Use of androgens and other hormones by athletes

INTRODUCTION — Some athletes use drugs to attempt to improve their performance. The focus of the general news media is on the professional athletes who are caught using hormonal drugs, most commonly, androgens, in sporting events such as the Olympic Games and major league baseball. However, the majority of individuals using these medications are recreational athletes (eg, weightlifters and bodybuilders) who use them to improve overall strength and personal appearance [1].

This topic will focus on the epidemiology, physical and adverse effects, and detection of hormones used to improve athletic performance and physical appearance. The use of nonhormonal agents and nonpharmacologic enhancement methods (such as blood transfusions) are reviewed separately. (See "Prohibited non-hormonal performance-enhancing drugs in sport".)

DEFINITIONS

●Performance-enhancing drugs – Agents used to attempt to enhance athletic performance, and in the case of weightlifters/bodybuilders, physical appearance, with a goal of appearing leaner and more muscular. Although users take these drugs to improve their performance, data supporting their efficacy are limited. (See 'Efficacy' below.)

●Doping – "Doping" refers to the use of banned substances in competitive sports.

●Androgenic steroids – These (naturally occurring or synthetic) hormones increase lean body mass and decrease fat mass and are the most frequently used class of performance-enhancing drugs. The synthetic hormones differ from testosterone, as described below. The author of this topic uses the term "androgens" or "androgenic steroids" rather than "anabolic-androgenic steroids" because the anabolic effects of a steroid cannot be separated from its androgenic effects. (See '"Androgenic steroids"' below.)

●World Anti-Doping Agency (WADA) – WADA is the organization that oversees anti-doping policies and determines the list of substances (and doping methods) that are banned from sports. This includes hormonal and nonhormonal drugs as well as dietary supplements.

EPIDEMIOLOGY — The use of androgens has spread from competitive sports to leisure and fitness sports [1-3]. Bodybuilders and nonathletes use androgens as a strategy to increase muscle mass, improve performance, and enhance physical attractiveness. The frequency of this use of drugs by athletes and nonathletes has been addressed in a number of studies:

●Use of androgenic steroids has become a serious global public health problem. In a meta-analysis of 187 studies, the overall global lifetime prevalence rate was 3.3 percent but was higher in men (6.4 percent) than women (1.6 percent) [4]. The rate was higher among recreational athletes than professional athletes (18.4 versus 13.3 percent) and varied by region (highest in the Middle East [22 percent] compared with other regions of the world [2 to 5 percent]).

●Androgenic steroid use is thought to be common among police officers and the military, although prevalence data are limited. In a study of the use in British soldiers, reported usage was low compared with other groups above: 4.2 percent for testosterone, 1.1 percent for other androgenic steroids, and 2 percent for growth hormone [5]. A survey of United States military personnel found that 1.4 percent of individuals reported prescription anabolic steroid use and/or misuse in the past 12 months, and 5.6 percent reported use/misuse in their lifetime [6].

●Up to one-third of users develop dependence; most individuals who develop dependence are men [7]. It is estimated that in the United States alone, one million men have experienced androgenic steroid dependence. In one report, androgenic steroid users with dependence were more likely than those without dependence to have coexisting substance abuse and mental health disorders (heroin use, anxiety, and depression) [8,9].

●In 2013, the United States Centers for Disease Control and Prevention (CDC) reported that 3.2 percent of high school students had taken androgenic steroids without a doctor's prescription at least once [10]. Among students nationwide, the prevalence increased from 1991 to 2001 (from 2.7 to 5.0 percent) and then decreased between 2001 and 2013 (from 5.0 to 3.2 percent). The lifetime prevalence of use in high school males and females was 2.2 and 4.0 percent, respectively.

●Although androgen use is common among teenagers [10,11], the average age of onset of use appears to be in the early 20s [7].

●Growth hormone, like androgens, has been linked to many prominent athletes in sports such as baseball, swimming, and cycling [12]. In addition, approximately 5 percent of United States high school students report using growth hormone [2]. (See 'Growth hormone' below.)

●Use of these medications is more common when there is a family or personal history of drug abuse [1,13,14].

Patterns of use — As most athletes who take androgens or other agents to improve athletic performance do so surreptitiously, the pattern of use differs substantially from that of other medications/drugs:

●Users most often obtain androgens from the internet. Suppliers often provide packages containing a variety of drugs: testosterone, synthetic androgens, aromatase inhibitors, human chorionic gonadotropin (hCG), and phosphodiesterase inhibitors [15,16]. Some users will take drugs intended for veterinary purposes or obtain substances from laboratories that are not regulated by government agencies for manufacturing quality, so they may contain more or less than the stated amount.

●Some bodybuilding dietary supplements contain androgens, resulting in unwitting ingestion of banned substances [17].

●Some users will take more than the prescribed dose or will use medications prescribed for others.

●Athletes often take these drugs in various patterns, including in escalating doses ("pyramiding") and/or combining two or more steroids ("stacking"). Often, androgen users "pyramid" their doses in cycles of 6 to 12 weeks. They start with low doses of each drug, slowly increase until the middle of the cycle, and then taper back down to zero. Androgen deficiency may occur during this interval, and users typically take other medications such as clomiphene citrate or hCG to attempt to help the hypothalamic-pituitary-gonadal axis recover more quickly, but there is no evidence that they do so [15].

●Users may attempt to counter a side effect of one medication with another medication. As examples, most stacks will include both androgens and other drugs such as growth hormone for additional anabolic effect, hCG to counteract the reduction in testicular size resulting from high-dose androgen use, an aromatase inhibitor to counteract gynecomastia, a 5-alpha reductase inhibitor to prevent balding and acne that occur with exogenous androgens, and diuretics to promote water loss. (See 'Use of hCG' below and 'Estrogen blockade' below and "Prohibited non-hormonal performance-enhancing drugs in sport", section on 'Agents used to prevent detection of banned substances'.)

●Athletes discontinue the medications periodically to avoid side effects and detection just before a competition. (See 'Avoiding detection' below.)

●Rather than asking a clinician, users typically seek information about these drugs from other athletes, trainers, magazines, underground publications, and the internet.

Banned drugs — In the past decade, the list of drugs banned by the World Anti-Doping Agency (WADA) has grown to over 100 [18]. The 2017 WADA list includes androgens, "peptide hormones, growth factors and related substances," hormone antagonists and modulators, diuretics and other masking agents, stimulants, narcotics, cannabinoids, alcohol, glucocorticoids, beta-agonists, and beta blockers. It also includes different prohibited methods of enhancement including oxygen transfer, chemical and physical manipulation, and gene doping. (See "Prohibited non-hormonal performance-enhancing drugs in sport".)

Clinicians caring for competitive athletes should be aware of doping regulations as some banned drugs may be taken for medical purposes (eg, beta blockers, diuretics, 5-alpha-reductase inhibitors). Although athletes are responsible for informing clinicians that they are subject to doping restrictions, they may not realize that they are taking a substance that is prohibited. Clinicians should consider reviewing drug and/or supplement use to determine if an athlete is taking a banned substance.

In some cases (such as an athlete under the jurisdiction of a sport's governing body and subject to dope testing), clinicians may be asked to provide documentation for therapeutic use exemption to use banned substances for medical conditions, eg, testosterone for hypogonadism or growth hormone for growth hormone deficiency. (See 'Therapeutic use exemption' below.)

ANDROGENS

Types of androgens — Virtually all androgens produced for human or veterinary purposes have been taken by athletes (figure 1). These include testosterone esters, which are usually taken by injection; the 17-alpha-alkylated androgens, which are usually taken orally; and androgen precursors. Most commonly used are testosterone, trenbolone, and boldenone (a veterinary steroid) [7]. Among elite athletes, the most commonly detected drugs are testosterone, stanozolol, and nandrolone.

Exogenous testosterone — The testosterone esters include the enanthate and cypionate, which are also used for hormone replacement. Testosterone preparations for clinical use are reviewed separately. (See "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)

"Androgenic steroids" — "Androgenic steroids," also referred to as "anabolic-androgenic steroids," are synthetic steroidal androgens: oral 17-alpha-alkylated androgens (such as stanozolol) or parenteral 19-nortestosterone derivatives (such as nandrolone). They were originally developed to have a greater anabolic to androgenic effect than testosterone [19]. The author and editors of this topic use the term "androgens" or "androgenic steroids" rather than "anabolic-androgenic steroids" for these compounds because the anabolic effects of a steroid cannot be separated from its androgenic effects.

Androgen precursors — The androgen precursors include androstenedione and dehydroepiandrosterone (DHEA).

●Androstenedione is widely used and promoted in bodybuilding magazines. Until 2004, products containing androstenedione ("andro") were available as over-the-counter nutritional supplements. However, in October 2004, the Anabolic Steroid Control Act classified androstenedione (and 17 other steroids) as controlled substances with significant health risks. As of January 2005, these substances may not be sold without a prescription [20].

●Androstenedione does not appear to have an anabolic effect like testosterone, and it has little, if any, effect on increasing the serum concentration of testosterone [21-23].

●DHEA is also available as a "nutritional supplement" and is widely touted in body-building magazines as an agent that increases muscle strength. It is not androgenic itself but is converted to testosterone and raises serum concentrations in women but not men [24-26].

SARMs — Selective androgen receptor modulators (SARMs) are nonsteroidal, orally active molecules developed to bind better to androgen receptors in certain tissues, such as muscle and bone, than to those in genital tissue, with the goal of improving muscle weakness, osteoporosis, and other conditions with less risk of worsening prostate diseases in men or causing virilization in women. Although none of these compounds have been approved for use in humans in any country, they are now widely available via the internet [27,28] and the SARM andarine was detected in a urine sample from an athlete [29].

Like many dietary supplements sold on the internet, the labeling for SARM products marketed as performance-enhancing drugs is misleading. In a study of 44 SARM products purchased from the internet and analyzed using procedures approved by World Anti-Doping Agency (WADA), only 18 had accurate labeling (eg, they contained the correct SARM [andarine, ostarine, or LGD-4033], and dosage) [30]. Four products contained no active compounds at all, and the remainder (22; 50 percent) were inaccurately labeled (the wrong SARM, an inaccurate dose of the SARM listed, and/or at least one additional unapproved drug or substance [eg, growth hormone secretagogues, "androgenic steroids"]). (See "Overview of herbal medicine and dietary supplements", section on 'Accuracy of labeling'.)

Other forms of androgen stimulation — Another approach to increasing endogenous testosterone concentrations is by taking exogenous human chorionic gonadotropin (hCG), antiestrogens such as tamoxifen or raloxifene, or aromatase inhibitors. These drugs result in an increase in serum testosterone concentrations, and all are banned by the World Anti-Doping Agency (WADA) [31]. (See 'Estrogen blockade' below.)

Estrogen blockade — Estrogen blockade with drugs that block estrogen action or synthesis is another strategy for raising serum testosterone levels in men. They are most commonly coadministered with androgens to prevent gynecomastia. Drugs in this category include antiestrogens and aromatase inhibitors. (See "Management of gynecomastia", section on 'Pharmacologic therapy'.)

Antiestrogens — Antiestrogens bind to and block the estrogen receptor. The original antiestrogens included the nonsteroidal drugs clomiphene and tamoxifen. These drugs are also referred to as selective estrogen receptor modulators (SERMs); they have estrogen agonist properties in some tissues and estrogen antagonist properties in others. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

Tamoxifen is an antiestrogen that is sometimes used off-label (10 to 20 mg/day) to treat adolescents and adults with painful gynecomastia (see "Management of gynecomastia", section on 'Selective estrogen receptor modulators (SERMs)'). Similar doses are used by bodybuilders and other athletes taking testosterone in order to prevent gynecomastia that develops because testosterone is converted to estradiol. Some dietary supplements on the market have been found to contain variable doses of tamoxifen (although they are not labeled as such) [32]. In one product, EstoSuppress, the amount of tamoxifen in two tablets, the recommended daily dose, varied from 0 mg to 7.6 mg. A dose of 7.6 mg is close to the therapeutic dose (10 to 20 mg) used clinically for men with gynecomastia and for men with breast cancer; in men with breast cancer, tamoxifen has been associated with sexual dysfunction and an increased risk of venous thromboembolism [33]. (See "Breast cancer in men", section on 'Endocrine therapy'.)

Aromatase inhibitors — Aromatase inhibitors are steroidal or nonsteroidal agents that block the conversion of androgens to estrogen. Examples include androstenedione analogs, such as testolactone, and the nonsteroidal agents letrozole and anastrozole. Although they are not very effective, they are used to reduce the development of gynecomastia and to attempt to elevate the serum testosterone concentration (see "Management of gynecomastia", section on 'Aromatase inhibitors'). Modest elevations of serum testosterone are seen with aromatase inhibitor use in men, but an effect on muscle strength has not been demonstrated [34]. There are sensitive assays available to detect aromatase inhibitors and antiestrogens [35]. These can be detected in urine by gas chromatography/mass spectrometry [36].

Use of hCG — Exogenous human chorionic gonadotropin (hCG), which binds to the luteinizing hormone (LH) receptor and stimulates the Leydig cells of the testes to secrete testosterone, has also been used by athletes. hCG leads to production of endogenous testosterone in the normal ratio to epitestosterone, making its use more difficult to distinguish from normal secretion [31]. LH has a very short half-life and is not likely to be abused.

Side effects of hCG include edema and gynecomastia. Detection of hCG is discussed below. (See 'Detection of banned substances' below.)

Efficacy — It seems intuitive that androgens increase muscle mass and muscle strength, given the obvious differences between males and females. Administration of supraphysiologic doses of exogenous testosterone to healthy young men has been shown to increase their muscle strength. However, there is no evidence that the androgen precursor, androstenedione, increases muscle strength, and the evidence for an effect of DHEA is conflicting.

●In one placebo-controlled, double-blind study of exogenous testosterone, 43 normal men were randomly assigned to one of four groups: strength-training exercise with either 600 mg of testosterone enanthate once per week (approximately six times a replacement dose) or placebo, or no exercise with either testosterone or placebo [37]. Testosterone treatment increased fat-free mass and muscle strength, both in men who exercised and in men who did not, but more so in those who exercised simultaneously.

●In a second, double-blind trial of exogenous testosterone, 61 healthy eugonadal men were randomly assigned to one of five groups, each treated with a gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and one of five weekly doses of testosterone enanthate from 25 to 600 mg [38]. Testosterone administration was associated with a dose-dependent increase in leg press strength and leg power. Improvements in strength and power correlated with serum total testosterone concentrations. Muscle fatigability did not change with treatment.

●In contrast, in a randomized, placebo-controlled trial of androstenedione in normal men, administration of 100 mg three times daily for eight weeks did not increase muscle strength; however, serum testosterone concentrations were not increased by this regimen [22]. Similarly, in a placebo-controlled study of 50 healthy men ages 35 to 65 years receiving androstenedione or androstanediol (200 mg/day), neither hormone altered body composition or muscle strength compared with placebo [39].

●Results from placebo-controlled studies of DHEA in normal men have been mixed. In one study in which 40 trained men were given DHEA (100 mg/day), androstenedione, or placebo, there were no differences in fat-free mass and muscle mass between the two drug groups and the placebo group [25]. In another trial, nine men and 10 women were randomized to receive 100 mg of DHEA or placebo daily for six months and then crossed over for another six months [26]. In the men, but not the women, knee and lumbar back strength increased during DHEA treatment compared with placebo.

Side effects and complications — All androgens have some side effects when taken in high doses; other side effects depend upon the structure of the androgen or the steroids to which it is converted (table 1). Some side effects occur only in women.

Cardiovascular — The effect of high doses of androgens on cardiac function is uncertain.

●Cardiac hypertrophy – Several case reports describe sudden death in young athletes who had no previously known heart disease but who were taking androgens; cardiac hypertrophy or myocarditis were found at autopsy [40,41]. It is not possible to establish causality in these sporadic cases (see "Athletes: Overview of sudden cardiac death risk and sport participation"). There are also reports of left ventricular hypertrophy in body builders and power lifters, but most of these studies have not been randomized or controlled for degree of exercise, which itself can affect the degree of cardiac hypertrophy [42]. In one randomized, placebo-controlled trial, eight body builders treated with nandrolone decanoate showed no difference in several echocardiographic parameters at the end of eight weeks from those treated with placebo, but this study was limited by the small numbers of subjects and short duration [43].

●Lipids – Although physiologic doses of testosterone have no consistent effects on serum lipid concentrations, pharmacologic doses of androgens, especially 17-alpha-alkylated androgens administered orally, decrease serum high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol concentrations (table 1) [44].

In a study of normal men aged 30 to 56 years given androstenedione (300 mg/day for 28 days), serum HDL cholesterol concentrations decreased by 15 percent, a change that, in the general population, would predict an increase in risk of coronary heart disease [23].

●Hemostatic system – Androgen administration is also associated with activation of the hemostatic system, as illustrated in a study of 49 weight lifters in whom androgen use was ascertained by history and urine testing. The confirmed steroid users had a higher percentage of abnormally high thrombin-antithrombin complexes in plasma than nonusers (16 versus 6 percent, p = 0.01); higher plasma concentrations of prothrombin fragment 1 (44 versus 24 percent, p<0.001), antithrombin III (22 versus 6 percent, p = 0.005), and protein S (19 versus 0 percent); and lower plasma concentrations of tissue plasminogen activator and its inhibitor [45]. The importance of hemostatic system activation with regard to risk of thrombosis is unclear.

●Erythropoiesis – Testosterone stimulates erythropoiesis, and in men made hypogonadal by administration of a GnRH agonist, it increases hemoglobin and hematocrit in a dose-dependent manner [46]. Erythrocytosis is a well-recognized side effect of treatment of hypogonadism with physiologic doses of testosterone. Erythrocytosis, sometimes to a severe degree, has also been reported in association with administration of pharmacologic doses of androgens but only in case reports [47]. (See "Testosterone treatment of male hypogonadism".)

Neuropsychiatric — Many psychological abnormalities have been described, both in the medical literature and anecdotally, in men taking high doses of androgens (table 1). Most descriptions are uncontrolled, although in one study an attempt was made to compare men taking and not taking androgens [48]. One hundred sixty men recruited from gyms responded to a questionnaire about androgen use and psychiatric symptoms. Psychiatric symptoms, including major mood disorders and aggressive behavior, were more common in the men who had taken androgens than in those who had never taken androgens, and among the former, the symptoms were more common when they were taking androgens. Controlled studies using supraphysiologic doses of testosterone enanthate, although lower than those athletes often use, for up to six months, demonstrate no [37,49,50] or minimal [51] psychological abnormalities.

Several studies describe an association between nonmedical use of androgens and risky or even criminal behavior. In mail surveys of approximately 10,000 to 15,000 college students from 1993 to 2001, nonmedical use of androgens was associated with cigarette smoking, other illicit drug use, drinking and driving, and Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM-IV) alcohol use disorder [8,52].

Examination of data from the Longitudinal Study of Adolescent Health, in which 6823 adolescents were surveyed on three occasions between 7^th and 12^th grade, demonstrated that nonmedical use of androgens was associated with violent behavior such as physical fighting [53].

Women who use anabolic steroids have described both hypomanic and depressive symptoms [54,55]. In addition, some women report rigid dietary practices (referred to as "eating disorder, bodybuilder type"), nontraditional gender roles, and dissatisfaction/preoccupation with their bodies (referred to as "muscle dysphoria").

Reproductive (women) — In women, side effects of androgens include acne, hirsutism, temporal hair recession in a male pattern, clitoromegaly, and deepening of the voice (table 1). Voice changes are irreversible [7]. Although not well studied, many women also develop oligomenorrhea or amenorrhea. Breast atrophy may also be seen.

Reproductive (men)

Hypogonadism following discontinuation of exogenous androgens — In men, all androgens suppress gonadotropin secretion and endogenous testicular function, both testosterone and sperm production (table 1). Testicular volume eventually decreases with chronic use of androgens, and spermatogenesis and fertility become greatly diminished.

Chronic exogenous androgen use can cause prolonged suppression of gonadotropins and, therefore, result in hypogonadism after the exogenous androgens have been discontinued [15].The prevalence of hypogonadism among exogenous androgen users is not known. However, one retrospective series found that 21 percent of 382 men with hypogonadism presenting for testosterone therapy had previously taken these drugs [56]. This observation highlights the importance of obtaining a careful drug history before prescribing testosterone to men with apparent hypogonadism. (See "Testosterone treatment of male hypogonadism", section on 'Appropriate candidates'.)

Among men who stop using androgens, the sperm count usually returns to normal within four months after discontinuation [57] but may take more than a year [58]. Gonadotropin and testosterone secretion remain suppressed for a few months after androgens are discontinued. Younger men may recover more quickly than older men [15]. Some men request hCG during recovery, but it should not be prescribed, because it has not been shown to speed this process and because some men say they want to stop taking androgens as an excuse to get a prescription for hCG.

Gynecomastia — Gynecomastia occurs because testosterone is converted to estradiol via the action of the aromatase enzyme complex, so that high doses of testosterone result in high serum estradiol concentrations. Androgens that have been 5-alpha reduced, such as dihydrotestosterone, and synthetic androgens in which the A ring has been modified cannot be aromatized and therefore cannot be converted to estrogens and do not cause gynecomastia.

As noted above, many male androgen abusers also take antiestrogens or aromatase inhibitors to prevent gynecomastia. (See 'Estrogen blockade' above.)

Other — Androgen abuse has been associated with a number of other adverse effects as well, including (table 1):

●Infection – Sporadic case reports describe infections due to injection of androgens, including local abscess at the site of injection, septic arthritis, hepatitis B and C, and human immunodeficiency virus (HIV) infection from sharing of needles [59].

●Prostate – Because the prostate is a testosterone-dependent gland, there is concern that the high doses of androgens that athletes take might increase the risk of benign prostatic hypertrophy and prostate cancer. A meta-analysis of replacement doses of testosterone in hypogonadal men did not show such increased risks [60], but the risk in athletes who take large doses of androgens has not been reported.

●Tendon rupture – The risk of tendon rupture (eg, triceps or biceps tendon rupture) appears to be increased in weight lifters who use androgens [61-63].

●Epiphyseal closure – Pharmacologic doses of testosterone or other androgens that can be aromatized to estrogens hasten epiphyseal closure in adolescents whose epiphyses have not yet closed. The frequency of androgen use in adolescents is discussed above. (See 'Epidemiology' above.)

●Hepatic side effects – Hepatic side effects occur only with oral 17-alpha-alkylated androgens and include high serum concentrations of liver enzymes, cholestatic jaundice, and peliosis hepatis, characterized by blood-filled hepatic cysts. Hepatomas have also been reported, but the number of cases is few and causality is uncertain.

Detection of banned substances — Exogenous administration of pharmacologic doses of androgens might be suspected in a man who competes in a sport in which excess androgens are perceived as improving performance and who has small testes, low sperm count, high hematocrit and hemoglobin values, undetectable serum LH, and low serum sex hormone-binding globulin (SHBG) concentration. In a woman, androgen abuse might be suspected in an athlete with hirsutism, balding, or acne. In both males and females, androgen abuse might be suspected in those who appear excessively muscular. Androgen use can be detected in the urine of such patients by one of several tests, depending upon the compound to be tested. Details of urine collection for testing are reviewed separately. (See "Prohibited non-hormonal performance-enhancing drugs in sport", section on 'Urine testing'.)

When a sports organization identifies a positive screening test in an athlete, it will take further action according to its own regulations (or anti-doping code) and the laws of the country where the testing occurred. These organizations may also issue fines and bans from participation in future events.

The WADA utilizes two main methods for detecting testosterone [35]:

●Testosterone/epitestosterone ratio – Testosterone taken exogenously cannot be distinguished from that produced endogenously by the usual methods for measuring testosterone, radioimmunoassay and tandem mass spectroscopy, so other methods must be used. The conventional method is to determine the urinary ratio of testosterone glucuronide to its endogenous epimer, epitestosterone glucuronide (T/E ratio). Normally the ratio is 1:1 to 3:1, but subjects taking exogenous testosterone, which suppresses the production of both testosterone and epitestosterone and replaces it only with testosterone, have higher ratios, usually >6:1 [64]. However, a T/E ratio of >4:1 is considered evidence of doping by WADA.

The limitation of the T/E ratio is shown by the much greater between, than within, subject variability [65]. The reason for this difference has been shown to result from heterozygosity in the uridine diphosphoglucuronosyl transferase UGT2B17 that converts testosterone to testosterone glucuronide (figure 2) [66]. No such heterozygosity apparently exists in the UGT2B17 that converts epitestosterone to epitestosterone glucuronide. The consequence is that a man who has a deletion of both copies of this enzyme converts testosterone to testosterone glucuronide poorly, so after an injection of exogenous testosterone, his T/E ratio is much lower than a man who has two copies of the gene. In one study, this deletion was more common in Korean than Swedish males [67]. Conventional monitoring by this ratio, therefore, is much less likely to detect the athlete who has both copies deleted and who takes exogenous testosterone than the athlete who has two normal copies of the gene (figure 2). The investigators who elucidated this heterozygosity proposed setting normal ranges for the T/E ratio depending on whether or not the athlete has two, one, or no copies of this gene. In addition, some single nucleotide polymorphisms in the promoter region of the CYP17 gene are associated with higher T/E ratio, which may explain why some normal individuals have naturally high T/E ratios in the absence of androgen abuse [68]. Another limitation of the T/E ratio is that athletes can mask testosterone use by taking gonadotropins or epitestosterone, which can reduce the T/E ratio [69].

●Carbon 13/carbon 12 ratio – The method currently considered most accurate is determination of the ratio of carbon 13 (13C) to carbon 12 (12C) in urinary metabolites of testosterone using isotope ratio mass spectrometry. This method is used to confirm exogenous testosterone use in men with a T/E ratio >4. The rationale is that pharmacologic testosterone preparations are synthesized from plant sterols, which have a lower ratio of 13C to 12C than do endogenous testosterones [70]. This method will show a low 13C to 12C ratio even if an athlete takes epitestosterone in an attempt to mask taking testosterone.

Thus, suspicion for exogenous testosterone use should be high in an athlete with a normal or elevated T/E ratio and low 13C to 12C ratio. These tests are offered by official testing bodies but not clinically. Offering them outside of the official process would alert those taking androgens.

Androgens other than testosterone can be detected by gas chromatography and mass spectrometry if the athlete is still taking the compound(s) at the time of testing [35]. These tests are usually performed at commercial laboratories. Androgens other than testosterone also cause a high T/E ratio since androgens suppress endogenous testosterone production.

SARMs can be detected in urine. This detection can be accomplished through solid-phase extraction followed by liquid chromatography-tandem mass spectrometry utilizing electrospray ionization [71].

hCG can be detected by immunoextraction of urine and mass spectrometry. The proposed male cutoff is 5 international units/L. Because hCG is elevated in patients with testicular cancer, it may be a false positive for doping in this condition [69].

Avoiding detection — Athletes are continually finding ways to avoid detection [71]. The most common way is to discontinue the drug before testing will occur. Screening tests can also be manipulated by urine substitutes, urine dilution, refusing to provide samples of urine or blood, and placing substances in the urethra to mask the samples. As an example, athletes may concomitantly take diuretics and increase fluid intake to dilute urine.

Other indicators of sample tampering include urine at room temperature from a newly obtained sample or specific gravity out of the range of normal. If the screening tests detect abnormal results, typically more advanced techniques such as liquid chromatography and mass spectrometry are used to confirm the results [2,72].

In one highly publicized case, a private laboratory synthesized an androgenic steroid specifically designed to avoid detection. The drug was identified when a syringe filled with it was provided to the US Anti-Doping Agency (USADA), which eventually determined that the drug was tetrahydrogestrinone [73].

Therapeutic use exemption — The WADA and USADA allow athletes to compete if they are taking a banned medication, provided the medication is required for therapeutic purposes. In this situation, they grant a therapeutic use exemption after reviewing a form completed by the athlete's clinician [74]. The clinician must state that the athlete would experience a significant health problem if not allowed to take the prohibited medication, the medication would not produce significant enhancement of performance, and there is no reasonable therapeutic alternative. An example is an athlete who takes testosterone because he has had bilateral orchiectomy for testicular cancer.

APPROACH TO THE PATIENT TAKING EXOGENOUS ANDROGENS

Challenges — The challenge in identifying athletes using drugs, in particular androgens, to attempt to enhance performance is that individuals are unlikely to tell their clinicians that they are using hormonal performance enhancement. The overall therapeutic alliance is key to obtaining the necessary medical history. Clinicians should educate athletes about the potential harms of using these drugs.

Few users of these drugs seek treatment [7]. However, for those who do, stopping them is challenging. Many individuals struggle with body image disorders (muscle dysmorphia) as well as depression related to their hypogonadism, and they need psychologic intervention [75]. Recovery of the hypothalamic-pituitary-testicular axis may be prolonged.

The American Academy of Family Physicians (AAFP), American Medical Association (AMA) Guidelines for Adolescent Preventive Services (GAPS), and American Academy of Pediatrics (AAP) all suggest that clinicians discuss the dangers of drug abuse with children and adolescents and include questions about substance abuse as a part of routine adolescent visits. Clinicians may also suspect abuse of androgens in adolescents who have problem behavior (eg, fighting, other substance abuse, risky sexual behaviors) [76].

When to suspect exogenous androgen use — Exogenous administration of pharmacologic doses of androgens might be suspected in an athlete who:

●Competes in a sport or activity in which excess androgens are perceived as improving performance. (See 'Epidemiology' above.)

●Exhibits a change in behavior, such as depression, irritability or aggression. (See 'Neuropsychiatric' above.)

●Develops high hematocrit, undetectably low serum luteinizing hormone (LH) concentration, and low sex hormone-binding globulin (SHBG). (See 'Cardiovascular' above.)

Individuals who should be suspected of use include:

●Men who exhibit a more rapid increase in muscle strength and mass compared with athletes who do not use androgens, gynecomastia, acne, small testes, and low sperm density. Tendon rupture is sometimes seen. (See 'Reproductive (men)' above.)

●Women who develop irregular menstrual cycles, hirsutism, acne, breast atrophy, temporal hair recession, deepening of the voice, clitoromegaly, increased muscle mass, and decrease in body fat. (See 'Reproductive (women)' above.)

●Children or adolescents who experience signs of early puberty (development of secondary sexual characteristics) followed by premature closure of epiphyses and a decrease in final height. (See 'Other' above.)

Androgen use can be detected in such patients by one of several tests, depending upon the compound to be tested. (See 'Detection of banned substances' above.)

Stopping — Men who take hormones, especially androgens, to enhance athletic performance are usually reluctant to stop, even when they no longer are engaged in the activity for which they took the drugs originally. However, if a man does not ask for advice about stopping, a clinician should encourage him to do so but advise him that he will likely become hypogonadal for a period, perhaps many months, before his pituitary-testicular axis recovers. Symptoms of androgen deficiency are likely to occur after stopping (depression, fatigue, decreased libido, sexual dysfunction).

Recovery of testicular function — These men often ask clinicians for human chorionic gonadotropin (hCG) or clomiphene to hasten this process, but there is no evidence that either does so. The clinician should also offer to follow the recovery by measuring the serum testosterone concentration, initially three months after discontinuation of the drug and, if the value is not normal, then periodically thereafter.

If fertility is desired, sperm density should be tested as well, also beginning at three months. Clinicians should be warned, however, that some men say they want to stop taking androgens as an excuse to get a prescription for hCG. When the clinician does not prescribe hCG, they may not return.

Reporting illicit androgen use — If a patient admits to using a drug to enhance athletic performance or if these substances are detected by testing, the clinician should attempt to educate the patient on the risks of continued use, although most patients who take these drugs think that they know more about them than the clinicians. If the drug is illicit, the clinician is not legally obligated to report, even if the patient is a minor. (See "Confidentiality in adolescent health care".)

Clinician's culpability — A clinician can be found guilty of anti-doping violations for prescribing banned substances to enhance athletic performance, but not if a therapeutic use exemption has been filed. Sports organizations may not be sympathetic and can administer harsh suspensions or penalties to an athlete for doping infringements, even if taking a banned substance for an urgent condition [77]. Due to difficulties in proving intent to cheat, the World Anti-Doping Agency (WADA) enforces strict liability for positive test results. Clinicians may be asked by an athlete to complete exemption forms prior to sports competitions in order to enable athletes to take WADA-banned substances that are required for medical treatment. In urgent cases, either a retroactive or a retrospective exemption form may be applied for and approved by the appropriate sport committee.

OTHER HORMONES

Growth hormone — Growth hormone, like androgens, has been linked to many prominent athletes in sports, including baseball, swimming, and cycling [12]. In addition, approximately 5 percent of United States high school students use growth hormone [2]. Growth hormone use by high school athletes in Germany is lower (0.4 percent) [78].

●Physical effects – Athletes take recombinant human growth hormone (rhGH) because of its demonstrated effects on body composition (more muscle, less fat) [79]. In earlier studies, growth hormone administration was not shown to be effective for either strength [80,81] or endurance [82].

In the largest study to-date in recreational athletes, men were randomly assigned to receive placebo, growth hormone (2 mg/day subcutaneously), testosterone (250 mg/week intramuscularly), or combined treatments, while women were randomly assigned to receive either placebo or growth hormone (2 mg/day) [83]. In both males and females, growth hormone significantly reduced fat mass, increased lean body mass through an increase in extracellular water, and improved sprint capacity but not strength, power, or endurance. The improvement in sprint capacity was greater when growth hormone was coadministered with testosterone to men. The effects of growth hormone disappeared after six weeks of being discontinued. The clinical significance of the increase in one physical performance parameter, but not others, in spite of supraphysiologic doses of both drugs is uncertain.

Growth hormone would be expected to cause acromegaly if given in high doses long enough, but no such cases have been reported. Cancer is another potential concern as epidemiologic data suggest an association between serum concentrations of insulin-like growth factor 1 (IGF-1) and cancer risk. (See "Risk factors for prostate cancer", section on 'Insulin and insulin-like growth factor'.)

A review of studies in which growth hormone was administered to healthy males and females showed an increased incidence of soft tissue edema compared with those not treated [79].

●Adverse effects – Growth hormone can cause insulin resistance, hyperglycemia, diabetes, sodium retention, hypertension, cardiomegaly, premature epiphyseal closure, myopathy, carpal tunnel syndrome, and swelling of the hands [12,84,85]. (See "Growth hormone deficiency in adults", section on 'Side effects'.)

Weightlifters who abuse growth hormone were found to have a high use of other risky drugs, such as opioids, cocaine, and others [86], similar to men who abuse androgens.

●Detection methods – Detection of growth hormone can occur only through the blood because less than 0.1 percent is excreted through urine. Two methods are used to detect use of growth hormone by athletes [87]:

•Markers of growth hormone action, such as IGF-1 and procollagen type III N-terminal propeptide (P-III-NP) – One study showed that when growth hormone in doses of 0.033 or 0.066 mcg/kg was administered daily for four weeks to healthy males and females, their serum concentrations of IGF-1 and P-III-NP were readily distinguishable from subjects administered placebo [88]. These effects were shown in a subsequent study to be greater in men than in women and were amplified by concomitant testosterone administration [89].

•Growth hormone isoforms – The pituitary gland normally secretes a variety of growth hormone isoforms, including a 20 kDa form and a 22 kDa form in monomers and dimers. However, rhGH consists only of the 22 kDa monomer. Immunoassays have been developed that can recognize either the 22 kDa form selectively or all of the isoforms nonselectively. Since administration of rhGH suppresses endogenous growth hormone secretion, an elevated ratio of the selective 22 kDa assay to growth hormone measured by the nonselective assay indicates administration of exogenous rhGH [87]. The first athlete detected using this test, a British rugby player, was reported in 2010 [90].

•The athlete biological passport (ABP), an approach that complements traditional drug testing, is based upon monitoring selected biological variables over time to detect the effects of doping rather than the doping substance itself. WADA has introduced ABP guidelines for detection of blood doping and androgen use; ABPs for growth hormone detection are in development. One study reported the feasibility of developing profiles of human growth hormone biomarkers (IGF-1, P-III-NP, and growth hormone isoforms), ie, an ABP for identifying human growth hormone abuse in individual athletes [91]. Recreational athletes (n = 35) were randomized to one of three different doses of recombinant growth hormone or placebo for three weeks, with 14 tests over three months. The ABP approach identified almost all subjects who had received recombinant growth hormone.

●Growth factors (IGF-1 and insulin) – The rates of IGF-1 and insulin use for performance enhancement are lower than growth hormone [12,92]. IGF-1 should have similar effects to growth hormone, but this has not been studied [12]. Athletes have also begun to use insulin, in particular, short-acting insulins, because of their anabolic effects on muscle.

Insulin and IGF-1 may lead to hypoglycemia. In one survey of 20 men who were recruited from gyms and admitted to using androgens, five reported that they also used insulin [93]. They reported ingesting large amounts of sugar after insulin injection to avoid hypoglycemia. Serum concentrations of IGF-1 may be associated with an increased risk of prostate cancer. (See "Risk factors for prostate cancer", section on 'Insulin and insulin-like growth factor'.)

IGF-1 can only be detected through blood. However, no commercial screen tests are available at this time [12]. Detection of insulins can be done in the urine with use of antibody/antigen reactions and liquid chromatography/mass spectrometry. However, it is often difficult to distinguish among human insulin, insulin analogs, and porcine insulin [71].

Erythropoietin — Athletes have used methods to increase the oxygen-carrying capacity of the blood and thereby athletic performance for decades, initially by training at high altitudes, then by transfusions, and more recently by hypoxia and administration of drugs such as erythropoietin that stimulate erythropoiesis [94]. Use of these methods in competitive cycling, such as the Tour de France, has been reported widely in the popular press. All increase oxygen transport.

The first available agent was recombinant human erythropoietin and later darbepoetin alfa, which has a longer half-life. Erythropoietin increases the blood's maximum capacity to transport and utilize oxygen, thereby augmenting aerobic power and physical exercise tolerance [84,94,95].

Major adverse effects of increased erythropoiesis include myocardial infarction, stroke, and thromboembolic disease [94]. It may also lead to hypertension, antibody-mediated anemia, and polycythemia. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Adverse effects' and "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

There are indirect and direct methods for detecting erythropoietin. Indirect methods include measurement of total hemoglobin mass, which can increase approximately 10 percent with erythropoietin use [94,96]. Hematocrit and reticulocyte counts may also increase. Erythropoietin can also be detected directly by immunoaffinity chromatography, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), isoelectric focusing, and mass spectrometry [71]. Some users of erythropoietin add proteases in their urine to degrade it [94], but protease inhibitors added to the urine immediately after collection can prevent degradation [97], and specific patterns of degradation suggest their use. Testing is not as well developed for other agents.

Glucocorticoids — Glucocorticoids alter glucose metabolism and possess anti-inflammatory and analgesic properties, leading some athletes to use them in sporting events [98]. Glucocorticoids are prohibited only within 12 hours in which an athlete is scheduled to participate in a sporting event and through the duration of the event itself. Their use and efficacy are not well documented for performance enhancement. Glucocorticoids may cause hyperglycemia, fluid retention, and acute mood changes (see "Major adverse effects of systemic glucocorticoids"). In chronic use they can suppress the hypothalamic-pituitary-adrenal axis and lead to reduced muscle mass and weakness, osteoporosis, diabetes, hypertension, weight gain and abdominal obesity, cataracts, and various psychiatric symptoms (eg, hypomania, depression, psychosis). (See "Pharmacologic use of glucocorticoids".)

OTHER PERFORMANCE-ENHANCING METHODS — Some athletes take several other drugs and supplements in addition to androgens, growth hormone, and erythropoiesis-stimulating agents to enhance performance. Examples include stimulants, creatine, and beta blockers. Nonhormonal performance-enhancing agents are reviewed separately. (See "Prohibited non-hormonal performance-enhancing drugs in sport".)

There are several methods of performance enhancement that do not involve taking drugs. Blood transfusions are among the most common [99]. Others include hypoxia induction and gene doping. All of these methods are reviewed separately. (See "Prohibited non-hormonal performance-enhancing drugs in sport".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Androgens and other banned substances in athletes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Growth hormone treatment in adults (The Basics)" and "Patient education: Hormones to boost sports performance: Risks and side effects (The Basics)")

SUMMARY

●The use of androgens, growth hormone, and other drugs to improve athletic performance is common, even in adolescents. (See 'Epidemiology' above.)

●Virtually all androgens produced for human or veterinary purposes have been taken by athletes (figure 1). These include testosterone esters, which are usually taken by injection; the 17-alpha-alkylated androgens, which are usually taken orally; androgen precursors; and possibly selective androgen receptor modulators (SARMs). (See 'Androgens' above.)

●Exogenous testosterone administration increases serum testosterone concentrations, fat-free mass, and muscle strength. There is no evidence that androstenedione increases muscle strength. The evidence for dehydroepiandrosterone (DHEA) is equivocal. (See 'Efficacy' above.)

●Adverse effects of androgen use include suppression of endogenous testicular function, gynecomastia, erythrocytosis, hepatotoxicity (with 17-alpha-akylated androgens), psychological disorders, a decrease in serum high-density lipoprotein (HDL) (especially with 17-alpha-akylated androgens), coagulation activation, premature epiphyseal fusion (in adolescents), infections, and virilization (in women). (See 'Side effects and complications' above.)

●Use of androgens for nonmedical purposes is associated with risky behavior, such as smoking and alcohol abuse, as well as violent behavior, but no causal relationship has been demonstrated. (See 'Neuropsychiatric' above.)

●Detection of androgen use by athletes is difficult. The conventional method used is the urinary ratio of testosterone glucuronide to its endogenous epimer, epitestosterone glucuronide (T/E ratio). Normally, the T/E ratio is 1:1 to 3:1; a T/E ratio of >4:1 is considered evidence of doping by the World Anti-Doping Agency (WADA) that requires confirmation. (See 'Detection of banned substances' above.)

●The utility of the T/E ratio is limited by its significant between-subject variability, due to genetically determined differences in the ability to convert testosterone to testosterone glucuronide. (See 'Detection of banned substances' above.)

●A man who wishes to stop abusing androgens should be encouraged to do so but warned that he will become hypogonadal for several months or even a year before he recovers endogenous gonadotropin secretion and testicular function. He should be monitored every few months until recovery occurs. Human chorionic gonadotropin (hCG) should not be prescribed, because it has not been shown to speed this process, and because some men say they want to stop taking androgens as an excuse to get a prescription for hCG. (See 'Recovery of testicular function' above.)

●Human growth hormone is also commonly used to enhance athletic performance. Clinical trial data suggest that while lean body mass may be increased by growth hormone use, strength and exercise capacity is not. (See 'Growth hormone' above.)

●Detection of exogenous growth hormone use by athletes is difficult. There are two approaches currently being used: measurement of markers of growth hormone action (insulin-like growth factor 1 [IGF-1] and procollagen type III N-terminal propeptide [P-III-NP]) and measurement of growth hormone isoforms that can distinguish exogenous growth hormone from recombinant human growth hormone (rhGH). (See 'Growth hormone' above.)

●Erythropoietin increases the blood's maximum capacity to transport and utilize oxygen, thereby augmenting aerobic power and physical exercise tolerance. Major adverse effects of erythropoietin include myocardial infarction, stroke, and thromboembolic disease. (See 'Erythropoietin' above.)

●Other banned substances and dietary supplements that are often used by athletes include stimulants, insulin, and beta blockers. Creatine is not currently on the list of banned substances of any governing bodies, but the National Collegiate Athletic Association (NCAA) prohibits its distribution to athletes by its member institutions. (See 'Other performance-enhancing methods' above.)