Testosterone-induced increase in skeletal muscle mass is associated with hypertrophy of both type I and type II fibers (460) and an increase in the number of myonuclei and satellite cells (461). Testosterone promotes the differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage (66,459). Androgens regulate mesenchymal multipotent cell differentiation by binding to AR and promoting the association of AR with β-catenin and translocation of the AR-β-catenin complex into the nucleus, resulting in activation of TCF-4 (458). The activation of TCF-4 modulates a number of Wnt-regulated genes that promote myogenic differentiation and inhibit adipogenic differentiation (458).
We do not know whether conversion of testosterone to DHT or to estradiol 17-β is required for mediating androgen effects on the muscle. Steroid 5-α reductase (SRD5A2), which converts testosterone to DHT, is expressed at low concentrations in skeletal muscle, but individuals with congenital SRD5A2 deficiency have normal muscle development at puberty.
Low testosterone is a common feature of many chronic diseases in men and is associated with loss of muscle mass and strength, bone density, sexual dysfunction, and loss of energy (276). The observations that androgen replacement or supplementation unequivocally increases FFM, total body mass, and maximal voluntary strength in hypogonadal men and healthy, eugonadal young and older men have led to the hypothesis that androgens might be useful in treating the loss of muscle and physical function seen in patients with chronic diseases such as HIV infection with wasting syndrome, COPD, and end-stage renal disease (ESRD).
There is a high prevalence of low testosterone levels in HIV-infected men, even among those receiving highly active antiretroviral therapy (25,153,423). Serum testosterone levels are lower in HIV-infected men with weight loss (120) and correlate with deficits in muscle mass and strength (65,62,215,483), low Karnofsky scores (25), depressed mood, and disease progression (218,412,433).
Some of the studies that have examined the effects of androgen administration on body weight and composition in HIV-infected men were not placebo controlled (54,205,235,413) and most failed to control energy intake and exercise stimulus. Three placebo-controlled studies of testosterone supplementation of HIV-infected men (62,65,482) reported gains in FFM, whereas others (119,152) did not. Significantly greater improvements in maximal voluntary strength have been shown in HIV-infected men treated with androgens vs. placebo (65,216,217,485). In a recent meta-analysis, testosterone therapy had a moderate effect on depression (−0.6 SD units, 95% confidence interval [CI] −1.0, −0.2), but no significant testosterone effect on quality of life (58). There were no significant differences in adverse event rates or changes in CD4+ T lymphocyte counts, HIV viral load, PSA, and plasma HDL cholesterol between testosterone- and placebo-treated men with HIV infection (58).
Testosterone trials in HIV-infected men have been small and characterized by heterogeneity across trials. There are no data on testosterone's effects on physical function and risk of disability or its long-term safety. Overall, short-term (3-6 months) testosterone use in HIV-infected men with low testosterone levels and weight loss can lead to small gains in body weight and lean body mass (LBM) with minimal change in quality of life and mood. This inference is weakened by inconsistent results across trials. These considerations led the Endocrine Society Expert Panel to “suggest (that) clinicians consider short-term testosterone therapy as an adjunctive therapy in HIV-infected men with low testosterone levels and weight loss in order to promote weight maintenance and gains in LBM and muscle strength” (59). The evidence supporting this suggestion is of moderate quality.
Five studies, including 4 randomized placebo-controlled trials, have investigated the effect of androgens in patients with COPD (102,125,183,438,542). Schols et al. (438) reported a 1.5 kg weight gain over 8 weeks in 217 men and women with COPD. Subjects receiving nandrolone decanoate (women, 25 mg; men 50 mg) plus nutritional and exercise interventions increased FFM to a greater extent than those receiving placebo plus the nutritional supplement and exercise (p < 0.03). Fat mass increases accounted for most of the weight gain in the placebo group. No differences in respiratory muscle strength between groups were noted. Similarly, Creutzberg and et al. (125) showed that men with COPD receiving 8 weeks of biweekly injections of 50 mg nandrolone decanoate experienced significantly greater increase in DEXA-determined FFM when compared with controls, 1.7 ± 2.5 vs. 0.3 ± 1.9 kg, respectively. Muscle function and exercise capacity improved to the same extent in both groups. Ferreira et al. (183) reported that underweight patients with COPD increased lean body mass by 2.5 kg after 6 months of treatment with 12 mg·d−1 oral stanozolol. Neither the stanozolol nor the control group demonstrated functional improvements or changes in maximum inspiratory pressure. In a multicenter, open-label trial of oral oxandrolone in men and women with COPD, Yeh et al. (542) showed an average 2.1 kg weight gain (1.6 kg lean mass) after 4 months of treatment. Neither spirometry nor 6-minute walk distance changed significantly.
Increased strength and resistance to fatigue might prove valuable in maintaining physical function required in activities of daily living. Because muscle cross-sectional area predicts mortality in patients with COPD (345), interventions that stimulate increased muscle mass would be expected to improve outcomes. However, small sample size, substantial heterogeneity across trials, relatively small androgen doses, and the lack of inclusion of patient-important outcomes in these trials contributed to the weak quality of available evidence and preclude a general recommendation about testosterone therapy in men with COPD at this time.
Glucocorticoid administration in pharmacologic doses is associated with muscle atrophy and a high frequency of low testosterone levels (278,336,416,417) due to suppression of all components of the hypothalamic-pituitary-testicular axis. In 2 randomized placebo-controlled trials (54,418), testosterone supplementation of men receiving glucocorticoid treatment for bronchial asthma or chronic obstructive pulmonary disease was associated with an average 2.3 kg (95% CI 2.0-3.6) greater gain in lean body mass and a greater decrease in fat mass (contrast −3.1 kg, 95% CI −3.5, −2.8) than placebo (57). These 2 trials (54,418) found an increase in bone mineral density in the lumbar spine (+4%, 95% CI 2-7%); the effect on femoral bone density was inconsistent and not significant (57). There are no data on the effects of testosterone supplementation on bone fractures in glucocorticoid-treated men. Testosterone administration was associated with a low frequency of mild adverse events (124,418). Based on such data, the Endocrine Society Expert Panel suggested (59) that “clinicians offer short-term testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone levels in order to promote preservation of LBM and bone mineral density” (59). These inferences are weakened by the small size of the studies, high rates of loss to follow-up in 1 study, and inconsistent results (57,59).
Approximately two-thirds of men receiving dialysis for treatment of chronic renal failure have low testosterone levels (3,457). Hypogonadism in men with ESRD has been associated with sexual dysfunction (385), osteoporosis risk (3), anemia (86), and malnutrition (189). Carotid artery intimal thickness and presence of atherosclerotic plaque have been shown to be negatively correlated with serum testosterone levels in patients with ESRD but positively related to endothelium-dependent vasodilation (282).
Exercise intolerance and malaise are common problems among many individuals undergoing maintenance hemodialysis (MHD) (252). Studies of exercise capacity and training in these patients frequently report low exercise tolerance (32,263,384,481), muscular weakness, low physical activity levels (268), and impaired physical function (73,266,267,271,299). Johansen et al. (271) have demonstrated that dialysis patients have significantly greater contractile area atrophy compared with healthy controls, even when corrected for habitual activity level. The muscle atrophy was associated with muscle weakness and reduced gait speed (271). Abnormalities in muscle function and physical performance begin early in the course of chronic kidney disease (CKD), become progressively worse as the disease progresses (318), and are a major determinant of self-reported quality of life in patients with ESRD (111).
Functional limitations in patients with ESRD are undoubtedly multifactorial; low levels of anabolic hormones such as testosterone and GH, physical inactivity, uremic myopathy, malnutrition, and carnitine deficiency have been proposed as contributors (138,271,299,302).
Strategies to increase muscle mass and strength are attractive because they would be expected to improve physical function and quality of life. Exercise training including endurance training, resistance training, and their combination, and androgens are possible approaches that may be used to overcome muscle atrophy and weakness.
In a recent 12-week, randomized controlled trial of nandrolone decanoate (100 mg·wk−1 for women, 200 mg·wk−1 for men) or placebo with or without resistance exercise training, Johansen et al. (270) confirmed their earlier findings of significantly increased LBM, 3.3 ± 2.0 kg with nandrolone treatment alone. The subjects receiving nandrolone in combination with resistance training also experienced significant gains in LBM, 3.0 ± 2.4 kg. Lean body mass did not change in either of the placebo-controlled groups. Quadriceps cross-sectional area increased significantly in both the nandrolone and exercise groups relative to the controls and was additive in the combined treatment group. Training-specific 3RM strength measures for the lower extremity improved only in the groups receiving resistance training. These effects on muscle size, strength, and body composition were not different between men and women. Neither intervention, alone or in combination, produced significant changes in measures of physical function, for example, gait speed, stair climbing, or chair stands. It is possible that the short study duration may have not allowed sufficient time for the neuromuscular adaptations that are necessary for translation of muscle mass and strength gains into functional improvements. Self-reported improvements in physical function were noted in the resistance-trained group but not in the nandrolone group. The doses of nandrolone decanoate used in this study were well tolerated. With 79 patients randomized (49 men) and an 86% completion rate, this was the largest randomized controlled trial to date using androgens or resistance exercise training in patients undergoing MHD. Even so, the study may not have had sufficient power to detect clinically meaningful changes in measures of physical function.
The ideal dose of nandrolone decanoate for anabolic effects in patients with chronic kidney failure has not been determined, and there is only limited evidence that changes in muscle size and strength in these patients can translate into functional improvements after androgen administration. Improvements in self-reported physical function, although not currently seen in studies of hemodialysis patients receiving androgen administration, are nevertheless important with respect to its association with lower morbidity and mortality in these patients (330). Additional adequately powered studies are needed to determine whether long-term treatment with androgens is safe and effective in improving physical function (both measured and self-reported), mobility, and health-related outcomes, and in reducing morbidity and mortality in patients with ESRD.
Cross-sectional as well as longitudinal studies are in agreement that total and free testosterone concentrations decline progressively with advancing age (32,128,178,184,212,228,363,401,404,454,550). In the Baltimore Longitudinal Study on Aging, 20% of men older than 60 years and 50% of men older than 80 years had total testosterone levels in the hypogonadal range (total testosterone less than 325 ng·dL−1) (228). Because SHBG concentrations are higher in older men than in young men (178,401), free testosterone concentrations decline to a greater extent than total testosterone concentrations. The age-related decline in testosterone concentrations is the result of defects at all levels of the hypothalamic-pituitary-testicular axis.
Age-related declines in verbal memory, visual memory, spatial ability, and executive function are associated with the age-related decline in testosterone (6,35,109,177,210,240,260,261,452,496).
The relationship of testosterone levels with depression has been inconsistent across epidemiologic studies (36,137,342,443,444,511). Low testosterone levels in older men appear to be associated more with subsyndromal depression and related symptoms than with major depression (443,444). In one study, testosterone levels were lower in older men with dysthymic disorder than in those without any depressive symptoms (443). In another study, men with low testosterone levels had higher Carroll Rating Index scores, indicating more depressive symptoms than those who had normal testosterone levels (137).
Several recent studies have evaluated the association of testosterone levels and mortality; 2 Veterans Administration (VA) studies (450,451) and the Rancho Bernardo Study (316) found higher overall all-cause mortality in men with low testosterone levels than in those with normal testosterone levels, but testosterone levels were not correlated with overall mortality in the MMAS (18). In the Rancho Bernardo Study, men in the lowest quartile of testosterone levels (<241 ng·dL−1) were 40% more likely to die over the next 20 years than those with higher levels (316). The increased risk of death in men with low testosterone levels was independent of multiple risk factors, including age, adiposity, and lifestyle (316).
Testosterone levels are not correlated with aging-related symptoms assessed by the Aging Male Symptom score or with lower urinary tract symptoms assessed by the AUA/IPSS prostate symptom questionnaire (323). A number of cross-sectional studies also found no difference in serum testosterone levels between men who had coronary artery disease and those who did not have coronary artery disease; other studies have reported testosterone levels or to be lower in men with coronary artery disease than in men without coronary artery disease (8,34,118,222,540). A cause and effect relationship cannot be inferred from these epidemiological studies, especially cross-sectional studies. Furthermore, even the associations between testosterone levels and health-related outcomes that have been found to be statistically significant are weak.
The risks and health benefits of long-term testosterone remain poorly understood. Overall, testosterone trials in older men have been characterized by small sample size, inclusion of healthy older men with low or low-normal testosterone levels who were asymptomatic, and the use of surrogate outcomes; these studies did not have sufficient power to detect meaningful gains in patient-important outcomes and changes in prostate and cardiovascular event rates (13,72,85,163,182,290,365,383,453,465,497,506,534).
Testosterone therapy also improves self-reported physical function, assessed by the physical function domain of MOS SF-36 questionnaire (0.5 SD units, 95% CI 0.03-0.9) (57,59). However, the effects of testosterone replacement on quadriceps strength, leg power, muscle fatigability, and physical function in older men have been inconsistent across trials, and its effects on risk of disability and falls have not been studied (39,163,365,383). Testosterone replacement increases lumbar bone mineral density but not femoral bone mineral density in older men with low testosterone levels (13,290,465), but we do not know whether testosterone reduces fracture risk. Testosterone replacement improves sexual function in older men with low testosterone levels (74,254) but not in men with erectile dysfunction who have normal testosterone levels. Testosterone therapy has been shown to improve visual-spatial skills, verbal memory, and verbal fluency in older men with low testosterone levels in some but not in all trials. It is unknown whether testosterone supplementation can induce clinically meaningful changes in cognitive function in older men. The effects of testosterone replacement on vitality and health-related quality of life have not been studied. Short-term administration of testosterone in replacement doses is safe, but the long-term risks of testosterone administration in older men remain unknown.
The potential adverse effects of testosterone in older men include the risk of erythrocytosis, induction or exacerbation of sleep apnea, gynecomastia, and clinically detectable prostate events. Testosterone administration by increasing the intensity of PSA surveillance will likely lead to increased number of prostate biopsies and increased detection of prostate cancers (95). It is possible that testosterone administration might make subclinical foci of prostate cancer grow and become clinically overt; we do not know what clinical impact this would have on patient morbidity and survival and health care costs (57,59). Because the efficacy of testosterone supplementation on health-related outcomes has not been demonstrated and its risks remain largely unknown, an expert panel of the Endocrine Society concluded that the available data did not permit a general recommendation about testosterone therapy for all older men with low testosterone levels (59). The panel suggested that until more information becomes available, testosterone administration in older men should be individualized and limited only to older men with unequivocally and consistently low testosterone levels who are experiencing significant symptoms of androgen deficiency; in these individuals, consideration of testosterone therapy should be preceded by a careful discussion of its potential risks and benefits with the patient and rigorous monitoring of potential adverse effects (59). An expert panel of Institute of Medicine on the Future Direction of Testosterone Research deemed this a priority area for further research and recommended coordinated trials of testosterone therapy in symptomatic older men in 4 efficacy areas: physical dysfunction, sexual dysfunction, vitality, and cognitive dysfunction (325).
Androgens are typically used by athletes in a “stacking” fashion, in which several different drugs are administered simultaneously. The basis for stacking is that the potency of one anabolic agent may be enhanced when consumed simultaneously with another anabolic agent. Athletes will typically use both oral and parenteral (injectable) compounds; however, the administration of androgens via injection appears to be the most common method of self-administration (as indicated by 77% of androgen users) (114). The primary reason for using parenteral compounds is thought to be related to health reasons and the belief that this route of administration results in greater results (114). Most users will take androgens in a cyclic pattern, meaning they will use the drugs for several weeks or months and alternate these cycles with periods of discontinued use. Often athletes will administer the drugs in a pyramid (step-up) pattern in which dosages are steadily increased over several weeks. Toward the end of the cycle, the athlete will “step down”' to reduce the likelihood of negative side effects. At this point, some athletes will discontinue drug use or perhaps initiate another cycle of different drugs (i.e., drugs that may increase endogenous testosterone production to prevent the undesirable drop in testosterone concentrations that follows the removal of the pharmaceutical agents). Although the length of each cycle is quite variable (ranges from 1 to 728 weeks), the median cycle length is reported to be 11 weeks (114). Recent surveys have indicated that the typical nonmedical use pattern is 4-6 months in a year (114,388). A typical androgen regimen involves 3.1 agents, and the dose being administered is reported to vary between 5 and 29 times greater than physiological replacement doses (395). Nearly 50% of individuals who self-administer androgens exceed 1,000 mg of testosterone or its equivalent per week (388). However, this number may be exaggerated, as Cohen et al. (114) in a more recent survey suggested that the number of androgen users who self-administer more than 1,000 mg of testosterone or its equivalent per week may be closer to 10%. Regardless, the higher pharmacologic dosages common among androgen users do appear to be important for eliciting the gains that these individuals desire. The importance of dose has been clearly demonstrated in a classical study published by Forbes in 1985 (187), in which total dose of androgens administered was shown to have a logarithmic relationship to increases in lean body mass. These results provide fuel to the more is better philosophy employed by many athletes using performance-enhancing drugs.
Another issue associated with androgens use is the polypharmacy that is often seen among individuals who self-administer these drugs. A recent study indicated that 96% of androgen users (481 of 500) admitted to using other anabolic agents and/or stimulants to exacerbate the performance gains or medications to reduce the side effects associated with androgen use (388). The most common type of accessory medication used by these individuals appears to be compounds designed to promote fat loss. More than 65% of users admit to using caffeine and ephedra/ephedrine during their drug cycle. In addition, one of every 4 individuals who admit to self-administering androgens also indicated that they concomitantly use GH, insulin, or IGF during their drug cycle (388). More than half of individuals who self-administer androgens also use medications to reduce or prevent side effects generally associated with androgen abuse (388).
In many cases, androgens are consumed along with other drugs as part of a “stack” or to mask steroid use in preparation for drug testing. Likewise, these drugs are banned substances that can result in a positive drug test and subsequent punishment. The following section briefly examines some other drugs that athletes may use in addition to androgens and hGH.
Masking agents are used to produce negative drug testing results by hiding the use of androgens and other drugs. In some cases, diuretics have been used to dilute urine and mask drug use. Sulfonamides decrease the excretion rate of various drugs and are used to slow the excretion rate of androgens metabolites. However, these drugs were more effective when drug testing was more primitive in its development. Current drug tests can detect anabolic steroids in the urine despite the use of sulfonamides. One commonly used sulfonamide, probenecid, has been added to the banned substances list, and its use has declined dramatically among athletes. Probenecid was developed in the 1950s to reduce the excretion of penicillin. Detection of probenecid results in a failed drug test and possible suspension.
Diuretics block sodium reabsorption in the kidneys and induce fluid and electrolyte loss in urine. Diuretics have been used to treat diseases such as hypertension, congestive heart failure, edema, and kidney and liver problems (80,241,492). Classifications include loop diuretics (block sodium reabsorption in the loop of Henle in the kidneys, that is, furosemide, bumetanide, ethacrynic acid, torsemide), thiazides (block sodium reabsorption at the distal tubule, i.e., chlorthalidone, hydrochlorothiazide, indapamide, metolazone, trichlormethiazide, quinethazone), and potassium-sparing diuretics (i.e., amiloride, triamterene, spironolactone). Other types of diuretics exist but are much less commonly used by athletes. Diuretics induce fluid/weight loss, have been used as masking agents for androgen tests by athletes (reduce the concentration of drugs in the urine via rapid diuresis), and have been used in sports that used weight classes and bodybuilding. Benzi (53) has reported that diuretics were the fourth most commonly used drug behind androgens, stimulants, and narcotics. Diuretics are banned substances, and urine samples containing diuretic residues result in a failed drug test.
Diuretics are used in the short-term. They pose many other serious side effects including fatigue, weakness, muscle cramps, soreness, headaches, confusion, nausea, loss of appetite, cardiac arrhythmia, and reduced muscle glycogen. Studies have shown that 40-126 mg of furosemide resulted in 2-4% losses in body weight and subsequent reductions in cycling performance, siddhao2max, muscle strength, and rate of force development (23). Aerobic exercise performance appears to be more highly reduced than anaerobic exercise performance, as some studies have shown some reductions in strength and power but others have shown no performance decrement with mild dehydration (33). A recent study has shown that 40 mg of furosemide (resulting in a 2.2% reduction in body weight) did not negatively affect 50-, 200-, or 400-m sprint times or vertical jump height (525).
Antiestrogens are drugs that inhibit the effects of estrogen by inhibiting the enzyme aromatase or by blocking estrogen receptor action (226). Similar to SARMs, SERMs have been developed to tissue selectively antagonize estrogen actions (226). Although antiestrogens have been successfully used to treat various diseases and ailments, that is, breast cancer, infertility (40,477), they are taken by athletes to reduce the aromatizing effects from anabolic steroid use. In males, antiestrogens may increase endogenous production of testosterone (226,358), which is why some athletes use them upon completion or near completion of an androgen cycle. Some androgens have minimal aromatizing properties (i.e., Deca-Durabolin) and some are more potent (i.e., Equipoise, Dianabol, Halotestin, testosterone) (495), thereby enticing athletes to use antiestrogens as part of the drug stack. Differential androgenic effects have also been reported among use of different testosterone esters, for example, testosterone enanthate vs. buciclate vs. undecanoate (526). Several undesirable side effects (i.e., gynecomastia, water retention, and other health risks) of androgens use are caused by aromatization into estradiol and other estrogens. Studies show substantial elevations in plasma estradiol concentrations with testosterone or anabolic steroid administration (85,508).
Two categories of antiestrogens include aromatase inhibitors and receptor blockers. Aromatase inhibitors block aromatization, that is, aminoglutethimide (Cytadren), exemestane (Aromasin), testolactone (Teslac), formestane (Lentaron), letrozole (Femara), and anastrozole (Arimidex). Aromasin is thought to be one of, if not the, most effective aromatase inhibitors among athletes (326). Selective estrogen receptor modulators and receptor blockers antagonize estrogen receptors, that is, clomiphene citrate (Clomid), tamoxifen citrate (Nolvadex), raloxifene (Evista), and cyclofenil. Clomid is a popular drug used by male bodybuilders (50-100 mg·d−1) and is frequently used for 4-6 weeks upon termination of a steroid cycle. Nolvadex is a popular antiestrogen used by athletes consumed ∼10-30 mg·d−1. Cytadren is also popular as athletes have reported use of 250-500 mg·d−1 (although higher doses may be used for the cortisol-controlling effect), and cyclofenil has been used ∼400-600 mg·d−1 for ∼4-5 weeks after a steroid cycle (326). Aromatase inhibitors, SERMs, and other antiestrogens such as Clomid are prescription drugs banned by sport governing bodies including WADA (537).
The thyroid gland produces 2 key regulatory metabolic hormones: triiodothyronine (T3) and thyroxine (T4). Thyroid hormones produce a multitude of functions in virtually all cells of the human body including critical functions in the nervous, bone, and muscular systems; metabolism; and energy expenditure (82,528). Thyroid drugs (primarily sodium levothyroxine) are typically used to treat thyroid insufficiency or hypothyroidism (167,530). Thyroid hormones are consumed in synergy with other drugs theoretically to potentiate the anabolic response. Athletes, especially bodybuilders, have used thyroid drugs to potentially enhance the anabolic growth processes and offset some negative metabolic effects associated with kilocalorie restriction. Some thyroid drugs used by athletes include Cytomel, Triacana, and Synthroid in supraclinical doses (326). Unsupervised use of thyroid drugs can disrupt the hypothalamic-pituitary-thyroid axis and produce negative side effects such as bone and skeletal muscle catabolism, heart palpitations, agitation, shortness of breath, irregular heartbeat, sweating, nausea, irritability, tremors, restlessness, and headaches (113,167). Thyroid drugs are prescription pharmaceuticals used for medicinal purposes and unethical when used to enhance athletic performance. There is a paucity of research examining potential ergogenic effects of thyroid drugs on athletic performance. Thus, their utility is unclear and use is contraindicated.
Stimulants increase central nervous system activity and increase mental acuity, alertness, physical energy, thermogenesis, and exercise performance, for example, muscle strength, endurance, improved reaction time, and weight loss (27,449). However, side effects such as nervousness, anxiety, heart palpations, headaches, nausea, cardiomyopathy, high blood pressure, and in some rare cases a stroke may occur. Stimulants include amphetamines, caffeine, cocaine, and ephedrine. Many stimulants are banned substances but still are commonly used by athletes (537). Caffeine, pseudoephedrine, synephrine, and both ephedrine and methylephedrine (in concentrations <10 μg·mL−1) are not prohibited. Amphetamines release stores of norepinephrine, serotonin, and dopamine from nerve endings and prevent reuptake that leads to increased amounts of dopamine and norepinephrine in synaptic clefts (27). The sympathetic response is greatly enhanced by greater neurotransmitter availability. The American Medical Association in conjunction with the NCAA began investigating alleged widespread use of amphetamines by athletes in 1957 (283). Bents et al. (52) showed that 7-16% of collegiate hockey players reported some past and present use of amphetamines. Ingested amphetamines are absorbed from the small intestine and peak blood concentrations occur 1-2 hours after use (27). Stimulant effects may be seen with 10-40 minutes after consumption and may last up to 6 hours. Amphetamine metabolites are excreted in the urine where they can be detected (up to 4 days after use) via drug testing.
Ephedra has been used to treat respiratory problems and is commonly present in pharmaceuticals such as bronchodilators, antihistamines, decongestants, and weight loss products. Ephedrine use is banned by the NCAA. Because ephedrine alkaloids are found in common cold medicines, American collegiate athletes need to be aware that consumption of these products can result in a failed drug test especially because some products contain higher quantities of ephedrine alkaloids than what is reported on the label (504). Chester et al. (107) showed that use of over-the-counter decongestants containing phenylpropanolamine and pseudoephedrine for 36 hours resulted in peak drug urine concentrations 4 hours after the last dose with elevations persisting up to 16 hours after. The incidence of ephedrine use has been shown to be high in bodybuilders (504), weightlifters (218), and gym members (280).
Performance changes with ephedrine use are less clear. Initial use of pseudoephedrine did not enhance running or cycling performance (108,110,202,489), although one study found greater peak power during cycling and muscle strength (201). Studies examining ephedrine supplementation alone have only shown limited ergogenic effects on performance (50,256). However, a caffeine/ephedrine stack can result in higher blood pressure, heart rate, blood glucose, minute ventilation, insulin, free fatty acids, and lactate concentrations during exercise (50,224) and result in greater increases in power output, time to exhaustion (50,51), and faster 3.2 km loaded run times (49).
Clenbuterol (i.e., Spiropent, Prontovent, Novegam, Clenasma, Broncoterol) is a β2 agonist used to treat asthma because it is a bronchodilator and has similar hormonal, metabolic, cardiovascular, and sympathetic nervous system effects as stimulants. Clenbuterol is banned in competition by WADA. However, athletes have used clenbuterol because (a) it has been shown to increase muscle hypertrophy and strength (more so than other β2 agonists) and (b) it increases lipolysis (99,158,277,471). Clenbuterol has been shown to enhance muscle strength and power (409) and is usually stacked with other drugs. It has been used in an “on/off” manner such that athletes will use for 2-3 weeks and then discontinue use for 2-3 weeks at doses of ∼60-140 mcg·d−1 (326). The half-life of clenbuterol is ∼35 hours and it accumulates with subsequent repeated doses. Approximately 97% of clenbuterol is removed from the body within 8 days (334). Side effects of clenbuterol use include increased heart rate, heart's force of contraction, tremors, muscle cramps, palpitations, insomnia, nervousness, and headaches (294).
Human chorion ganadotropin is a dimeric glycoprotein hormone found in the placenta of women (226). Athletes use hCG because it has been shown to stimulate the Leydig cells to produce testosterone naturally (226). In men, hCG acts very similar to LH, as it has specific target receptors on Leydig cells, activation leads to activation of a cyclic adenosine monophosphate secondary messenger system, and stimulates steroidogenesis (292). It has been shown that 3,000 IU of hCG resulted in significant elevations in testosterone in athletes (264). A 50% elevation in plasma testosterone level was observed 2 hours after injection of 6,000 IU of hCG (430). The response appears biphasic in that peak elevations in plasma testosterone may be observed 3-4 days after hCG administration (292). About 20-30% of hCG administered is excreted in urine within 6 days (292). Often hCG is stacked with androgens when athletes are cycling down in an attempt to enable athletes to rejuvenate their own testicular size and testosterone-producing capacity and to maintain some of the anabolic effects associated with androgens. Despite acute elevations in testosterone after 1 injection of hCG in androgen users just coming off of a cycle (346), it appears administration of hCG (5,000 IU) 3 times per week for a few weeks may be needed to maintain normal testosterone concentrations (347). In addition, use of hCG to increase natural testosterone production has been used to stabilize the T:E ratio (as epitestosterone increases) for athletes doping with testosterone (292). Kicman et al. (291) and Cowan et al. (123) have shown that a single-dose hCG administration (5,000 IU) resulted in substantial elevations in testosterone, yet no significant change in the T:E ratio. Because hCG increases testosterone, several side effects with testosterone or anabolic steroid use may also be seen with hCG, especially at higher doses. Doses of 1,000-7,000 IU of hCG injected every 5 days have been used by athletes in 3-4 week cycles, although others have used greater quantities for cycles extending beyond 8 weeks (326).
Site enhancement drugs are mostly used by bodybuilders. These drugs, for example, Synthol, Nolotil, Caverject, cause temporary muscle size increase when injected locally (326). A drug formerly used, Esiclene, was used as well because it led to swelling and inflammation when injected locally. However, other drugs are now used by bodybuilders for local site enhancement. Synthol is composed of medium-chain triglycerides, lidocaine, and benzyl alcohol and is injected intramuscularly where it lodges between the fascicles. Repeated injections lead to greater volume within the muscles. Bodybuilders have been suggested to inject 1-3 mL every day or every other day for 2-3 weeks (326). Scientifically, little is known about these drugs and potential side effects currently. Use of these drugs is unethical and could lead to potential serious side effects.
The scientific evidence concerning the prevalence of the nonmedical use of androgens within the U.S.A. is sorely lacking. A recent report has indicated that since 1993 the lifetime use of androgens for nonmedical reasons has remained at a consistent 1% in the college student population (348). Considering that there are more than 40 million college graduates in this country (369), it can be crudely extrapolated that more than 400,000 college graduates have used androgens during their lifetime. In addition, a recent survey has suggested that nearly half of all users of androgens hold a college degree (114). Considering then that half do not, it may be further extrapolated that more than 800,000 individuals in the U.S.A. have used androgens during their lifetime. However, most surveys examining the nonmedical use of androgens have focused on collegiate and adolescent students and athletes. Information concerning adult use is generally limited to surveys of individuals who are self-administering androgens.
In the adult population of androgen users, the median age of individuals using androgens is 29 years, with nearly half of them holding at least a bachelors degree and more than 5% of self-admitted users holding a terminal degree (e.g., JD, MD or PhD) (114). Most adult users of androgens in the U.S.A. are whites (88.5%) and employed as professionals with yearly income exceeding that of the general population (114). The primary reason for drug use among the general population of androgen users appears to be related to increases in strength and muscle mass and wanting to “look good” (114,246). Other motivating reasons for drug use also include reduction of body fat, improvement to mood, and attraction of sexual partners. Interestingly, of the 1,955 androgen-using males surveyed bodybuilding and sports performance were either not motivation for androgen use or of little importance (114). Although recent media reports have focused on performance-enhancing drug use in professional athletes and youth, the majority of adults who self-administer androgens for nonmedical purposes appear to be intelligent, economically stable, white men who are not competitive athletes.
Based on media exposure, the underlying belief is that the use of performance-enhancing drugs, specifically anabolic steroids and GH, is rampant among professional athletes today. Although 67% of the U.S. powerlifting team in 1995 was reported to have used anabolic steroids (520) and anecdotal reports suggested that anabolic steroid use in the NFL ranged between 50 and 90% of players during the 1970s and 1980s (543), the available scientific evidence of the past few years indicate that illegal performance-enhancing drug use among competitive athletes is declining. In a survey of almost 14,000 NCAA student athletes, the NCAA reported that the number of collegiate athletes who self-admitted to androgen use has declined over the past 12 years (14,368). According to the survey, the number of collegiate athletes who self-admitted to androgen use has decreased from 4.9% in 1989 to 1.4% in 2001. These trends were apparent in all sports including football, in which androgen use among those athletes was reduced by approximately 50% during this same period (14,368). Interestingly, the racial/ethnic differences reported among the general population of androgen users appear to become more balanced among collegiate athletes. Androgen use among African-American collegiate athletes (1.1%) appears to be as common as that seen in white student athletes (1.1%) (213). Regardless, specific use patterns among professional and Olympic caliber athletes remain a mystery and unfortunately professional sport organizations within the U.S.A. do not release any of their drug testing results to the general public. Consequently, most information emanating from professional sports has been based on innuendo and hearsay.
A concern that first appeared on NCAA performance-enhancing drug surveys was the change in the age of initial androgen use among collegiate athletes who self-admitted to using these drugs. During the initial years of the survey, the majority of college athletes using these banned drugs did so toward the end of their college careers. Presumably, this was to enhance their chances of playing at the next level (i.e., professional sports); however, the trend seen in recent publications of the survey began to show a decrease in the age of initial androgen use. It appears that more than 40% of college athletes who admit to using androgens today appear to first begin using these drugs in high school (368). Even more disturbing were reports that androgens use was also beginning to be seen in middle school students (175,478). However, a recent study was unable to support these findings (246).
Examination of androgens use among the adolescent population appears to be following the same trend seen in the professional and collegiate athlete. Early studies examining performance-enhancing drug use in adolescents reported that androgen use at the secondary level ranged from 6% (91) to 11% in males (274). During the past 10-15 years, the use of androgens among adolescents appears to also be on the decline with self-reported use ranging from 1.6 to 5.4% (154,159,246,253,370,441,493). Studies showing a higher incidence (>6% self-admitting) of use have specifically examined high school football players (478). However, comparisons of androgen use among adolescent athletes and nonathletes have been inconclusive. Although some studies have indicated that there is no difference in androgen use among adolescent athletes and nonathletes (154,370), others have suggested that athletes tend to use these drugs with greater frequency than nonathletes (441,493). The pattern of performance-enhancing drug use among adolescents does appear to increase as students move through high school, with a recent study indicating that 6% of high school male twelfth graders admitted to using androgens (246). In addition, androgen use among adolescents may be more prevalent in the south (3.46%) vs. adolescents living in the Midwest (3.0%), west (2.02%), or northeast (1.71%) (159). In contrast to adults who self-administer androgens, adolescents who use these drugs appear to have below-average academic performance and are more apt to use recreational drugs (159,359). Interestingly, recent research has suggested that substance use, fighting, and sexual risk are better predictors of adolescent androgen use than participation in competitive sports (359).
One of the biggest changes in androgen use patterns has become the prevalence seen in female athletes and adolescents. Males have generally been reported to have a 3- to 4-fold greater prevalence in androgen use than females, with frequency of use patterns in females varying between 1.2 and 1.7% (159,160). However, in contrast to the declining use reported among male adolescents, the early part of this decade has resulted in several investigators reporting a greater frequency of androgen use in female adolescents that have ranged from 2.0% (359) to 2.9% (253). However, several recent studies have indicated that this trend toward a greater frequency in androgen use among female adolescents may have been overstated or at least declining (154,246).
Results from recent studies do suggest a decline in androgen use among collegiate athletes and adolescent males. However, the earlier onset of initial anabolic steroid use, a potentially greater prevalence in the female population, and the frequency of use in the nonathletic population indicate that the problem of androgens is becoming more societal than segmental regarding specific population groups.
The surreptitious nature of androgen abuse has rendered it difficult to conduct systematic investigations of the adverse effects of androgens in athletes and recreational bodybuilders. Consequently, these investigations have been sparse and confounded by the enormous variability in the types of drugs used; the dose, frequency, and duration of androgen use; the age at initiation; and concurrent use of accessory drugs. The veracity of self-reported drug use is always suspect.
It is remarkable that the frequency of serious adverse effects associated with androgenic steroid use has been as low as it has been reported; this has abetted the false perception that these drugs are “not too dangerous” and contributed to a sense of complacency among regulatory agencies. Some of this false sense of safety relates to the low frequency of adverse effects observed with substantially lower doses of androgens used in clinical trials than those used by athletes and recreational bodybuilders. Although the highest dose of testosterone enanthate used in clinical trials has been 600 mg weekly, 60% of androgen users in a survey reported using 1,000 mg of testosterone or its equivalent (388). Furthermore, 25% of androgen users also used GH or insulin (388).
A number of deaths due to unexpected coronary and cerebrovascular events have been reported among androgen users (351,531), but these reports are largely anecdotal and they do not establish a causative role of androgen use in these deaths. There have been remarkably few systematic investigations of the mortality and health consequences of androgen use by athletes. Parssinen et al. (389) investigated mortality and underlying causes of mortality among 62 powerlifters who had achieved the top 5 positions in weightlifting competitions in the 82.5-125.0 kg weight categories during the 1977-1982 period. The reference group included age-matched individuals from the general population. Thirteen percent of powerlifters and 3% of the age-matched control group died during this period. Suicides, myocardial infarction, hepatic coma. and non-Hodgkin's lymphoma contributed to deaths among powerlifters. Thus, in this relatively small series, the risk of death among the powerlifters was 4.6 times higher than that in the control population. In another study, the median age of death among androgen users who died and were autopsied was 24.5 years (398); this remarkably young age of death among androgen users is even lower than that for heroin or amphetamine users (398). Another study of patient records in Sweden (399) also reported substantially higher standardized mortality ratios for subjects who were androgen users than for those who were not, indicating increased risk of premature death among androgen users.
A majority of androgen users who die prematurely also have used other psychoactive drugs (398). Androgen users who commit suicide have been noted to express depressive or hypomania-like symptoms or to have committed acts of violence or experienced interpersonal difficulties at work or in personal life in the period immediately preceding suicide (499).
Androgens affect the lipoprotein profile, myocardial mass and function, cardiac remodeling, and the risk of thrombosis (75,143,284,340,351,372,431,488). Several potential mechanisms have been proposed to explain the adverse cardiovascular effects of androgens (351). High doses of androgens may induce a proatherogenic dyslipidemia and thereby increase the risk of atherosclerosis, increase the risk of thrombosis through their effects on clotting factors and platelets, induce vasospasm through their effects on vascular nitric oxide, or induce myocardial injury because of their direct effects on myocardial cells (180,349,351).
The effects of androgens on plasma lipids and lipoproteins depend on the dose, the route of administration (oral or parenteral), and whether the androgen is aromatizable or not (29,47,58,75,151,255,265,289,463,464,529,545). Parenteral administration of replacement doses of testosterone is associated with a small decrease in plasma HDL cholesterol levels and little or no effect on total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels (58,463,529), but supraphysiologic doses of testosterone, even when administered parenterally, markedly decrease HDL cholesterol levels (63,456). In contrast, orally administered, 17-alpha-alkylated, nonaromatizable androgens produce greater reductions in plasma HDL cholesterol levels and greater increments in LDL cholesterol than parenterally administered testosterone (265).
Increases in left ventricular mass have been reported among users of androgenic steroids (143,144,284,288,351,392,488). As many androgen users are powerlifters who engage in high-intensity resistance training that can induce left ventricular hypertrophy, it is not clear whether the left ventricular hypertrophy reported in powerlifters is a consequence of resistance training or androgen use or both (392). Although we do not know for sure whether the increase in left ventricular mass observed in androgen users is beneficial or deleterious, a study of left ventricular function in power athletes who were using androgens found significant impairment of both systolic and diastolic function (140,145). In another study, Urhausen et al. (507) used echocardiography to assess left ventricular mass and wall thickness among male powerlifters and bodybuilders who were currently using androgens, ex-users who had not used androgens for more than 12 months, and weightlifters who had never used androgens. Current androgen users had higher left ventricular muscle mass than nonusers or previous users (507). The E:A ratio (a measure of the peak velocity of the early rapid filling [E-wave] and filling during atrial systole [A-wave]) is reduced in powerlifters using androgens, suggesting altered diastolic function (479). Large doses of androgens may increase the risk of heart failure and fibrosis (143,144,288,351,372,392,488). Myocardial tissue of powerlifters using large doses of androgens is infiltrated with fibrous tissue and fat droplets (372).
There are several case reports of sudden deaths among power athletes who were abusing androgens (143,144,150,185,186,231,333,488). Many of the sudden deaths have been associated with myocardial infarction. Some of the myocardial infarctions were deemed nonthrombotic, leading to speculation that androgens might induce coronary vasospasm (392). These case reports are largely anecdotal, and a causative relationship between androgen use and the risk of sudden death is far from established. Power athletes using androgens often have short QT intervals but increased QT dispersion in contrast to endurance athletes with similar left ventricular mass who have long QT intervals but do not have increased QT dispersion (479). QT interval dispersion has been used as a noninvasive marker of susceptibility to arrhythmias (411); we do not know whether this predisposes powerlifters who abuse large doses of androgens to ventricular arrhythmias.
Anecdotal reports of rage reaction in androgen users, referred to as “roid rage,” have attracted a great deal of media attention. However, placebo-controlled trials of testosterone have shown inconsistent changes in anger scores or measures of aggressive behaviors (129,303,407,487,503,541). Several factors may have contributed to this inconsistency of results across trials. The instruments used to measure aggressive behavior have varied across trials, and it is possible that the self-reporting questionnaires did not have sufficient sensitivity to detect small, but significant, changes in aggression. Differences in weight training and related practices; concurrent use of other substances, such as alcohol, psychoactive drugs, and dietary supplements; and preexisting personality or psychiatric disorders are important confounders in interpretation of data related to behavioral effects of androgens (30). None of the controlled trials of testosterone have demonstrated significant change in aggression at physiologic replacement doses of testosterone. In fact, testosterone replacement in healthy androgen-deficient men has been reported to improve positive aspects of mood and attenuate negative aspects of mood (522). It is notable that only a small number of subjects (less than 5%) in controlled trials have demonstrated marked increases in aggression measures, and only with the use of supraphysiologic doses of testosterone, a majority of participants show little or no change (129,303,407,487,503,543). It is possible that high doses of androgens might provoke rage reactions in a subset of individuals with preexisting psychopathology. Indeed, aggressive individuals-perhaps those with certain personality disorders-may be more prone to abuse androgens. In a survey, more AAS users than controls had worked as doormen or bouncers (357). Among certain groups of criminals, the risk of having been convicted of a weapon offense was higher for androgen users than for nonusers (295). Anecdotal reports suggest that even among individuals without histories of psychiatric disorders or antisocial personality disorder or violence, the use of high doses of androgens might predispose men to violent or homicidal behavior (405).
It is possible that because of strong societal constraints against aggressive behavior, the self-reporting instruments fail to capture changes in the participant's behavior. However, when confronted with a provocative challenge, the individuals receiving high doses of androgens might display unexpectedly high level of aggression and rage. This hypothesis was tested by Kouri et al. (303) using an innovative study design. These investigators reported that administration of supraphysiologic doses (600 mg weekly) of testosterone enanthate to healthy young men was associated with a significant increase in aggressive responses than placebo administration. During the investigation, healthy young men randomly received either placebo or graded doses of testosterone. At baseline and at the end of the treatment period, the participants were asked to play a game against a fictitious opponent; the participants were unaware that the opponent was fictitious. The participants had the choice of pressing button A to receive a financial reward or button B that would take money away from a fictitious opponent (aggressive responding). The objective of the game was to achieve the highest monetary gain and the best strategy to achieve that goal was to keep on pressing button A. Remarkably, individuals receiving supraphysiologic doses (600 mg weekly) of testosterone enanthate opted to select button B (to punish the fictitious opponent) with greater frequency and thus had higher scores on aggressive responding than those associated with no testosterone or lower doses of testosterone. Thus, when provoked by a hostile situation, the level of aggressive response was higher when individuals were receiving high doses of testosterone than when they were receiving placebo or lower doses of testosterone enanthate.
Steroid users experience high frequency of mood disorders, such as mania, hypomania, or major depression, during androgen use (339,406,408,509). Major depression has been reported during periods of androgen use but is more often observed during withdrawal of high-dose androgen use (339,406,509). A high proportion of women athletes using high doses of androgens report symptoms of hypomania and depression, rigid dietary practices, and dissatisfaction and preoccupation with their physique (219).
The elevations of liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis have been reported mostly with the use of oral 17-alpha alkylated androgenic steroids (94,146,301,390,466,467) but not with parenterally administered testosterone or its esters (95). Most cases of hepatic neoplasms in association with androgen use have occurred in patients with myelodysplastic syndromes (366). The risk of hepatic dysfunction during androgen administration probably has probably been overstated (145,247), being extremely uncommon in individuals receiving parenteral androgens. Furthermore, it is not clear whether elevations in aspartate aminotransferase and alanine aminotransferase during androgen administrations are the result of liver dysfunction or of muscle injury resulting from strength training or a direct transcriptional effect of androgens on AST gene (145,397).
Androgen administration suppresses endogenous pituitary LH and follicle-stimulating hormone (FSH) secretion and indirectly testicular testosterone and sperm production (200,337). Because of predictable suppression of the hypothalamic-pituitary-testicular axis, men using androgens may experience subfertility or infertility (327). Indeed, androgens, alone or in combination with other gonadotropin inhibitors, are being investigated as potential male contraceptives (538).
After discontinuation of the exogenously administered androgen, the recovery of the hypothalamic-pituitary axis may take weeks to months, depending on the dose and duration of prior androgen use (88-90,262). After discontinuation of exogenous androgen use, circulating testosterone concentrations may fall to very low levels as the effects of exogenous testosterone wear off and the endogenous axis has yet not recovered. During this period, the users may experience troublesome symptoms of androgen deficiency, including loss of sexual desire and function, depressed mood, and hot flushes. Some patients who find these withdrawal symptoms difficult to tolerate may revert back to using androgens or may seek recourse to other psychoactive drugs, thus perpetuating the vicious cycle of abuse, withdrawal symptoms, and dependence (88-90). Others may resort to off-label use of aromatase inhibitors or hCG obtained illicitly based on the folklore widely prevalent in the gymnasia that these agents can accelerate the recovery of the hypothalamic-pituitary-testicular axis, although there is no evidence to support this premise. The long-term suppression of the hypothalamic-pituitary-testicular axis with its attendant risk of dependence and continued use of androgenic steroids are serious complications of androgenic steroid use that have not been widely appreciated.
Breast tenderness and breast enlargement are frequently associated with the use of aromatizable androgenic steroids (28,81,139,484). The exact prevalence of breast enlargement in androgen users is unknown, but prevalence rates as high as 54% have been reported (28,139,406,484). In a series of 63 patients referred for surgical correction of gynecomastia, 20 men had used anabolic steroids (28). It is not uncommon for athletes to use an aromatase inhibitor or an estrogen antagonist in combination with androgenic steroids to prevent breast enlargement.
The effects of testosterone on insulin sensitivity are biphasic and depend on the dose. In cross-sectional studies, low testosterone levels are associated with increased risk of insulin resistance and type 2 diabetes mellitus (132,164,220,221,402,403). Testosterone replacement in castrated rats and hypogonadal men improves measures of insulin sensitivity (249); however, supraphysiologic doses of testosterone render castrated rats insulin resistant (249). Orally administered 17-alpha alkylated androgens also have been associated with insulin resistance and glucose intolerance (115).
The majority of androgen users administer androgens by intramuscular route; 13% of those who use intramuscular injections reported unsafe injection practices (388). Self-administration of intramuscular injections increases the risk of infection, muscle abscess, and even sepsis (172). Transmission of HIV infection and hepatitis has been reported among parenteral androgen users, presumably because of needle sharing or the use of improperly sterilized needles and syringes.
Excessive muscle hypertrophy without commensurate adaptations in the associated tendons and connective tissues may predispose athletes using androgens to the risk of tendon injury and rupture and unusual stress on joints (173).
There are concerns about potential effects of androgens on the risk of prostate disease (57,59,61). The long-term effects of supraphysiologic doses of androgens on the risk of prostate cancer, benign prostatic hypertrophy, and lower urinary tract symptoms are unknown.
Women taking androgens may undergo masculinization and experience hirsutism, deepening of voice, enlargement of clitoris, widening of upper torso, decreased breast size, menstrual irregularities, and male pattern baldness (141,390). Some of these adverse effects may not be reversible. In addition, epidemiologic studies have reported an association of elevated testosterone concentrations in women with increased risk of insulin resistance and diabetes mellitus (149).
In addition to the adverse effects observed in adults, adolescents may be susceptible to some unique adverse effects of androgens (103,425,514). Pre- or peripubertal boys and girls may undergo premature epiphyseal fusion, which may result in reduced adult height (103,514). Androgen abuse by children is associated with other unhealthy behaviors, such as use of alcohol, tobacco, and other drugs; less frequent seat belt use; more sexual activity; antisocial behavior; declining academic performance; and more fasting, vomiting, diet pill, and laxative use by young girls (514). Boys may undergo premature or more accelerated pubertal changes, whereas girls may experience virilization.
Relative to the various analytical method of androgen detection, current detection techniques suffer from an extensive sample pretreatment and thus from low sample throughput. Developing new test methods, which requires the preparation of suitable reference compounds, will allow modern drug testing techniques to be more widely and more effectively utilized. The availability of numerous synthetic steroids and recombinant peptide hormones has made testing an analytical challenge. Recent advances in mass spectrometry have provided an opportunity to decrease detection by utilizing gas chromatography (GC) coupled to high-resolution mass spectrometry (HRMS). A further improvement may be seen with GC-MS/MS and quadrupole ion traps. Electrospray high-performance liquid chromatography (HPLC) coupled to high-resolution MS (HPLC-MS) has also been applied to the detection and confirmation of peptide hormones in urine. The ability to detect subtle differences in oligosaccharide structure may provide a way to detect abuse of recombinant glycoproteins. Simply decreasing detection limits is not enough; new technology also allows development of a foundation on which to base interpretation. Application of HPLC-MS/MS has allowed direct measurement of steroid conjugates in urine (1,2). The relative importance of sulfate, glucuronide, and other conjugates and metabolites of testosterone and epitestosterone can now be assessed (2). A 2-stage procedure, the liquid chromatography-mass spectrometry (LC-MS) technique, will become a much more effective and straightforward testing method, thus offering additional reliability on doping testing.
In light of this, various athletic commissions around the world have begun to analytically detect androgens by way of the steroid glucuronides-liquid chromatography/mass spectrometry. Once androgens have been ingested, the body starts to convert them so that they can be more easily discharged or eliminated as bodily waste matter. The main androgen derivatives found in urine samples are combined with glucuronic acid. Testing for exogenous androgen use is carried out on a sample of an athlete's urine. It is analyzed using a 2-stage LC-MS (2). The components of the urine sample are first separated using liquid chromatography, and then the presence of androgens is detected using mass spectrometry (2). The results can be quantified by comparison with those obtained from a series of standard solutions with known concentrations of androgen glucuronides (133). These androgen derivatives are complex molecules, and because several reaction steps are involved as well as the purity required, their preparation takes a long time and so the substances are expensive. Furthermore, based on recent change in the threshold for androgen detection where the T:E ratio is now at 4:1 rather than 6:1, methods of detection must now employ the capability of greater sensitivity. More recent advances in MS have provided this capability.
Accredited laboratories are required to detect certain androgens at levels of 2 ng·mL−1 or lower. Detection at such low levels requires HRMS or tandem mass spectrometry (MS/MS), both of which are more sensitive than conventional mass spectrometry. A mass spectrometer bombards a chemical substance with an electron beam to produce charged particles (ions) that are separated and detected based on their mass to charge ratio. By tuning the instrument to characteristic molecular fragments, drugs can be detected sensitively with little interference from other compounds, which produce different fragments. High-resolution mass spectrometry (HRMS) is better able to distinguish between fragments of interest and those arising from other chemical compounds in the urine and allows detection of steroid residues in urine at levels 5-10 times lower than was possible using the conventional technique. In MS/MS, the fragments from the initial ionization are again bombarded and mass analyzed. New purification techniques have also been introduced, which have been developed as a complement to sensitive detection techniques to increase the sensitivity of drug detection. A method using HPLC to prepare clean extracts for most androgens and their metabolites has been developed and validated. This methodology is now in routine use. An instrument capable of performing MS/MS analysis can complement HRMS, in that MS/MS can give a definitive result with some samples that prove difficult to confirm by HRMS. The main advantage of these sensitive techniques is that androgens can be detected for a much longer time after administration; androgen use can now be identified for weeks longer than was possible a few years ago.
The usual technique for detection of androgen use is to compare its concentration with that of a related compound, epitestosterone, in the urine (T:E ratio). A T:E ratio greater than 4 may indicate androgen use. However, there is a wide variation in natural T:E ratios between individuals, so that in some cases the T:E ratio may be above 6 even though the individual has not taken androgens, whereas in others the value may stay below 4 despite androgen use. The natural T:E ratio, measured over a period, tends to be constant, and any variation in an individual's T:E ratio over time may indicate androgen use. One technique that can complement the measurement of T:E ratios is the use of GC coupled to IRMS (GC-IRMS). This technique utilizes the fact that natural and administered substances, such as testosterone, have small but measurable differences in the ratio of carbon-12 to carbon-13 isotopes (C12:C13 ratio) (because of the different pathways used in the preparation of the natural and synthetic forms). By measuring the C12:C13 ratio of androgens detected in urine, GC-IRMS can distinguish exogenously administered androgens (synthetic form) from endogenously synthesized androgens (natural form). This provides an ability to identify androgen abuse in cases that would have previously gone undetected. The application of this technique is not simple because the instrumentation is expensive and requires high precision, and larger sample sizes are needed, which increases the amount of sample preparation required before analysis.
The primary biological fluid used for detecting androgen use has typically been urine. Urinary analysis has been successful for the majority of androgens, especially the synthetic varieties that have specific structures easily identifiable by GC-MS. However, the detection of androgens is not absolute and does involve limitations. Methods for detecting the use of androgens depend on alterations in the normal urinary testosterone (T) level. Much work has been done with the intent of determining appropriate urinary markers indicative of androgen use. Traditionally, the ratio of androgen glucuronides to epitestosterone (E; 17-α-hydroxy-4-androstene-3-one) has been used, as was adopted by the Medical Commission of the IOC, with a cutoff point of ≥6 being the primary indicator of androgen self-administration (386) compared with the normal urinary T:E ratio for healthy athletes not using androgens being approximately 1 (293). The increase of the T:E ratio after high-dose androgen use results from increased T excretion and a subsequent decrease in E output (134). Even so, however, some athletes have produced false-positive results revealing T:E ratios ≥ 6 with subsequent verification that no androgens had been administered (133). It has been suggested that this problem could be attenuated by taking into account the sulfate excretions of epitestosterone in the T:E ratio, thereby suggesting that the relevant threshold of the T:E ratio being 3 would be a more sensitive maker of covert androgen use (134).
World Anti-Doping Agency defines as suspect a T:E ratio of 4:1. This is more than 6 SDs for the expected norm of 1:1 in the general population. Using a smaller ratio, however, would be impractical. For example, using publicly available data, only 3 of nearly 500 cases since 2004 where the T:E ratio was between 4:1 and 6:1 resulted in a confirmed adverse analytical finding under the WADA system. The preliminary GC/MS screen for testosterone in urine is known as the T:E ratio test. T stands for testosterone; E, epitestosterone, a natural, inactive isomer of testosterone. In most individuals, the T:E ratio is ∼1:1. A T:E ratio of 4:1 may indicate the presence of synthetic testosterone. World Anti-Doping Agency has established that a T:E ratio of ≥4:1 is the threshold that triggers further testing of an athlete's sample. Upon collection, each sample from an athlete is split into 2 vials, A and B, and sample A is tested first. The T:E test has 2 parts: a screening phase and a confirmation phase. T and E are identified by the main MS fragment ions produced from their respective trimethylsilyl derivatives in the screening phase. Once a chromatogram is produced, the T:E ratio is estimated on the basis of the peak area ratio. If the T:E ratio is ≥4:1, then a GC/MS confirmation test is performed. Two new aliquots, one that is hydrolyzed and one that is not, are prepared for this test. The aliquot without hydrolysis measures free T and E to verify that the urine sample did not break down.
Interestingly, because the secretion of testosterone is under the control of LH, it has been suggested that the urinary T:LH ratio could conceivably be a useful marker for detecting androgen use (87). High-dose androgen use is known to result in dose-dependent suppression of both serum and urinary LH (291), based on the premise that LH excretion is typically reduced to a lesser extent than the decrease in both epitestosterone and testosterone conjugates. Therefore, increased serum and urinary T:LH ratios in the presence of a normal T:E ratio may be indicative of androgen use. In light of this, it has been shown that a urinary T:LH ratio of ≥30 is a more sensitive marker of androgen use than the urinary T:E ratio of ≥6, and remains sensitive for twice as long as urinary T:E (396).
Doping tests for the past 10 years have demonstrated that Asian individuals excrete a reduced amount of testosterone glucuronide (136,387), which may result in an increased risk of a false-negative drug test in this ethnic group. This was part of the motivation for changing the upper normal limit of 6 to 4 for the T:E ratio. Recent studies have suggested that a deletion polymorphism in the gene coding for uridine diphospho-glucuronyl transferase 2B17 (UGT2B17), the principle enzyme for the glucuronidation of androgens and their metabolites, is associated with a T:E ratio below 0.4 (259). This was seen to be more common in Asian than in a white population.
Although androgens have always required a physician's prescription for use, it was not always listed as a controlled substance. However, as a result of mounting pressure related to androgen use among American adolescents, the U.S. Congress in 1990 amended the controlled substances act to include androgens. This was known as the Anabolic Steroid Control Act. The passing of this law reclassified androgens as a schedule III substance. The impact of this was to make it a crime to use these drugs for nonmedical purposes. Other schedule III substances include weak opioids such as codeine and Vicodin, barbiturates, amphetamines, and methamphetamines. By 2004, an amended version of the Anabolic Steroid Control Act was passed that modified the definition of androgens to include 26 additional compounds that comprised designer androgens, such as THG, and prohormones, such as androstenedione.
The simple possession of any schedule III substance including androgens is punishable by up to a year in prison and/or a fine of $1,000. However, if the person who is caught in possession of androgens has a previous conviction for drug possession or another crime they will be imprisoned for at least 15 days and up to 2 years with a minimum fine of $2,500. A third conviction for possession will require imprisonment for at least 90 days but not more than 3 years with a minimum fine of $5,000. Selling anabolic steroids or possessing androgens with intent to sell is a federal felony offense. First conviction is punishable by up to 5 years in prison and/or a $250,000 fine. A second conviction for distribution of androgens may result in a prison sentence of up to 10 years with fines not exceeding $500,000.
Conviction of androgen possession or distribution results in not only potential prison time and/or fine but may also jeopardize future employment opportunities. If the convicted person holds a license for employment, such as medical and allied health professionals, a conviction may result in a loss of licensure. In addition, students convicted of possession or distribution of schedule III substances may forfeit their rights to financial aid and other benefits. Clearly, users of illegal performance-enhancing drugs face significant risk for jail time, fines, and jeopardize both present and future employment opportunities.
The efficacy of androgen treatment in muscle wasting diseases has clearly been established. Continued research is needed to further identify clinical populations that may benefit from androgen therapy and combined exercise and androgen treatments. In addition, identification of dosing-related adverse events will provide a clearer understanding of risk vs. reward regarding androgen treatment. Research on selective AR modulation is very promising in this regard and needs to be further elucidated.
Regarding androgen use in healthy athletic populations, there is a need to increase research on maximizing performance gains through modulations in nutritional and exercise regimens and when appropriate the inclusion of legal and efficacious supplements. Providing viable alternatives to athletes contemplating illegal drug use could potentially reduce the number of athletes who are willing to take such chances. In addition, further understanding of the effect of changes in androgen profiles in athletes during the competitive season is warranted. Although anabolic and catabolic hormonal changes have been well documented during various exercise stresses, there are only limited data available concerning changes in competitive athletes during a season of training and competition. Furthermore, investigations designed to study the effect of various recovery methods, nutritional interventions, sport supplements, and exercise routines on endocrine function in such athletes would provide valuable information to coaches and athletes regarding potential methods used to promote an optimal training environment and maximize athletic performance.
The purpose of this overview of GH is presented for the most part beyond what is found in classical endocrine textbook aspect of GH physiology. It is vital to gain an understanding of what lies beyond the typical physiology and is related to the use of GH for physical development and enhancement of sport performance.
Growth hormone also called somatotropin in the older literature is a pleiotropic peptide hormone synthesized, stored, and released from the anterior pituitary gland (353). The most commonly measured form of GH is the 191 amino acid isoform. This 22-kDa isoform contains numerous cleavage sites and can be structurally distinguished via its positioning of cysteine residues that are responsible for its internal disulfide loop and smaller disulfide loop located at the C-terminus. Other variants include a 20-kDa form produced by the gene deletion for 14 amino acids and many other post-translational isoforms of unknown physiological significance (42). The GH produced for commercial use is 100% the 22-kDa isoform. This is important information for the detection of hGH abuse.
At present, detection of hGH abuse has not been validated, and this provides the primary motivation for use by athletes. In addition, the measurement and elucidation of its biological properties are complex, as hGH does not exist as a single, molecular species. It has been suggested that more than 100 different hGH isoforms exist, all arising from one of 2 genes (41,43). Post-translational modifications include acetylation, deamination, and hetero- and homo-oligomerization (43,320). The ability to form oligomers via either noncovalent or peptide (cystine) bonds may serve to increase the half-life of the peptide in circulation or may have undiscovered biological properties, such as competitive binding to the GH receptor. Dimeric hGH appears to be the most abundant of the post-translationally modified products, although oligomers up to pentameric GH have been reported. Homo- and hetero-oligomers have been described for the 22- and 20-kDa isoforms. Of particular interest is that small proteolytic fragments and large aggregates are also formed (43). The variable nature of these GH isoforms exists in circulation and encompasses a wide range of molecular weights (42). Thus, understanding the impact of ergogenic use of GH as an anabolic agent is likely complex.
Mediation of GH effects occurs with its interaction with the GH receptor. The GH receptor is a 70-kDa class I cytokine/hemapoietin superfamily protein (319). It is composed of 2 complexes that interact with the GH ligand in a sequential manner to dimerize. Intracellular signaling then occurs through a phosphorylation cascade via the JAK/STAT pathway. The GH receptor exists in abundance in many tissues, including the liver, muscle, and adipose tissue. However, the GH receptor may not be specific to all the GH variants (208,251). For instance, the tibial line receptors, used in a bioassay, do not seem to interact strongly with the 22-kDa monomer (208,251).
Its physiological role is linear growth in children, to promote anabolic (tissue building) metabolism, and to alter body composition as part of this anabolic role. Growth hormone actions include the hepatic and local synthesis and release of its main mediator, IGF-1. Its growth-promoting effects include longitudinal bone growth by actions at the epiphysis and the differentiation of the osteoblasts (420). It shares some of these roles with IGF-1, meaning that the direct effect of GH and/or local production of IGF-1 are both required for optimal linear growth.
The release of GH is stimulated by growth hormone-releasing hormone (GHRH) and is inhibited by somatostatin, both hypothalamic hormones. However, there are many other factors that affect GH regulation, most of which use these hypothalamic hormones as a common path. Stimuli to GH release include deep sleep; exercise; stress including heat; hypoglycemia; nutritional intake; some amino acids (see below); some pharmacologic agents, including clonidine, l-DOPA, estrogens, and androgens (through an estrogen-dependent mechanism, especially in adolescents). Inhibitory influences include obesity, ingesting a carbohydrate-rich diet, and several pharmacologic agents, for example, beta-2 adrenergic agonists. The release of GH from the anterior pituitary is pulsatile, meaning that its release is not constant but occurs in bursts (236,251) The largest peak GH secretion occurs about an hour after the onset of sleep, with subsequent smaller peaks occurring during the rest of the sleep period (374).
Its major metabolic effects can be deduced from the alterations in GH-deficient subjects-the reduction of lean body mass, an increase in body fat, and a reduction in bone mineral density. Administering hGH may reverse many of these alterations (see below); however, it is not quite so simple in that hGH has different acute effects depending on the time after natural secretion or exogenous administration. It is insulin-like in the first minutes, but then becomes diabetogenic (anti-insulin) at the liver and at peripheral sites several hours after administration. Glucose utilization is decreased, lipolysis is increased, and the tissues are refractory to the acute insulin-like effects for several hours. Its direct actions include amino acid transport in muscle leading to protein synthesis and an increase in nitrogen balance, increased fat mobilization through lipolysis (increased triglyceride hydrolysis to free fatty acids and glycerol and reduction in fatty acid re-esterification), and an augmentation of lipid oxidation. Clinically these effects can be noted in the longer term by a decrease in body fat and a decrease in the adipopcyte size and lipid content.
The outcome of GH therapy in GH-deficient adults may be an increase in FFM, both body cell mass (muscle), total body water, especially the extracellular compartment, and a decrease in body fat with redistribution from central to peripheral stores (242).
Growth hormone has numerous functions in the organism, including growth and development, metabolism, bone health, hydration status, and cardiovascular function. The diverse multitude of functions would appear to imply that more than one form of GH (i.e., molecular variants) may be necessary to mediate all these functions. However, for the purposes of this review, the focus will be on the effects of hGH on protein synthesis in muscle, as heavy resistance training is primarily focused on this target tissue for development. In fact, understanding the interactions of hGH with other anabolic hormone signals is vital because it is unlikely that athletes use hGH alone. As noted previously, it is likely that GH and anabolic steroids are taken concurrently. Figure 6 depicts the role of GH signaling in response to resistance exercise and also the associated influence of other anabolic hormones, which are commonly associated with anabolic drug use.
The effect of hGH on muscle hypertrophy appears to lie in its ability to indirectly stimulate the mammalian target of rapomyosin (mTOR) pathway via dimerization with its receptor and subsequently activating the phosphorylation cascade of the JAK/STAT pathway. The mTOR pathway has direct control over several components of translation in protein synthesis via its downstream effectors, ribosomal S6 kinase 1 (S6K), eukaryotic initiation factor-I 4E binding protein-1 (eIF 4E-IGFBP-1), and elongation factor 2 kinase (eEF2) (198,232,338).
The mTOR pathway can also be activated by the extracellular ligand-regulated kinase (ERK) pathway via phosphorylation of the JAK/STAT pathway subsequent to GH ligand binding to the GH receptor in disease states such as cancer and likely occurs during musculoskeletal protein synthesis (19,335,426) A further role of GH in skeletal muscle growth is related to its ability to increase myonuclear number and to facilitate the fusion of myoblasts with myotubes (469).
It has also been reported that hGH has stimulating role in the incorporation of ingested amino acids on protein synthesis, probably occurring through decreasing leucine oxidation and increasing lipolysis. Growth hormone also potentially blunts insulin proteolytic action and increases free fatty acid availability, both of which may have a sparing effect on the amino acid pool.
However, the most potent anabolic effects of hGH may be related to its role in amino acid metabolism. In a study of exogenous GH infusion, Copeland and Nair (121) reported that an acute local infusion of hGH in healthy men immediately inhibited whole body leucine oxidation independent of other hormones. In contrast to this finding, others have reported that local skeletal muscle protein uptake occurred in response to local hGH infusion in the forearm, but total body protein metabolism was not affected (197). Furthermore, it appears that uptake by local contractile muscle also occurs, with differences in arteriovenous concentrations reported in at least one exercise study (79). However, the independent effects of GH on amino acid metabolism remain controversial, as other GH-mediated hormones such as IGF-1 may also play a significant role (362).
Human growth hormone was first prepared in the 1940s and in such small amounts that there was likely virtually none available for athletic performance (321). It is only the human (and monkey) pituitary GH that has efficacy in man and thus none of the other species' GH can be used (297). With the synthesis of recombinant hGH (rhGH) in the 1980s, a virtually unlimited supply became available, and clinical studies were undertaken in children and adolescents with subnormal growth and adults with GH deficiency, aging, and for performance or aesthetic purposes (see below). The evidence for rhGH to produce salutary ergogenic and performance effects among athletes is neither robust nor clear (324,539).
Growth hormone is administered to promote linear growth in short children. The following are the Food and Drug Administration (FDA)-approved indications for GH:
The most common efficacy outcome in infants, children, and adolescents is an increase in linear growth, although it prevents hypoglycemia in some infants with congenital hypopituitarism.
Growth hormone is administered to promote physiologic and psychological well-being and altered body composition in adults with GH deficiency, muscle wasting due to HIV/AIDS, and short bowel syndrome. All other use is “off-label” and has become of intense interest in the sporting world, especially earlier this year with the Congressional hearings related to Major League Baseball.
Clinical research with GH in children is mainly about promoting growth in various pathological conditions, which may stunt growth. In some syndromes, for example, the Prader-Willi syndrome, the alterations in body composition (lean body mass, fat mass, and especially the regional distribution of body fat) are being investigated.
For the adult, the bulk of GH research involves the study of 2 opposite conditions:
Growth hormone is listed under class S2 of hormones and related substances in terms of the 2006 prohibited list. Other peptides in this category include EPO and corticotrophin (ACTH) in addition to IGF-1 and insulin. Growth hormone is likely being abused at increasingly prevalent rates, but before describing some of the data, it should be noted that much of what is purported to be hGH, especially on the Internet is not. Of course, any drug taken orally cannot be hGH. Many of the products advertised on the Internet and in magazines are hGH releasers-mainly amino acids and rarely, analogues of hGH-releasing hormone (435). The notion that amino acids release hGH is on solid scientific ground, given that tests for GH sufficiency may include arginine or the closely related amino acid, ornithine. What is not stated is that very concentrated solutions of these amino acids are administered intravenously before GH is released. Also not prominent (note that these are dietary supplements and not subject to FDA oversight) is the physiologic concept of the absolute and then relative refractory period after GH release, irrespective of the cause.
There are many reports that note an increasing prevalence of hGH abuse. These come (mainly) from anecdotal reports including “information” of benefits, from the Internet, a very favorable write-up in The Underground Steroid Handbook, and an increasing number of seizures from elite athletes including cyclists and swimmers. What is it that athletes wish to obtain from administering hGH? The athletes wish improved performance, but such studies are difficult to do, either as “clinical trials” or observational studies in athletes; for they rarely take agents singularly but often a “cocktail” of dietary supplements and 1 or more doping agents. Although hGH has not been shown to unequivocally increase muscle strength or to improve performance (324), it is considered one of the drugs of choice because it is extremely difficult to prove that one is receiving it (more about the “window of detectability” later). The structure of rhGH is identical to that of the main isoform of natural hGH; it is secreted in pulsatile manner, meaning that its levels fluctuate widely, from undetectable to clearly in the “doping” range with a short half-life in the circulation. Exercise is potent stimulus to hGH release, and release may be modified by variations in nutrition and legitimate nutritional supplements, as noted previously.
Lean body mass increased in the hGH-treated groups compared with those not treated [2.1 kg (95% CI, 1.3 to 2.9 kg)], with a small but not statistically significant decrease in fat mass (−0.9 kg [CI −1.8 to −0.0 kg]). Body weight did not change significantly. Only 2 studies appropriately evaluated change in strength (142,550). These were the longest trials of 42 and 84 days. On 1RM voluntary strength testing, those receiving hGH showed no change in biceps strength (−0.2 kg [CI −1.5 to 1.1 kg]) or quadriceps strength (−0.1 kg [CI −1.8 to 1.5 kg]). In the second study, none of the 7 other muscle groups evaluated showed a positive change in strength.
Minor effects of hGH have been noted on basal metabolism with a slight decrease in respiratory exchange rate reflecting the preferential burning of fat rather than carbohydrate at rest. Additionally, there is very little effect on exercise capacity. The 6 studies evaluated used quite different protocols, and the results may be summarized as noting that lactate levels trended higher and that plasma free fatty acid concentrations and glycerol concentrations were significantly increased, reflecting the lipolytic metabolic effect of hGH, but the respiratory exchange ratio did not change.
These studies showed very little ergogenic effects of administered hGH in recreational athletes. They were of short duration and unlikely represent how elite athletes administer hGH, with reference to dose, duration, or other supplements, either legal or illegal. It is clear that many athletes abuse steroids in addition to the “noted” amounts of hGH. None of the studies would have been able to detect differences of 0.5-1.0% in “performance.” These small differences are those that are relevant to the time (track events), distance, or height (field events) that separate the champion from any other finishing position.
Adverse events were common in the larger group of studies and mirrored those of adult subjects administered hGH in what were at that time, child and adolescent doses. These included soft tissue edema, joint pain, carpel tunnel syndrome, and excessive sweating. Most are related to fluid retention and considered to be secondary to the GH effect on salt and water balance by the kidney.
Virtually all studies examining hGH supplementation had significant methodological limitations. These included limited examinations on strength and exercise capacity, short duration of supplementation, and doses not consistent with the method used by most athletes. Liu et al. (324) suggested that “Claims regarding the performance-enhancing properties of growth hormone are premature and are not supported by our review of the literature. The limited published data evaluating the effects of growth hormone on athletic performance suggest that although growth hormone increases lean body mass in the short term, it does not appear to improve strength and may worsen exercise capacity. In addition, growth hormone in the healthy young is frequently associated with adverse events.”
This has been quite a difficult task for the analytical chemists because the amino acid sequence of recombinant GH is identical to that of the main GH isoform secreted by the pituitary: unlike other peptide hormones, it has no N-linked glycosylation sites; its secretion is pulsatile with a short half-life (16-20 minutes); there are circulating GH-binding proteins; potential cross-reactivity with other peptide hormones (e.g., prolactin); and it is stimulated by exercise and stress. Blood sampling is required for all detection methods because less than 0.1% may be found in the urine. Its renal secretion is poorly understood and highly variable within and between subjects (250).
The analytical approaches rely on immunoassays as opposed to the more established doping tests for anabolic steroids, which depend on GC/MS technology. There are 2 general approaches to detection of doping with rhGH. The first approach (direct) measures the GH isoform composition by the differential immunoassay method (70). For this approach, one constructs pairs of antibodies whose primary focus is “all” of the isoforms of hGH and a second set that is virtually restricted to the 22-kDa isoform-the one that is 100% of the recombinant hGH. The first assay is called “permissive” (pituitary) and the second, specific (recombinant). The principle (rationale) is that the more one takes the rhGH (22 kDa), the less pituitary hGH (especially, 20 kDa) will be secreted, meaning that the ratio of the specific to the pituitary will rise. As an example, the ratio rises from 0.6 to 1.5 in subjects administered rhGH, but this assay would only be valid within a few days of the last injection of rhGH. The validation of this technique requires knowledge (testing) of the effects of exercise on the recombinant to pituitary ratio, an independent confirmatory test (see below), knowledge of the “window of opportunity,” and data from athletes, both recreational and elite. This method is unable to detect doping with pituitary-derived hGH or the abuse of the GH secretagogues, IGF-1 itself or in combination with its major circulating binding protein, IGFBP-3 (IGF-1/IGFBP-3) (250).
The second is the indirect approach in which specific analytes dependent on hGH (or IGF-1) would be measured. Variables from the IGF system and collagen/bone have been chosen because they change markedly during rhGH administration, and it appears that combinations of variables using discriminant functions are the most promising. Detection of rhGH supplementation is possible at least until 2 weeks after the last administration, although there is progressively decreasing sensitivity after the first week. Normative data in athletes have been established (233). The physiological changes in GH-dependent markers in adolescent athletes are far more dramatic than in older athletes, thus making it quite difficult to detect in this age range without constructing a complex algorithm that would depend more on maturational age than it would on the chronological age-another complication for doping control. Data using this approach have noted only minor effects due to trauma, micro-injury, or ethnic background (166). As with any assay, rigorous standardization is required and interference by concomitant drug abuse, especially anabolic steroids, is a likely complication. For the moment, the most informative combination of analytes is IGF-1 and procollagen III peptide levels and individual discriminant functions for men and women.
Future research in the doping detection field will require the determination of combinations of GH-dependent analytes that are longer lasting than the ones currently used and perhaps other methods for the direct determination of the IGFs and GH secretagogues. It would seem that use of hGH (or other peptide hormones) manufactured by the major pharmaceutical companies around the world could be markedly diminished by adding, for example, an inert fluorescent marker that would be excreted in the urine. Detection of that (unnatural) marker might then be considered a doping offense. We suspect that that would markedly diminish but not stop doping offenses with these hormones.
The era of gene doping, for example, adding hGH or IGF-1 genes to specific muscles, is upon us. Experiments have been done in animals (37). No detection methods presently available could detect this type of doping.
As is true for many legitimate drugs, physicians may prescribe off-label, meaning that trials for that particular condition have not been performed, but that it is “logical” to use a particular already approved drug for a specific patient. Recombinant hGH is quite different. It is illegal to prescribe hGH off-label for age-related conditions (anti-aging) or performance enhancement. Unlike most FDA-approved medications, hGH can only be prescribed for indications specifically authorized by the Secretary of Health and Human Services (for indications, see above). In addition, hGH is not considered a “dietary supplement” and is not subject to the DSHEA legislation because it is not administered orally and it had formerly been classified as a “drug” [FDCA 21 USC 321 (ff) (2) (A) (i)].
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