle mass that can be readily appreciated in some sports, such as in the increased bone and muscle mass in the dominant arm of tennis players (22). But these changes are primarily mediated by the anabolic hormones, as discussed later. Exercise regimens, especially early in life, can results in an increase in peak bone mass, an effect that can be sustained by continuing exercise but diminishes with reduced exercise (22). Amenorrhoea, even when exercise related, can have the deleterious skeletal effect of reducing bone mass (18, 21).

The two thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃), have actions on essentially every organ system in the body and notable muscle (20). While there are important sports-related actions by thyroid hormones on all organ systems, especially skeletal and cardiac muscle, these effects are not generally reflected by any consistent changes in circulating levels of the hormones during exercise. However, especially relevant to sports, peripheral muscle weakness and cardiac muscle dysfunction are seen in both hyperthyroidism and hypothyroidism. Since both conditions can be readily treated, the thyroid axis cannot be commonly blamed for impairing sports activity. Appropriate treatment of hyperthyroid and hypothyroidism maintains athletic performance. Abuse of thyroid hormone is more commonly seen in attempts to control weight and while this can occur in a sports context, it occurs more widely in the general population (2, 20).

The pancreatic hormones play a well-known role in glucose homoeostasis (23). Among the major pancreatic hormones, insulin and glucagon have sports-related significance. They served their well-known action in glucose metabolism of providing fuel, especially for muscles, during athletic activity. Insulin’s general anabolic properties are important in maintaining the requisite integrity of exercise-related organ systems, especially muscle and bone. The anabolic activity of insulin provides the rationalization used by athletes to abuse insulin in their training regimens (1, 2). But, like most hormones, there is no convincing evidence that insulin enhances performance. Furthermore, insulin puts the abuser at great risk for hypoglycaemia. Of course, people with diabetes are expected to use insulin at all times, even during competitive sports activities (2).

The pleiotropic actions of cortisol are well- known. Equally well known is the fact that ACTH-stimulated cortisol levels increase during exercise and that there is a direct correlation between this increase and the intensity of the exercise (8). Along with the adrenergic axis, cortisol is a major participant in long-recognized and well-known fight or flight response. It is not then surprising that corticosteroids are among the most widely abused drugs in sport. This despite the fact that performance has not been shown to be improved by the administration of supraphysiological doses of cortisol (24). Furthermore, glucocorticoids used chronically decrease muscle mass and increase bone resorption, both of which are harmful, especially for athletes (6, 21, 24, 25). This abuse is complicated by the fact that there are legitimate uses of corticosteroids in sport, such as their intra-articular injection and use in asthmatic people. This widespread use results in a substantial incidence of adrenal gland suppression in athletes, best documented for cyclists.

Sex steroids, also produced in lesser amounts in the adrenal cortex, have profound anabolic effects on most organ systems, especially bone and muscle. These effects are chronic, and exercise is not associated with a substantial increase in endogenous testosterone. (25). Nevertheless, androgens are among the most commonly abused drugs in sport. Athletes attempt to take advantage of their anabolic effects on the musculoskeletal system in order to enhance performance (1, 2). Early studies evaluated the relationship between performance parameters and physiological concentrations of testosterone and found no substantial relationship to muscle strength; however, later studies demonstrated a correlation with muscle strength and serum testosterone levels that exceed the normal range (26). In the male with hypogonadism, muscle mass is decreased and athletic ability impaired. In the male with precocious puberty and increased testosterone, muscle mass is increased. Both conditions can be ameliorated by appropriate treatment (2, 25, 26).

Conversely, impaired estrogen production in the exercising female is a major problem in sport for several reasons (18). Athletic-related amenorrhoea is seen in elite female athletes such as swimmers, runners, ballerinas, and gymnasts. Even eumenorrhoeic female athletes can have anovulatory cycles. Delayed puberty is common in this group of female athletes. (19) The low or absent oestrogens in such females leads to the failure to achieve peak bone mass and/or the development of osteoporosis, infertility, and abnormalities in lipid metabolism, which increase coronary heart disease risk. Oestrogen administration can be useful in reversing these abnormalities, but the reversal is often incomplete, especially as it relates to bone mass (18, 21).

In addition to the classic endocrine organs, other organs secrete chemicals that have all of the characteristics of hormones. Most notable is erythropoietin (EPO) from the kidney. By increasing red blood cell mass, EPO helps to deliver oxygen, especially to active muscles (27). This regulatory pathway is abused by athletes in two ways, by the direct administration of EPO and by blood transfusion, called blood doping (2, 3). These forms of abuse are common among cyclists; here evidence for sustaining athletic activity is reasonably convincing despite the absence of controlled studies (3, 27).

Sports activities have been classically divided according to gender in order to accommodate the seeming inherent performance advantages that males have over females (28). This gender difference can be largely attributed to the differences in muscle mass and circulating concentrations of testosterone found in males and females. Androgen administration to female to male transsexuals and androgen deprivation of male to female transsexuals can attenuate these differences in muscle mass (25, 26). For male to female transsexuals, anti-androgens are usually combined with oestrogens. Commonly used antiandrogens are cyproterone acetate and medroxyprogesterone. Finasteride, while an antiandrogen, is banned by the International Olympic Committee (IOC). Long-acting GnRH can also be used for male to female transsexuals. Testosterone is the common treatment for female to male transsexuals. These hormonal ministrations have the desired phenotypic results after about 1 year of treatment, but effects on athletic performance are more difficult to quantitate (28).

Chromosomal sex, specifically the determination of Barr bodies in buccal smears, had been commonly used to make the male to female distinction in athletes (2, 28). However, it has become increasingly appreciated that the male–female dichotomy for gender is an oversimplification and that there are many athletes, as well as nonathletes, who can be loosely categorized as intersex. Many sports organizations, most notably the IOC, but other international and national sports bodies as well, now allow sex-reassigned transsexuals to compete with members of their new sex if they meet certain criteria (28). In addition to hormonal administration, gonadectomy and legal recognition of newly assigned sex is required for athletic participation. It should be noted that sex steroid administration is generally prohibited otherwise for participants in competitive sports.

In most instances, hormones are usually given as a pill or injection, and the hormones so delivered at a relatively short time of action (2). The identification and isolation of specific genes that encode peptides and proteins, including hormones, has led to the development of molecular methods that allow for the administration of these genes to experimental animals as well as patients (3). These genes can then express their product and provide a sustained amount to the recipient.

While this methodology can be effective in genetic treatment of disease, it could also be used to introduce to the recipient genes that encode for performance and enhancing agents–gene doping (2–4). Although there are other genetic procedures that can be used to enhance athletic performance, gene doping is the closest to realization. In fact, the World Anti-Doping Agency (WADA), formed in 1999, has identified gene doping as the nontherapeutic use of genes, genetic elements, and/or cells which have the capacity to enhance athletic performance (Box 1.9.1).

Although there has not been a confirmed episode of gene doping in sports, WADA has prohibited the technique for competing athletes worldwide. Many hormones with putative performance enhancing characteristics, such as growth hormone, are susceptible to such techniques that could be used in performance enhancement. As the medical use of gene therapy progresses, it is likely that unscrupulous athletes from all countries will appropriate the methodology for performance enhancement (2, 4).

Genetic variations that can confer extraordinary increases in bone and muscle mass are largely unknown (29). While the effects of increased bone mass on athletic ability is not well defined, the advantage that increased muscle mass can have in sport is well known (4). Some of the genes responsible for increased muscle mass, such as myostatin, have been identified. This opens the door to the use of gene doping to confer athletic advantage at local, regional, national, and international venues (30).

The importance of exercise for athletic ability, as well as for the treatment of some diseases, is obvious. But the discipline necessary for regular exercise is often wanting. Agents have been recently identified that could serve as exercise mimetics by regulating the metabolic and contractile properties of muscle (29). These agents are based on the role for both the peroxisome-proliferator-activated receptor δ (PPARδ) and AMP-activated protein kinase in regulating muscle function. Both regulate the expression of oxidative genes in muscles and the metabolic phenotype of myofibres by causing a conversion from fast twitch type II myofibres to slow twitch type I myofibres fibres, which are able to perform sustained aerobic work, a conversion that is also caused by exercise. A PPAPδ agonist, named GW1516, given to exercising mice can increase the expression of oxidative genes in muscles and increase exercise endurance by about 70%. An activator of AMP-activated protein kinase, called AICAR (5-aminiimidizole-4-carboxamide-1-δ-ribofuranoside) given to sedentary mice can increase exercise endurance by about 40%. Pharmaceutical companies are developing agents like these in order to treat obesity in patients such as those with diabetes who are unable to exercise because of musculoskeletal or cardiovascular disease (29). Will they become the next generation of drugs for enhancing athletic ability?

The combination of sophistication and the naïveté about endocrinology that has been manifest in the international use, abuse, and detection of performance enhancing is surprising (1–4). The pharmacopoeia of agents, mostly hormones, that are used by athletes from all over the world to gain an unfair edge extend well beyond the scope of ‘steroids’ and include many if not most hormones. The method of abuse include oral, mucosal, dermal, and parenteral administration; the agents are taken in continuous, intermittent, and periodic regimens, many designed to avoid detection; and the regimens also use masking agents such as diuretics, α-reductase inhibitors, probenecid, urine dilution, and plasma expansion, and even contraptions to switch urine collections, such as intravaginal and intra-anal containers of substituted urine. The common use of urine rather than blood samples allows such switching to take place more readily. Furthermore, the common practices of ‘stacking’ (administration of multiple drugs) and ‘pyramiding’ (use of ascending and descending doses) are intended to elude detection as well as enhance performance. Random and unannounced testing, especially when performed unrelated to competition, may help to counter the deceit, but only a small percentage of the estimated cheaters are caught (3, 4).

Anabolic steroids are the biggest offenders (2, 31). Advances in steroid chemistry in the mid-1900s led to the development of many androgens, but toxicity and the limited legitimate market for these agents resulted in their commercial abandonment. Many of these abandoned agents, or agents relegated to veterinary use, became the basis of the illegitimate anabolic steroids use in sports. Legislation in this area has been complex and full of loopholes with many agents failing to be regulated or weakly regulated as dietary supplements (2, 32). And the internet has magnified this market by providing an international 24-h pharmacy. While there are attempts at regulation in many nations, WADA with its ever-expanding, frequently updated list of prohibited drugs, now dominates the regulation of these agents in sports, but enforcement remains elusive (33). The WADA list includes anabolic steroids, EPO, growth hormone, chorionic gonadotropin, LH, insulins, and corticotropins, Among the hormone modulators are aromatase inhibitors, selective oestrogen receptor modulators and selective androgen receptor modulators, clomifene, adrenergic drugs, glucocorticoids, and cannabinoids. Box 1.9.2 lists the hormone and hormone-like agents prohibited by WADA. In addition, other prohibited agents include diuretics and masking agents such as probenecid, narcotics, alcohol in competition in certain sports, and PPARδ agonists. Prohibited methods include gene doping and enhancement of oxygen transfer with blood doping.

Endocrine testing is at the core of clinical endocrinology. However, the methodology is often modified for testing in sports endocrinology. Here the task is more difficult, since immunoassays have to be designed that can distinguish exogenous, usually recombinant, recombinant molecules from endogenous hormones on the basis of the chemical and immunochemical signature that derives from their molecular size and glycosylation state (14). For example, because recombinant hormones are not glycosylated during the usual production processes, chemical methods, such as isoelectric focusing for recombinant EPO and darbepoetin, are needed to distinguish them from their glycosylated normal counterparts (2). Even so, agents such as these can be detected for only a few days in the blood, even though their effects can last for weeks. So the sophisticated abuser can stop taking the drug before an athletic event to allow for its decay and to diminish measurable levels in the blood. In addition, many monitoring programmes do not allow blood testing because of ‘privacy’ concerns.

Many endocrine tests are also performed by gas chromatography mass spectrometry and with use of liquid chromatography tandem mass spectrometry (2). Chromatography separates the analytes, and mass spectrometry identifies them by fragmentation patterns in comparison with known standards. These procedures are less widely applicable to proteins and peptides, for which immunochemically based methods are required. Even sensitive and specific immunoassays are limited in their application to illegal use of protein and peptide hormones. For example, insulin and its analogues, recombinant growth hormoneand EPO cannot be readily distinguished from their natural counterparts by standard immunoassays (2, 14). An additional example of testing complexity is illustrated by the procedures needed to distinguish natural testosterone from its pharmaceutical counterpart: gas chromatography-combustion-isotope ratio mass spectrometry can detect the 13C difference between the two. Similarly, the ratio of epitesterone to testosterone can be used to detect drug abuse because the pharmaceutical preparation of testosterone contains none (2).

Basic principles of endocrine regulation can also inform drug testing and deceit (3). Abusers learn about the half-lives of the various agents and the influence thereon of different routes of administration. The pseudosophisticated taking of clomifene has been used in an effort to stimulate suppressed levels of testosterone, resulting from endogenous administration (31). Furthermore, drug testing must conform to the rules of scientific reliability for the relevant jurisdiction (2).

There have been challenges in developing a test for recombinant growth hormone (14). The test used at the 2004 and 2008 Summer Olympics used an immunoassay to determine the difference between exogenous and endogenous growth hormone, but there have been difficulties in distributing testing kits to the WADA global network of accredited testing laboratories due to a limited supply of the distinguishing antibody. Even then, the test can only detect recombinant growth hormone use going back 1–2 days, severely limiting its effectiveness. Because the test was used almost exclusively at the Olympics, guilty athletes knew it was coming and simply stopped using recombinant growth hormone several days prior to the games. Indeed, through 2008, antidoping agencies had yet to announce a positive test for recombinant growth hormone.

‘Designer’ anabolic steroids create yet another challenge for the perpetually underfunded antidoping community (2, 31). Since the standard method for testing urine is performed using gas chromatography and high-resolution mass spectrometry, it can detect only some of the offending substances it is designed identify (2). Self-styled biochemists can render a known anabolic steroid virtually undetectable by tweaking a few molecules, or by re-engineering an old steroid that was created but never marketed (2). Victor Conte, the founder of BALCO and the architect of its underground doping programme, used what came to be known as tetrahydrogestrinone (THG), which had the unique characteristic of dissolving when the urine was heated for the purposes of gas chromatography. It was only after a used syringe of THG was mailed to the US Anti-Doping Agency that Dr Don Catlin and his UCLA laboratory were able to reverse-engineer THG and develop a method for detecting it in urine (2).

As a result of the above, in the USA the sport of baseball has belatedly begun to address drug abuse among its athletes. Even though years later than in other major sports, a drug policy was finally instituted in 2008. It took an exposé of drug use in baseball (4) to prompted Major League Baseball to begin an investigation of the problem. Some athletes, though, choose to beat the test instead of beating the tester (34). According to US Anti-Doping Agency statistics, nearly 10% of planned out-of-competition tests are ‘missed,’ either for innocent or more nefarious reasons (29). An athlete may have had a last-minute change in plans and neglected to update antidoping authorities. Or he or she may have purposely said they would be in one place when they were in another, creating a window to complete an anabolic steroid cycle or administer a dose of recombinant EPO. Several high-profile Russian track and field athletes were barred from the 2008 Summer Olympics after DNA testing allegedly proved their out-of-competition urine samples did not belong to them, suggesting a widespread conspiracy within the Russian track and antidoping federations. There also have been increasing reports of ‘contraptions’ designed to foil tests. An NFL player was caught in 2005 with ‘The Whizzinator’, a prosthetic penis attached to a jock strap with a compartment to store and heat ‘clean’ urine from freeze-dried packets. At the 2004 Summer Olympics, WADA officials accused members of Hungary’s track and field team of using a crude device that stores a ‘clean’ urine sample in a small reservoir hidden in a body cavity. There have even been reports of athletes going so far as to use a catheter to fill their bladder with untainted urine shortly ahead of a drug test (31). All the while, presumably, their endocrine systems were dramatically being altered by an array of banned performance-enhancing substances (35).

There are hundreds of examples of athletes from essentially every country who have been caught abusing drugs and hormones (31). In addition to individual athletes, national programmes have been documented (East Germany) as well as suspected (China) of systematically providing their athletes with performance-enhancing drugs. This virtual epidemic is also illustrated by the recent identification of over 100 US baseball players who took performance-enhancing drugs. While recognizing that there are legitimate uses for physiological hormone replacement, endocrinologists have been naïve in failing to recognize the type of risk-to-benefit analysis that athletes apply in considering the pharmacological use of performance-enhancing agents. The abusing athletes consider the benefits to their performance while minimizing the risk, and some accept substantial risk for even the slightest edge. The practicing endocrinologist must be aware of this dissonance.

Supported by the Department of Veterans Affairs and the National Institutes of Health. Dr. Deftos is Distinguished Professor of Medicine at the University of California, San Diego, and Professor of Law at the California Western School of Law, San Diego California. Mr. Zeigler is on the staff of the San Diego Union Tribune.

The confrontation of medical science with the law and with sports culture continues. Jail sentences have been levied and several prominent athletes are being tried in court about lying to federal agents about illegal drug use. And sports legacies have been tarnished by admitted and even suspected use of performance enhancing drugs. Even related deaths have occurred. While some issues have been clarified others have been obscured. The selected illustrations that follow exemplify the continuing turmoil in this World.

A recent study partially funded by WADA was conducted to determine the effect of growth hormone alone or with testosterone on body composition and measures of performance (36). The design was a randomized, placebo-controlled, blinded study of 8 weeks of treatment followed by a 6-week washout period of 96 recreationally trained athletes (63 men and 33 women) with a mean age of 27.9 years (SD, 5.7). Men were randomly assigned to receive placebo, growth hormone (2 mg/d subcutaneously), testosterone (250 mg/wk intramuscularly), or combined treatments. Women were randomly assigned to receive either placebo or growth hormone (2 mg/d).

Growth hormone significantly reduced fat mass, increased lean body mass through an increase in extracellular water, and increased body cell mass in men when coadministered with testosterone. Growth hormone significantly increased sprint capacity, by 3.9% in men and women combined and by 8.3% when coadministered with testosterone to men; other performance measures did not significantly change, and the increase in sprint capacity was not maintained 6 weeks after discontinuation of the drug.

The authors concluded that growth hormone supplementation influenced body composition and increased sprint capacity when administered alone and in combination with testosterone. But they noted that the athletic significance of the sprint capacity improvement was not clear. Furthermore, they pointed out that the study was limited to recreational, not elite, athletes and that a modest dose of growth hormone was used over a short period of time.

The United Kingdom Anti-Doping agency announced in early 2010 the first instance where human growth hormone blood testing resulted in an athletic sanction. A rugby player accepted a 2 year sanction from playing or coaching because of an out-of-completion positive test, a procedure that had been applied t the 2004 and 2008 Olympics without apparent impact. The athlete was subsequently found hanged (37). The improved blood test will now be applied to Minor League baseball players, but the U.S Major Leagues still resist.

The confusion that still reigns here has been recently displayed by the off label use of growth hormone in Canada and the United States (38). In Canada, human growth hormone can generally be prescribed for ‘off-label’ uses, whereas such uses are banned by U. S. Federal law (U.S. law limits distribution of human growth hormone to adults to three specific FDA-approved treatments: for AIDS-related wasting, short bowel syndrome, and growth hormone deficiency). So while Canadian doctors can use human growth hormone to treat conditions for which the drug has not been explicitly approved, even bringing human growth hormone into the U.S. is illegal, and using human growth hormone to treat athletes without therapeutic-use exemptions violates sports doping rules. And while off-label prescribing of drugs is not uncommon in the U.S., federal law bans such use of human growth hormone. But in a seeming paradox, anabolic steroids, which are controlled substances, can be prescribed off-label. Legal complexities notwithstanding, human growth hormone use has been widely reported in athletics, including well-known international athletes. And interpreting the law has been confusing for many American and Canadian doctors.

The safety and efficacy of testosterone treatment in older men who have limitations in mobility was studied in community-dwelling men, 65 years of age or older, with limitations in mobility and a low serum testosterone (39). The subjects were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. The testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. But the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. So the risk/benefit analysis did not support testosterone use.

Transgender disputes have invaded the usually sedate world of golf (40). A former police officer who had a male to female sex change operation challenged the female-at-birth requirements for competitors of the U. S. Ladies Professional Golf Association (LPGA). In a suit filed in San Francisco federal court claiming the LPGA violates a California civil rights law, the golfer is seeking to prevent the LPGA from holding tournaments in the state until its policy is changed to admit transgender players. She also sued three LPGA sponsors and the Long Drivers of America, which holds the annual women’s long drive gold championship that she won in 2008 but was barred from competing in this year after organizers adopted the LPGA’s gender rules. In double irony, a golfer was among the first athletes in America to be banned from professional golf tournaments, and he was not a good golfer (41).