Journal of Strength & Conditioning Research:
Position Stand on Androgen and Human Growth Hormone Use
Hoffman, Jay R1; Kraemer, William J2,3; Bhasin, Shalender4; Storer, Thomas4,5; Ratamess, Nicholas A1; Haff, G Gregory6; Willoughby, Darryn S7; Rogol, Alan D8,9
1Department of Health and Exercise Science, The College of New Jersey, Ewing, New Jersey 08628; 2Department of Kinesiology; 3Department of Physiology and Neurobiology, The University of Connecticut, Storrs, Connecticut 06269; 4Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, Boston, MA; 5Department of Kinesiology, Division of Health Sciences, El Camino College, Torrance California; 6Division of Exercise Physiology, Department of Human Performance and Applied Exercise Sciences, West Virginia University, Morgantown, West Virginia 26508; 7Department of Health, Human Performance, and Recreation, Baylor University, Waco, Texas 76798; 8Department of Pediatrics, University of Virginia, Charlottesville, Virginia; and 9Department of Pediatrics, Riley Hospital, Indiana University School of Medicine, Indianapolis, Indiana
Address correspondence to Jay R. Hoffman, firstname.lastname@example.org.
Hoffman, JR, Kraemer, WJ, Bhasin, S, Storer, T, Ratamess, NA, Haff, GG, Willoughby, DS, and Rogol, AD. Position stand on Androgen and human growth hormone use. J Strength Cond Res 23(5): S1-S59, 2009-Perceived yet often misunderstood demands of a sport, overt benefits of anabolic drugs, and the inability to be offered any effective alternatives has fueled anabolic drug abuse despite any consequences. Motivational interactions with many situational demands including the desire for improved body image, sport performance, physical function, and body size influence and fuel such negative decisions. Positive countermeasures to deter the abuse of anabolic drugs are complex and yet unclear. Furthermore, anabolic drugs work and the optimized training and nutritional programs needed to cut into the magnitude of improvement mediated by drug abuse require more work, dedication, and preparation on the part of both athletes and coaches alike. Few shortcuts are available to the athlete who desires to train naturally. Historically, the NSCA has placed an emphasis on education to help athletes, coaches, and strength and conditioning professionals become more knowledgeable, highly skilled, and technically trained in their approach to exercise program design and implementation. Optimizing nutritional strategies are a vital interface to help cope with exercise and sport demands (516-518). In addition, research-based supplements will also have to be acknowledged as a strategic set of tools (e.g., protein supplements before and after resistance exercise workout) that can be used in conjunction with optimized nutrition to allow more effective adaptation and recovery from exercise. Resistance exercise is the most effective anabolic form of exercise, and over the past 20 years, the research base for resistance exercise has just started to develop to a significant volume of work to help in the decision-making process in program design (187,248,305). The interface with nutritional strategies has been less studied, yet may yield even greater benefits to the individual athlete in their attempt to train naturally. Nevertheless, these are the 2 domains that require the most attention when trying to optimize the physical adaptations to exercise training without drug use.
Recent surveys indicate that the prevalence of androgen use among adolescents has decreased over the past 10-15 years (154,159,246,253,370,441,493). The decrease in androgen use among these students may be attributed to several factors related to education and viable alternatives (i.e., sport supplements) to substitute for illegal drug use. Although success has been achieved in using peer pressure to educate high school athletes on behaviors designed to reduce the intent to use androgens (206), it has not had the far-reaching effect desired. It would appear that using the people who have the greatest influence on adolescents (coaches and teachers) be the primary focus of the educational program. It becomes imperative that coaches provide realistic training goals for their athletes and understand the difference between normal physiological adaptation to training or that is pharmaceutically enhanced. Only through a stringent coaching certification program will academic institutions be ensured that coaches that they hire will have the minimal knowledge to provide support to their athletes in helping them make the correct choices regarding sport supplements and performance-enhancing drugs.
The NSCA rejects the use of androgens and hGH or any performance-enhancing drugs on the basis of ethics, the ideals of fair play in competition, and concerns for the athlete's health. The NSCA has based this position stand on a critical analysis of the scientific literature evaluating the effects of androgens and human growth hormone on human physiology and performance. The use of anabolic drugs to enhance athletic performance has become a major concern for professional sport organizations, sport governing bodies, and the federal government. It is the belief of the NSCA that through education and research we can mitigate the abuse of androgens and hGH by athletes. Due to the diversity of testosterone-related drugs and molecules, the term androgens is believed to be a more appropriate term for anabolic steroids.
1. Androgen administration in a concentration-dependent manner increases lean body mass, muscle mass, and maximal voluntary strength in men. However, the upper concentration for maximum effects remains unknown.
2. Combined administration of androgens and resistance exercise training is associated with greater gains in lean body mass, muscle size, and maximal voluntary strength in men than either intervention alone.
3. Testosterone therapy is approved only for the treatment of hypogonadism in adolescent and adult men. However, the anabolic applications of androgens and selective AR modulators are being explored for the functional limitations associated with aging and some types of chronic illness.
4. The magnitude and frequency of adverse effects among androgen users have not been systematically studied. Potential adverse effects of androgen use in men include suppression of the hypothalamic-pituitary-gonadal axis, mood and behavior disorders, increased risk of cardiovascular disease, hepatic dysfunction with oral androgens, insulin resistance, glucose intolerance, acne, gynecomastia, and withdrawal after discontinuation. In addition, the polypharmacy of many androgen users (psychoactive and accessory drugs) may have serious adverse effects of their own.
5. The adverse effects of androgen administration in women are similar to those noted in men. In addition, women using androgens may also experience virilizing side effects such as enlargement of the clitoris, deepening of the voice, hirsutism, and changes in body habitus. These changes may not be reversible on cessation of androgen use.
6. In pre- and peripubertal children, androgen use may lead to virilization, premature epiphyseal closure, and resultant adult short stature.
7. Since 1990, the use of androgens for a nonmedical purpose is illegal. Androgens are labeled as a schedule III drug. Possession of any schedule III substance including androgens is punishable by fine, prison time, or both. Prescribing androgens for bodybuilding or enhanced athletic performance is also punishable as noted above.
8. Human growth hormone increases lean body mass within weeks of administration; however, the majority of the change is within the water compartment and not in body cell mass.
9. Human growth hormone is unlikely to be administered as a single agent but often in combination with androgens.
10. Combined administration of hGH and resistance exercise training is associated with minimal gains in lean body mass, muscle size, and maximal voluntary strength in men compared with resistance exercise alone.
11. Human growth hormone is approved for the therapy of children and adolescents with growth hormone deficiency, Turner syndrome, small for gestational age with failure to catch-up to the normal growth curves, chronic kidney disease, Prader-Willi syndrome, idiopathic short stature, Noonan syndrome, and SHOX gene deletion. For adults, hGH is approved for the treatment of GH deficiency, AIDS/HIV with muscle wasting, and short bowel syndrome.
12. The magnitude and frequency of adverse events associated with hGH use are clearly dose related. Potential adverse events include suppression of the hypothalamic-pituitary GH/IGF-1 axis, water retention, edema, increased intracranial pressure, joint and muscle aches, and those of needle injection (hepatitis and HIV/AIDS). These should be the same in women as well as in men.
13. Continued effort should be made to educate athletes, coaches, parents, physicians, and athletic trainers along with the general public on androgen and hGH use and abuse. Educational programs should focus on potential medical risks of these illegal performance-enhancing drugs use, optimizing training programs and concurrent nutritional strategies to enhance physiological adaptation and performance. In addition, educating coaches on setting realistic training goals and expectations for their athletes will help reduce the pressures to use illegal PED and assist in potentially identifying potential users of illegal PED.
14. The NSCA supports and promotes additional research funding to be directed toward effective educational programs, documentation of both acute and long-term adverse effects of androgen and hGH abuse, strategies for optimizing athletic performance through training and nutritional interventions, strategies to help athletes discontinue androgen and hGH use, and strategies for the detection of abuse of androgens and hGH.
The use of androgens by athletes has received a lot of attention in the media over the past decade. The current media attention to this topic has falsely suggested that androgen use by athletes is a relatively new phenomenon. It contrast, it is something that has been around for many decades. For the past half century, the use of androgens by athletes has increased medical and scientific focus on the efficacy and dangers of these compounds. The medical risks associated with androgens as well as ethical considerations have led the major sport governing bodies to initiate measures to combat their use. All major national and international sport organizations have banned androgens from use by their athletes, and detection of use results in suspension from competition. Although educational and awareness programs have been developed to combat the use of androgens, the efficacy of these programs is not clear. Considering that most athletes and coaches are aware of the potential side effects and risks associated androgens use, including the risk of becoming barred from competition, they still continue to search for ways to mask their use to avoid detection or have redirected their efforts to use anabolic drugs that are not detectable (e.g., human growth hormone [hGH]).
A number of position stands and review papers have been written on this subject. However, the information contained in these reviews is often outdated, incorrect, or incomplete. Previous position stands published by the National Strength and Conditioning Association (NSCA) and the American College of Sports Medicine (ACSM) are more than 15-20 years old. In light of the intense media scrutiny that has been recently focused on these performance-enhancing drugs, it appears that an updated review and examination of this issue are required. It is acknowledged that there are other performance-enhancing drugs that are presently being used by athletes (e.g., erythropoietin [EPO], insulin, thyroid hormone). However, this report will focus on the most widely publicized drugs: androgens and hGH. The important clinical use of these drugs will be discussed as well. Each of these drugs will be examined separately, with specific emphasis on their physiological role, history of use, research on the efficacy as a performance-enhancing drug, medical issues associated with their use, and when applicable, dosing patterns, frequency of use, detection methods, masking agents, and other drugs that are commonly used concomitantly with these anabolic agents. In addition, legal issues associated with these performance-enhancing drugs, direction of future research, and performance-enhancing drug education programs will be discussed.
Androgen is a sex hormone that promotes the development and maintenance of the male sex characteristics. Testosterone is the principal secreted androgen in men. Androgens have both masculinizing (development of male secondary sex characteristics, including hair growth) and anabolic effects (increase in skeletal muscle mass and strength). For decades, pharmaceutical companies have attempted to develop androgens that have preferential anabolic activity and reduced or no androgenic (masculinizing) activity; these compounds have been referred to as anabolic steroids. However, there are few clinical trial data in humans to support the view that such compounds are purely anabolic; the steroidal compounds available to date have both androgenic and anabolic activities. A number of terms-anabolic steroids, androgenic steroids, anabolic-androgenic steroids, and androgens-have been used in literature to describe these androgen derivatives. For the sake of uniformity and accuracy, we have used the term “androgen” to describe these compounds that bind androgen receptor (AR) and exert masculinizing as well as anabolic effects to varying degrees.
What Is the Physiological Role of Testosterone?
Testosterone is a 19-carbon steroid (Figure 1) with a ketone group at position 3, hydroxyl group at position 17, and a double bond at position 4. Its basic structure is composed of 3 cyclohexane rings and 1 cyclopentane ring with a methyl group at positions 10 and 13 (472). The biosynthesis of testosterone begins in the adrenal cortex where cholesterol is converted through a multistep process to dehydroepiandrosterone (DHEA) and androstenedione. The androgens androstenediol and androstenedione are natural testosterone precursors. The biosynthesis of testosterone takes place within the testicular Leydig cells in 2 metabolic pathways. During the progesterone pathway (delta-4 pathway), pregnenolone is metabolized to progesterone by the 3-beta-hydroxysteroid dehydrogenase and an isomerase. Progesterone is then converted to 17-alpha-hydroxyprogesterone by 17-alpha-hydroxylase and C17:C21-lyase to androstenedione, then to testosterone by reduction of the 17-keto group by 17-beta-hydroxysteroid dehydrogenase. The DHEA pathway (delta-5 pathway) leads from pregenolone to 17-alpha-hydroxypregnenolone to DHEA and is then converted to 5-delta-androstenediol by C17:C21-lyase.
Testosterone and the other C-19 androgens can also be converted into the compound dihydrotestosterone (DHT) or into estradiol by the action of the enzyme aromatase (Figure 2). In males, more than 95% of testosterone is secreted by the Leydig cells under the control of luteinizing hormone (LH). The remainder is produced via conversion in the adrenal cortex. This is a major way in which females produce testosterone in addition to the ovaries (although testosterone concentrations are much lower in women). Healthy men produce approximately 4.0-9.0 mg of testosterone per day with blood concentrations ranging from 300 to 1,000 ng·dL−1 (10.4-34.7 nmol·L−1), whereas for females blood concentrations range from 15 to 65 ng·dL−1 (0.5-2.3 nmol·L−1) (38,59). Dihydrotestosterone is mostly formed via peripheral conversion in other target (non-skeletal muscle) tissues via the enzyme 5α-reductase, an enzyme that converts testosterone to DHT in the cytoplasm. Once secreted, testosterone travels through the circulation either free (i.e., free testosterone) or bound to a carrier protein. About 35-38% of testosterone travels bound to albumin, with the remaining bound to the glycoprotein sex hormone-binding globulin (SHBG) (472). According to the free hormone hypothesis, it is only the free testosterone that is bioavailable and able to diffuse through the cell membrane and bind to its cytosolic receptor, or perhaps bind to some membrane receptor (414). However, recent evidence that SHBG-bound testosterone may also be internalized through the megalin family of proteins and be biologically active (225,367). There is a growing body of evidence that albumin-bound testosterone may dissociate in many organs such as the liver and brain and become biologically available (356,432). Only about 0.5-2.5% of circulating testosterone is in the free form. Thus, free testosterone concentration is a function of total testosterone concentration and binding protein concentration. Testosterone plays a number of important roles in the human body. Testosterone affects many physiological systems, which are listed in Table 1. It is believed that most actions of testosterone are dependent on total circulating concentrations and directly produced via testosterone's interaction with the AR. The increase in gene transcription and translation of proteins elicits several changes that enhance muscle hypertrophy, strength, endurance, and power (285,287,458). In addition, testosterone has been suggested to lead to muscle anabolism via antiglucocorticoid actions (i.e., testosterone may bind with high affinity to cortisol receptors, thereby attenuating potential catabolic actions or inhibit glucocorticoid action via cross-regulation with ARs), potentiation of muscle insulin-like growth factor-1 (IGF-1), and attenuation of myostatin action and signaling (38,285,546). Last, testosterone plays a key role in development of secondary sex characteristics, for example genital growth during puberty, deepening of the voice, hair growth, and so on.
Feedback Control of Testosterone Synthesis and Secretion
Control of testosterone synthesis and secretion begins in the hypothalamus, which links the nervous and endocrine systems and secretes several regulatory hormones that act on the anterior pituitary gland to either increase or inhibit hormonal release. One hormone secreted by the hypothalamus is gonadotropin-releasing hormone (GnRH). Gonadotropin-releasing hormone is secreted in pulses every 90-120 minutes and binds to gonadotropes in the anterior pituitary where it stimulates the secretion of LH. Luteinizing hormone secreted into circulation binds to receptors on Leydig cells of the testes where it stimulates testosterone secretion. Testosterone elevations, via negative feedback, eventually will reduce further testosterone secretion via direct inhibition at the hypothalamic and anterior pituitary axis. Much of the inhibition stems from peripheral aromatization of testosterone to estradiol. Estradiol elevations feedback directly to the hypothalamus, thereby reducing secretion of GnRH and subsequently LH from the anterior pituitary. Androgens use negative feedback on the hypothalamic-pituitary axis such that the body's own endogenous testosterone production is minimized. Thus, during exogenous androgen use, testicular shrinkage may ensue. The adverse effects associated with androgen use have prompted many athletes to use endogenous testosterone enhancers when coming off of androgen cycles. This will be discussed in more detail later in this report.
Mechanisms of Testosterone Effects on the Skeletal Muscle
Testosterone-induced increase in skeletal muscle mass is associated with hypertrophy of both type I and type II fibers (470) and an increase in the number of myonuclei and satellite cells (491). Testosterone promotes the differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage (515,532). 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 T-cell factor 4 (TCF-4) (548). The activation of TCF-4 modulates a number of Wnt-regulated genes that promote myogenic differentiation and inhibit adipogenic differentiation (548).
Testosterone also inhibits preadipocyte differentiation into adipocytes (548). The effects of testosterone on myogenic differentiation in vitro are blocked by the AR antagonist, bicalutamide, indicating that these effects are mediated through an AR pathway (548). It is possible that androgens might exert additional effects through nongenomic mechanisms. Testosterone increases fractional muscle protein synthesis and improves the reutilization of amino acids by the muscle (448,506).
Classical genomic actions of androgens are mediated through the AR. The AR gene is located on the long q arm of chromosome X at position 11-12 and contains 8 exons coding for the N-terminus, central DNA binding, and C-terminal ligand-binding domains (199,375). The first exon contains several regions of repetitive DNA sequences including the CAG triplet repeats (313). The length of this sequence is variable and long CAG repeats interfere with androgen actions, whereas short repeats enhance androgen action. The AR is a 110-kDa receptor consisting of 919 amino acids, 12 α-helices, and 2 β-sheets that belong to a large family of nuclear transcription factors. A truncated AR protein (87 kDa) with similar function has also been identified (532). Studies have shown that ARs are located in virtually all tissues except in the spleen and adrenal medulla (393,491).
Free testosterone diffuses through the cell membrane and binds to the C-terminal ligand-binding domain, causing dissociation of the AR from a group of heat shock proteins in the cytoplasm. Testosterone binding to AR results in conformational changes in the AR protein, recruitment of tissue-specific coregulators, and translocation of liganded complex into the nucleus where it binds the androgen response elements of AR target genes (161,548). Considering that skeletal muscle contains little 5α-reductase, testosterone is the primary ligand (not DHT) inducing transcription. In addition, the N-terminal region is the primary site for interaction with large families of coregulators that function to amplify the transcriptional signal and mediate AR action (157). Coregulator binding forms a bridge between the DNA-bound AR and the transcriptional machinery, thereby modulating transcription and tissue selectivity. Approximately 300 coregulators have been identified (523).
Androgen binding stabilizes the AR (547,548). The half-life of AR without androgen binding is 1 hour, whereas the AR-androgen complex extends the half-life to 6 hours (287). Androgens slow AR degradation by prolonging nuclear retention. Testosterone (the primary androgen interacting with ARs in skeletal muscle) dissociates from the AR 3 times faster than DHT or synthetic androgens and is less effective for stabilizing the AR (547). However, similar stabilizing effects occur with larger doses of testosterone in comparison with lesser dosages of DHT (287,547). Thus, it appears AR stabilization is dose dependent. The AR is capable of undergoing multiple bouts of recycling between the nucleus and the cytoplasm after ligand binding and dissociation (427). Upregulation of AR content is affected by other hormone-receptor interactions including IGF-I, growth hormone (GH), and triiodothyronine, whereas glucocorticoids and estrogens downregulate AR messenger RNA (mRNA) (97,161,169,322,419).
The AR concentration in skeletal muscle depends on several factors including fiber type, contractile activity (e.g., resistance training), nutritional supplementation, and the concentrations of testosterone (31,84,155,307,415). Resistance training upregulates AR content within a few days after a workout (31). However, the initial response may be downregulation (415) unless nutritional (e.g., protein, carbohydrate) interventions are applied (307). The regulation of AR mRNA by androgens varies with androgen dose duration and mode of administration (16,169,306,308,331,355,380,448). Long-term exposure to high concentrations of androgens may downregulate AR content in some tissues (83).
Nongenomic Actions of Testosterone
Although most actions of testosterone are mediated within the cytoplasm via the AR, some studies have suggested that some rapid actions of testosterone (i.e., that take place within seconds or minutes) may be mediated via nongenomic activity (414). Evidence supporting nongenomic actions has been attained from studies showing these actions of testosterone to occur despite either cytosolic AR inhibition or administration of a testosterone molecule unable to diffuse across the cell membrane (170). For example, nongenomic actions of testosterone have been identified to occur in Sertoli cells, hypothalamus, anterior pituitary, prostate, osteoblasts, immune cells, cardiovascular tissues, and skeletal muscle (170,414). In skeletal muscle, testosterone administration has been shown to rapidly (within minutes) increase intramuscular calcium and extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation (a class of mitogen-activated protein kinase and an intermediate involved in muscle hypertrophy) (170). Similar intramuscular calcium increases have been reported in cardiac myocytes after testosterone administration (515). It has been suggested that these nongenomic actions of testosterone may be mediated by a membrane-bound AR (coupled to a G-protein-linked second messenger system) (170) or perhaps by a membrane-bound SHBG receptor for non-free testosterone still bound to SHBG (414). However, a membrane receptor for testosterone has not yet been isolated and the evidence for nongenomic actions remains inconclusive.
In addition to peripheral conversion to DHT and estradiol, testosterone is inactivated by the liver and excreted in urine via 2-phase metabolism. In phase 1 metabolism, the liver converts most circulating testosterone (and other androgens) to various inactive metabolites via enzymatic oxidation, reduction, and hydroxylations to the A, B, C, and D rings (437). The major urinary metabolites of testosterone, androsterone and etiocholanolone, are formed via the enzyme 17β-hydroxy dehydrogenase and are excreted as 17-ketosteroids. Phase 2 reactions in the liver and/or kidneys include conjugation of phase 1 metabolites with either glucuronic acid or sulfuric acid. Conjugation reactions are enzymatically controlled (e.g., UDP-glucuronosyltransferase enzymes) (48). Not all androgens are excreted as conjugates, some are unconjugated including oxandrolone and some metabolites of stanozolol (437). Detection of androgens or their metabolites in the urine is the basis of current drug testing.
Types of Androgens
Testosterone, when administered orally, has a short half-life because of its first-pass presystemic metabolism. 17-Alpha alkyl substitutions in the testosterone molecule render it less susceptible to first-pass presystemic metabolism. However, 17-alpha alkylated derivatives are potentially hepatotoxic and markedly suppress high-density lipoprotein (HDL) cholesterol levels. They are not recommended for clinical use.
Esterification of the 17-beta-hydroxyl group renders the molecule more hydrophobic; testosterone esters such as cypionate, undecanoate, and enanthate, when injected in an oily suspension intramuscularly, are released slowly from the hydrophobic oil depot into the general circulation, thus extending their duration of action. The degree of hydrophobicity is related to the length of the ester side chain; the longer esters such as cypionate and enanthate have more extended duration of action than shorter esters such as propionate. The de-esterification of testosterone esters is not rate limiting; thus, the plasma half-life of testosterone esters is not significantly different from that of unesterified testosterone. The long duration of action of testosterone esters is mostly due to the slow release of the testosterone ester from the oily depot in the muscle.
Slight biochemical modifications can alter biological activity by modifying presystemic metabolism, half-life, AR binding affinity, AR stabilization, coactivator recruitment, nuclear translocation, DNA binding affinity, and tissue selectivity. Also, biochemical modifications may determine whether the resulting molecule can undergo aromatization or 5-α reduction. Only a limited amount of information is available about the structure-activity relationships of the testosterone molecule.
One of the first changes made to the testosterone molecule was the addition of a methyl or ethyl group to the 17-alpha-carbon position. This addition inhibits the presystemic metabolism of the molecule, greatly extending its half-life and making it active when administered orally. However, orally administered 17-alpha alkylated androgens are potentially hepatotoxic and markedly lower plasma HDL cholesterol. 17-Alkyl substitution also lowers the interaction with aromatase (148).
Because there are many agents in production and literally hundreds more that have been synthesized, this discussion focuses on the basics involving the steroid ring substitutions and how these substitutions affect the properties of the drug. Detailed analysis is limited to those agents that are available or have been approved for use in the U.S.A. Table 2 provides specific structure and chemical information on selected, popular androgens (AAS).
Testosterone esters have seen an increase in their use in replacement therapy and in their propensity for abuse. The testosterone esters all have the testosterone molecule with a carboxylic acid group (ester linkage) attached to the 17-β hydroxyl group in common. These esters differ in structural shape and size and function only to determine the rate at which the testosterone is released from tissue. Larger esters are released into the bloodstream more slowly, as the ester decreases the solubility of the steroid in water and increases its fat solubility. When a steroid has an ester attached, the steroid is rendered inactive because the ester prevents it from binding to a receptor. For the steroid to become active again, the enzyme esterase must detach the ester and restore the hydrogen to form the hydroxyl group attached to C-17. Once the molecule is converted back to testosterone, it is able to bind to a receptor and is an active steroid. Esters, as mentioned earlier, are usually attached at C-17, although they are sometimes found at C3. Generally, the shorter the ester chain, the shorter the half-life and quicker the drug enters circulation. Longer/larger esters usually have a longer half-life and are released into the circulation more slowly. Once in the circulation, the ester is cleaved, leaving free testosterone. Common testosterone preparations include testosterone propionate, testosterone cypionate, and testosterone enanthate.
In testosterone cypionate, the hydrogen from the hydroxyl group on C-17 has been removed and replaced with an 8-carbon side chain containing 1 cyclopentane ring and 1 carbonyl (=O) group. This is one of the larger esters of testosterone. In order of size, from smallest molecular weight to largest, the esters of testosterone are acetate, propionate, phenylpropionate, isocaproate, caproate, enanthate, cypionate, decanoate, undecylenate, undecanoate, and laurate. The largest of these esters, laurate, contains 12 carbon atoms, 24 hydrogen atoms, and 2 oxygen atoms. These esters can be attached to other steroids as well and are not limited to testosterone.
Common Testosterone Derivatives
The development of androgens was apparently centered on the need for drugs that exhibited characteristics different from those of testosterone. In general, the goal was to develop drugs that were more anabolic and less androgenic than testosterone, capable of being administered orally, and had less effect on the hypothalamic-pituitary-gonadal axis. Most androgens are derived from 3 compounds: testosterone, DHT, and 19-nortestosterone. The latter compound is structurally identical to testosterone except for the deletion of the 19th carbon, thereby resulting in its name. These parent compounds offer different properties with regard to action and metabolism that are generally constant throughout the entire family of compounds.
Methyltestosterone (Metesto, Android) is a very basic androgen with the only addition being a methyl group at C-17. This eliminates first-pass degradation in the liver, making oral dosing possible. It also causes dose-related hepatotoxicity. It is metabolized by aromatase to the estrogen, 17-alpha methyl estradiol, and is also reduced by 5-α reductase to 17-alpha-methyl DHT. This compound appears to exhibit very strong androgenic and estrogenic side effects, and its use is generally avoided for these reasons.
Methandrostenolone (Dianabol) has an added cis-1 to cis-2 double bond in an attempt to reduce both estrogenic and androgenic properties. However, it does undergo aromatization to the estrogen, 17-alpha methyl estradiol, but is reduced by 5-α reductase to α-dihydromethandrostenolone (475). This steroid was first commercially manufactured in 1958 by Ciba under the brand name Dianabol and quickly became the most used and abused steroid worldwide to date. This agent is very anabolic with a half-life of approximately 4 hours. The methyl group at C-17 makes this anabolic-androgenic steroid an oral preparation and potentially hepatotoxic. Both Ciba and generic firms in the U.S.A. discontinued methandrostenolone in the late 1980s, but more than 15 countries worldwide still produce it in generic form.
Fluoxymesterone (Halotestin) is a potent androgen that is a substrate for 5-α reductase for conversion to DHT metabolites. With the addition of a 9-fluoro group, it becomes an androgen with very little anabolic activity; however, an added 11-β hydroxyl group inhibits its aromatization. The C-17 methyl group makes oral administration possible but not without apparent hepatotoxicity. This drug does not appear to be favored in clinical practice due to its poor anabolic effects, yet athletes typically use it for its apparent androgenic nature and lack of peripheral aromatization.
Common Nandrolone Derivatives
Nandrolone Decanoate: Nandrolone decanoate (Deca-Durabolin) is 19-nortestosterone with the addition of a 10-carbon decanoate ester added to the 17-β hydroxyl group. This addition extends the half-life of the drug considerably. Nandrolone is apparently a potent anabolic drug with a relatively favorable safety profile at therapeutic dosages. It is reduced by 5-α reductase in target tissues to the less potent androgen, dihydronandrolone. Nandrolone appears to possess a low affinity for aromatization to estrogen (501). Nandrolone and its esters (decanoate and phenylpropionate) differ only in their half-lives due to the difference in ester properties. Nandrolone decanoate is an injectable preparation and lacks the hepatotoxic C-17 group. It is one of the most widely abused drugs due to its efficacy, safety profile, and worldwide manufacture.
Ethylestrenol (Maxibolin, Orabolin) is an oral 19-nortestosterone derivative and was marketed in the U.S.A., but it has since been discontinued. It differs from nandrolone by the addition of a 17-α-ethyl group to reduce first-pass metabolism as well as the deletion of the 3-keto group. This latter omission seems to reduce AR binding. This drug appears to possess very little anabolic or androgenic effect at therapeutic doses.
Trenbolone is a derivative of nandrolone with several additions. First, the addition of a cis-9 to cis-10 double bond supposedly inhibits aromatization, and a cis-11 to cis-12 double bond is considered to greatly enhance AR binding. This drug appears to possess potent androgenic and anabolic characteristics. It is comparably more androgenic than nandrolone due to its lack of conversion to a weaker androgen by 5-α reductase. Trenbolone is a European drug with a very high abuse record. In the U.S.A., it is used in veterinary preparations as trenbolone acetate.
Common Dihydrotestosterone Derivatives
Oxandrolone: Oxandrolone (Anavar) is a derivative of DHT, and because it is C-17 methylated, it is an oral preparation. The second carbon substitution with oxygen is thought to increase the stability of the 3-keto group and greatly increase its anabolic component. This drug is considered to be very anabolic with little androgenic effect at therapeutic doses. 5-α reductase does not appear to reduce oxandrolone to a more potent androgen, and because it is a DHT derivative, it cannot be aromatized. Oxandrolone is one of a few agents to be routinely abused by female athletes due to its mild androgenic properties. Athletes such as weightlifters, boxers, and sprinters use oxandrolone seeking to increase strength without additional weight gain.
Stanozolol (Winstrol) is a drug with supposed anabolic and androgenic characteristics due to the stability afforded by the 3,2 pyrazol group on the first cyclohexane ring, which apparently greatly enhances AR binding. This drug can be C-17 methylated, thus making it an oral preparation; however, it also can be prepared as an injectable without C-17 methylation. Stanozolol appears to be active in both androgen- and anabolic-sensitive tissues. It is a weaker androgen than DHT that appears to exert comparatively less androgenic effect. As a result, it does not appear to aromatize to estrogenic metabolites.
Oxymetholone (Anadrol) is an oral drug because it is C-17 methylated. The 3-keto stability added by the 2-hydroxymethylene group supposedly enhances the drug's anabolic properties. The action of this agent in androgen-sensitive tissues is much like that of DHT; therefore, it quite androgenic. Oxymetholone is the only anabolic-androgenic steroid to date to be considered a carcinogen (466). This drug does not appear to be susceptible to aromatization. However, it is thought to activate estrogen receptors via the 2-hydroxymethylene group, thereby exerting many estrogenic side effects. In addition, because of the drug's C-17 methylation, it is considered to be hepatotoxic.
Indeed, an emerging clandestine industry has allowed athletes to evade detection via the use of novel “designer androgens.” Several test-evading designer androgens have been identified in the past 3 years including a compound known as desoxymethyltestosterone, also known as Madol, that was never marketed (445) and a novel chemical entity that was specifically synthesized to evade detection (tetrahydrogestrinone, THG) (105). Desoxymethyltestosterone possesses the characteristics of a selective androgen receptor modulator (SARM) and displays potent anabolic effects (147). Tetrahydrogestrinone, implicated in the Bay Area Laboratory Cooperative (BALCO) investigation, was never marketed and apparently developed as a potent androgen that was undetectable by conventional International Olympic Committee (IOC)-mandated urinary sports doping tests. Tetrahydrogestrinone is a potent androgen and progestin that binds with high, but unselective, affinity to the AR and is able to transactivate AR-dependent reporter gene expression. However, this level of expression is 2 orders of magnitude lower compared with DHT (195).
Relative to designer androgens, their distribution for use at high doses without any prior biological or toxicological evaluation poses significant health risks. Although this diversion of science may highlight the possibility of tissue-specific effects highlighting the beneficial effects of androgens, the potential for undesirable effects may go unnoticed. As such, further developments require better understanding of the post-receptor tissue selectivity of designer androgens, comparable to the mechanism underlying that of selective estrogen receptor modulators (SERMs).
Selective Androgen Receptor Modulators
Testosterone and their synthetic derivatives, which are known to produce significant side effects (discussed in more detail later), spurred the development of SARMs. These synthetic ligands were designed to produce selective tissue-specific anabolic actions in muscle and bone, with minimal androgenic actions in other peripheral tissues. Selective androgen receptor modulators were first reported in 1998, and currently, several classes of SARMs exist including quinolines, tricyclics, bridged tricyclics, bicyclics, aryl propionamides, and tetrahydroquinolines (381,442). These ligands bind to the AR with high affinity, thereby strengthening the anabolic properties, yet are not subject to aromatase or 5α-reductase activity so their androgenic properties are low (381,442). In addition, they have favorable pharmacokinetic properties and great potential for biochemical modifications indicative of a more favorable alternative to anabolic steroids and related compounds for therapeutic interventions (442).
History of Androgen Use
The interest in improving physical performance appears to have occurred as an offshoot of early research, which sought to determine the physiological and performance effects of testicular extracts (194). As early as 1849, scientists had suggested that a substance secreted by the testes into the blood stream was related to physiological and behavioral characteristics of male animals (194). In 1889, Brown-Séquard, considered by many as one of the founding fathers of modern endocrinology, published results from his autoexperimentations on testicular substances in which he reported increases in muscular strength, mental abilities, and appetite (156,194). Although the results of his work were never substantiated, it did give rise to the new field of organotherapy in which testicular extracts were injected or testicles were transplanted into patients with various disorders (194). By the end of 1889, some 12,000 physicians were administering Brown- Séquard's testicular extracts as the new “elixir of life” (227,494).
Largely based on Brown-Séquard's work, Zoth and Pregl began to investigate the effects of injections of testicular extracts on muscle strength and athletic performance (156,244). Zoth and Pregl injected themselves with extracts from bull testicles and measured strength of their middle fingers and recorded fatigue curves during a series of exercises. In 1896, Zoth published an article suggesting that injections of testicular extracts improved muscular strength and the “neuromuscular apparatus” (156,244). Although it is likely that these results were placebo effects, Zoth may be the first person to suggest injecting athletes with hormones in an attempt to increase performance (243,244).
Not until 1929 was the first sex hormone isolated (156,243,244). In 1929, Butenandt was the first to isolate the sex hormone estrone from the urine of pregnant women and later was credited with isolating 15 mg of androsterone (“andro” = male, “ster” = sterol, “one” = ketone) from the urine of local policemen (156). Ultimately, comparisons were made between sex hormones isolated from urine and those isolated from the testes. These comparisons revealed that the hormones isolated from the testes had greater androgenic properties than those extracted from the urine (244). Once sex hormones were isolated, a new path of scientific discovery was initiated.
In the 1930s, pharmaceutical companies were very interested in isolating the testicular hormone, which in 1935 was termed testosterone (“testo” = testes, “ster” = sterol, “one”= ketone) by Kàroly David and his research team (130,156). During the 1930s, there was a great interest in synthesizing artificial testosterone, and in 1935, Butenandt and Hanish published the first paper documenting the synthesis of testosterone from cholesterol (130,156). Only 1 week later Ruzicja and Wettstein also published a paper that outlined another method for the synthesis of artificial testosterone (429). Around this time, Kochakin reported that androgens could stimulate protein anabolism and stimulate growth. It was further speculated that androgen therapies may be effective in stimulating growth and restoring tissue in subjects with a variety of disorders (156,245). Shortly after its synthesis, oral and injectable testosterone preparations became available to the medical community (544).
Much of the early research looking at human use of testosterone was conducted in Germany before World War II (500). In fact, some have speculated that German athletes may have been given testosterone in preparation for the 1936 Olympics (544). Additionally, it has been suggested that German soldiers were given testosterone to increase aggressiveness in battle during this time frame (519). However, to date, no data have been discovered to substantiate the use of testosterone by either German athletes or soldiers during this period (544).
Clinical trials designed to explore the effect of exogenous testosterone use on humans were underway as early as 1937 (244). This early work involved the injection of testosterone propionate and the oral consumption of methyltestosterone (156,244). Ultimately, the early testosterone studies explored the effects of the newly synthesized compound as a tool for treating men with hypogonadism and impotency (244). At this time, testosterone therapies were also used to treat a variety of medical conditions associated with women including menorrhagia, painful breast syndrome, dysmenorrrhea, and estrogen-driven breast cancers (244). The administration of testosterone in women during this period revealed that the daily use of topical testosterone preparations resulted in increased sexual desires and clitoral hypertrophy (243,244). Although the administration of testosterone to women consistently resulted in an increased sex drive, it did not become a standard therapy because of the noted side effects associated with the drug. Clinicians in this period noted that women who were treated with testosterone preparations not only experienced clitoral hypertrophy but also experienced increased hair growth on the body and face and demonstrated a deep husky voice (243,244). The occurrence of these side effects resulted in many heated debates in the scientific literature about the efficacy of using testosterone therapies in women (244).
In 1939, Bjoe suggested that sex hormones might enhance physical performance (71). During the 1940s, it was discovered that testosterone could facilitate muscular growth and much speculation about the performance effects of testosterone occurred (244). This hypothesis was confirmed in 1942 when Kearns and colleagues (286) reported that the implantation of a testosterone pellet in a gelding coupled with training significantly improved physical performance. It was also speculated that the age-induced declines in working capacity were directly related to the concomitant declines in testosterone seen with aging. This led to further speculation that testosterone therapies may be able to increase working capacity as one ages (243,244).
de Kruif in his popular text “The Male Hormone” raised the hopes and expectations for the use of testosterone by suggesting that the administration of testosterone could increase muscle mass, rejuvenate individuals, and elevate their working capacity (135). In fact, de Kruif suggests that it would be interesting to see what athletes who were systematically using testosterone could do in competition (500). Several reports suggest that West Coast bodybuilders in the late 1940s and early 1950s began experimenting with the use of testosterone preparations (244,544). Additionally, it appears that the use of testosterone and its synthetic derivatives began to infiltrate sports during the 1950s (500,544).
At the 1952 Olympic Games, the Soviet Union did exceptionally well in the weightlifting competition, which led to speculation that some sort of hormone manipulation was being employed (500). This contention seems to be supported by statistical analyses of the performance of the Soviet weightlifters during this time frame (176). In 1954 at the World Weightlifting Championships, Dr. John Ziegler was told by his Soviet counterpart that the Soviet weightlifters were indeed using testosterone (500). After the completion of the world championships, Dr. Zeigler returned to the U.S.A. and immediately began experimenting with testosterone use. In his early work with testosterone he became concerned with potential side effects, such as prostate problems and increased libido (500). Ultimately, this led him to search for a drug that had pronounced anabolic effects while minimizing the androgenic effects (500).
In 1958, the first U.S. manufactured androgen Dianabol (methandrostenalone) was approved by the U.S. Food and Drug Administration (156,500). This new drug provided a potential solution to the side effects noted with testosterone use. To explore the effectiveness of Dianabol administration in athletes, Dr. Ziegler administered the drug to 3 members of the York Barbell Weightlifting team (500). Dianabol proved to be a very effective drug when coupled with resistance training, and the athletes experienced a meteoric rise in performance (500). News of the drug's application as an ergogenic aid spread to other strength- and power-based sports including the field events in track and field and American football (544).
In 1960, the use of androgens by Olympic athletes was still not a major problem and was probably limited to American and Soviet strength athletes (544). By the 1964 Olympic Games, the use of androgens became significantly more extensive in all strength sports (500,544) and was a growing problem (98). In 1965, oral turinabol was synthesized by a German Democratic Republic (GDR) state-owned pharmaceutical company (505). By 1966, the GDR began a state-sponsored doping program designed to enhance sports performance and prepare athletes for the 1968 Olympic Games in Mexico City (191). Interestingly, it appears that the GDR was the first to administer the drug to women athletes as they prepared for the 1968 Olympic Games (191,505)
With the increasing use of performance-enhancing drugs and several high-profile deaths of athletes from various sports, the IOC established a medical commission in 1967. The primary goal of the IOC Medical commission was to develop a list of prohibited substances and methods (192). The IOC also adopted a medical code that encompassed 3 principles: (a) protection of the health of the athlete, (b) respect for both medical and sports ethics, and (c) equality for all competing athletes (192).
By the 1968 Olympics, an incremental increase in use was seen in track and field (544). Support for this contention can be seen in reports that suggest that one-third of the U.S. track and field team (i.e., throwers, sprinters, hurdlers, and middle distance runners) had used these drugs in the lead up to the 1968 Olympic Games (500). Additionally, documentation has been discovered that reveals that at the 1968 Olympics many of the male and female athletes from the GDR were systematically using various anabolic-androgenic drugs to enhance athletic performance (191). Although androgen use was on the rise during this time frame, there was little debate about the ethics of taking androgens. Most discussion among athletes centered on which drugs were most effective (544).
In 1969, androgen use was so prevalent that John Hendershott the editor of Track & Field News called these drugs the “breakfast of champions” (234). Throughout the 1960s, the overall volume of androgen use increased dramatically. In fact, it appears that athletes increased the dosages used to levels that were 2-5 times above the recommended therapeutic dosage (544) and performance gains increased (191). Additionally, athletes began preferentially taking androgens and began experimenting with stacking drugs that included a combination of oral and injectable forms (544). During these years, the IOC failed to include androgens on the banned substance list. One reason for this was that the medical community suggested that androgens were ineffective and were unwilling to consider that the use of these drugs could impact performance. This was primarily based on several poorly designed studies (this will be discussed in greater detail in the next section). Ultimately, this caused a large credibility gap between athletes and the medical community as many athletes developed a large distrust for medical doctors (500). The second reason for the exclusion of androgens was that there simply were no reliable and valid tests at this time (500).
In 1973, the first testing procedures for androgens were proposed. The first method used radioimmunoassay procedures, whereas the second suggested using a combination of gas chromatography and mass spectrometry (GC-MS) techniques. The IOC ultimately adopted both methods to ensure the highest accuracy in testing; however, very few laboratories in the world could conduct the test at the levels required by the IOC. The testing protocols were first implemented in the 1974 Commonwealth Games in Auckland, New Zealand, where 9 out of 55 samples were positive for androgens (500).
Throughout the early 1970s, the GDR expanded its doping program to include most sports, and it became customary to provide drugs to most athletes including minors (191). In fact, the overall dosages of the drugs used by athletes from the GDR continued to escalate to the point at which damaging side effects became apparent, especially in the female athletes who were outwardly androgenized (191). With the advent of testing in 1974, the GDR faced a very unique problem in that it was apparent that the use of androgens was a key to their success in international competition, but the advent of drug testing created a possible problem to the systematic program being used. At the 1974 European Athletic Championships in Rome, drug testing of urine samples revealed no positive steroid tests. However, the IOC was developing new drug testing processes that created a situation in which the GDR feared many of its most successful athletes would test positive (191).
In 1974, the GDR government instituted a top secret program that provided for the administration of androgens and other doping products to male and female athletes. This program contained 6 central concepts, which included (a) the mandate that doping plays a central role in the training process and preparation of athletes for major international competition; (b) the establishment of a monitoring program in which sports physicians conducted regular evaluations of the athletes; (c) the development of a centralized drug distribution and documentation program, which was under the control of the Sportmesizinischer Dienst (SMD); (d) the organization of a systematic research program into the development of new doping products and the establishment of drug administration programs, which would allow for the avoidance of detection during doping controls; (e) the development of a comprehensive educational program in which coaches and physicians would be instructed about doping; and (f) the classification of the doping program as an Official State Secret (191). The timing of the program was extremely important as the IOC had planned to test at the 1976 Olympic Games and the GDR wanted to continue to build upon its growing success in international competitions.
In 1976, drug testing was first initiated at the Olympic Games in Montreal (500). A relatively low number of athletes tested positive for androgens during these games (8 out of 275 tests) (500). Although it appeared few athletes were doping based on the drug testing program instituted by the IOC, survey data collected during the games suggested that as many as 68% of the athletes competing had used androgens during their training (98). It is likely that the early drug testing programs were not as effective due to the fact that the IOC had left off many drugs from their testing program (500). For example, norbolethone, which was never approved for human consumption, was reported to be taken by several athletes but was not present on the early lists of banned substances (98). Additionally, it has been reported that many athletes reverted to the use of testosterone, as it was not part of the original testing program (500).
By 1979, the GDR doping program had expanded to the point that athletes were being given complex combinations of drugs. For example, Franke and Berendonk (191) reported that one GDR weightlifter was administered 11.55 g of oral turinabol, 13 injections of testosterone esters, and human chorionic gonadotropin (hCG). Most noted was the development of “steroid bridging,” which replaced readily detectable steroids with testosterone esters in the weeks before competition to circumvent drug testing protocols. Typically, athletes would receive repeated intramuscular injections of testosterone esters of various fatty acid chain lengths in the time period leading up to a major competition (191). This process was quite commonplace in the GDR and many other countries. Before the 1980s, there was no method available for the detection of testosterone use to drug testers.
In 1980, Professor Manfred Donike the head of the IOC-approved drug testing laboratory in Cologne, West Germany, developed a method for detecting testosterone use by comparing the testosterone to epitestosterone ratio (T:E ratio) (500). Because the use of testosterone results in an increase in testosterone levels without a concomitant increase in epitestosterone, athletes who possessed a T:E ratio of 6:1 were suggested to be doping. After the 1980 Olympic Games in Moscow, the T:E ratio was determined and it was detected that ∼20% of all athletes tested had a T:E ratio of >6:1 (29) and 7.1% of female athletes tested had a T:E ratio of >6:1 (191). After the development of the T:E ratio test, the IOC implemented the protocol as part of its doping controls.
The advent of the T:E ratio test caused significant problems for the state-instituted doping program of the GDR. In a 1981 meeting in the GDR, it was determined that a program to find alternatives to exogenous testosterone administration was needed and that testosterone was to be replaced by its precursors (i.e., androstenedione, DHT, dihydroanodrostenedione, or DHEA) (191). By 1982, scientists from the GDR had determined that 3 days after the injection of 25 mg of testosterone propionate, the T:E ratio would be below the 6:1 cutoff used by drug testers. Additionally, it was discovered that hCG and clomiphene did not alter the T:E ratio (191). By 1983, the GDR had determined a method for simultaneously injecting testosterone and epitestosterone, which consistently kept the T:E ratio below the 6:1 cutoff. With this information in hand, the GDR had a method that allowed them to circumvent doping controls.
The T:E ratio test was first administered at the 1983 Pan American Games in Caracas, Venezuela, where a total of 15 athletes tested positive (11 weightlifters, 1 cyclist, 1 fencer, 1 sprinter, and 1 shot putter) (500). There may have been more positive tests but 12 American athletes chose to leave the games before competing and thus avoided being tested. Journalists and commentators seemed shocked by the apparent doping problems that were brought to light by the Pan American Games in Caracas (500). At this time, journalists began reporting that androgens were not only a part of Olympic sports such as weightlifting but were also a part of every other professional sport in America. More disturbing was the fact that collegiate (e.g., National Collegiate Athletic Association [NCAA]) and professional sport (e.g., NFL, MLB, NBA, and NHL) organizations, and even professional bodybuilding, were doing nothing to curb the use of androgens (500). For example, it has been speculated that between 50 and 75% of offensive and defensive linemen in the NFL used steroids during the 1980s, but the precise level of use will probably never be known (544).
Although the T:E ratio test was implemented at the 1984 Olympic Games in Los Angeles, the most famous androgen positive occurred at the 1988 Seoul Olympic Games when Canadian sprinter and then current world's fastest man Ben Johnson tested positive for stanozonol (98). This positive test sent shock waves through the sporting community, ultimately resulting in the U.S. government passing the Anti-Drug Abuse Act, which made it illegal to distribute or possess androgens (98). Additionally, the IOC expanded the banned substance list to include diuretics, such as probenecid, and other products typically used to mask androgens use (315). In 1990, the U.S. government went a step farther when it passed the first Anabolic Steroid Control Act and inserted 27 steroids, along with their muscle building salts, esters, and isomers as class III drugs and simple possession could result in prison time (117)
As drug testing became more developed, the interest in the use of dietary supplements as performance enhancement tools increased. In 1994, the U.S. government passed the Dietary Supplement Health and Education Act (DSHEA), which was designed to protect the consumer from the risks of taking certain substances. For example, the Food and Drug Administration used this act to ban ephedra (117). In 1996, the prohormone androstenedione, which was first used by the GDR in 1981, was introduced to the American market as a new dietary ingredient (117). Because it was classified as a new dietary ingredient, it was not subject to regulation by the DSHEA (117). In fact, androstenedione became a very popular dietary supplement when Mark McGwire admitted to using it in 1998 (116).
In 1999, the IOC took an unprecedented step and convened the World Conference on Doping in Sport in Lausanne, Switzerland. Ultimately, this conference served as the foundation for the formation of an international anti-doping initiative, which resulted in the formation of the World Anti-Doping Agency (WADA) in 2001 (192). By 2002, WADA had developed the world anti-doping code, which contained 3 major parts: (a) the code, (b) international standards, and (c) models of best practice (192). The international standards serve as the operational and technical areas that are contained within the anti-doping program and integrate anti-doping agencies with the overall anti-doping code. The anti-doping code contains international standards for (a) laboratories, (b) testing procedures, (c) substances contained on prohibited lists, and (d) mechanisms and rules for therapeutic exemptions (192). As a whole, WADA oversees doping controls for international competitions including the Olympic Games and world championships as well as other sporting events that fall under the IOC (192). These doping controls are not only performed at competitions but are also performed as no-notice out-of-competition controls. In this capacity, WADA requires athletes to report their whereabouts so that random drug testing can be conducted. If the athlete either fails a doping control test or fails to show for testing WADA has the power to sanction athletes, which ultimately can withhold them from competition indefinitely depending upon the number of doping offenses the athlete has. Since 2000, WADA has performed out-of-competition testing for sports, which are encompassed under the IOC governance. However, to date, professional sports in America have yet to allow WADA to perform in or out-of-competition testing in their sports, and it is unlikely that they ever will.
In 2003, a syringe containing an unknown compound was sent to the U.S. Anti-Doping Agency that would expose a doping program that could only be compared with the program once run by the GDR (105,296). Eventually, the compound in the syringe was isolated and determined to be THG, which was at the time a new undetectable steroid (105,296,298). After its isolation, the drug source was linked to the BALCO, and the subsequent scandal associated with this drug exposed a widespread doping problem in American sports (298). By 2004, a second designer steroid known as Madol was isolated by the UCLA laboratory (445). The discovery of these designer steroid compounds suggests that unscrupulous athletes and scientists are still trying to circumvent the drug testing controls, much like the GDR did in the 1980s.
In 2004, the U.S. Senate held hearings on the abuse of androgens and their precursors by athletes. By the end of 2004, a new Anabolic Steroid Control act was implemented, which contained 26 new steroid compounds, including many of the steroid precursors such as androstenedione and androstenediol. Additionally, designer steroids such as THG were also added to the controlled substances listed by the act (117).
Another change in the world of doping controls occurred in 2005 when WADA lowered the T:E ratio, which indicated an adverse analytical finding from 6:1 to 4:1 (536). If the athlete were to test positive for an elevated T:E ratio (>4:1), then a follow-up test consisting of the use of an isotope ratio mass spectrometry (IRMS) procedure was to be used (536). Ultimately, the IRMS test was suggested to be an accurate way to determine if synthetic doping products were taken by the athlete (1). The advent of these new testing procedures would result in some interesting doping findings in 2006 (further discussion on testing for androgens will be presented later in this report).
In 2006, the sporting world was yet again rocked by another doping scandal. Before the 2006 Tour de France, the Spanish Civil Guard began investigating Dr. Eufemiano Fuentes for providing doping products to cyclists and athletes from other sports (328). The investigation resulted in several high-level cyclists being excluded from the Tour de France in 2006 and some were subsequently sanctioned. At the end of the 2006 Tour de France, it was revealed that the winner American Floyd Landis tested positive for an abnormal T:E ratio and as of 2008 he has been stripped of his title under the suspicion of using testosterone (168). Up to this point, it was widely believed that androgens use was limited to strength and power athletes. However, evidence from this race revealed that androgen use was now prevalent in endurance-based sports as well.
In 2007, Marion Jones admitted to taking banned drugs including THG during the 2000 Olympic Games in Sydney, Australia (410). What is unique about the Marion Jones case is that she was proven guilty of doping without ever testing positive for performance-enhancing substances. She was initially linked to the BALCO scandal in 2004 and repeatedly denied using anabolic steroids, but in 2007, she admitted to using performance-enhancing drugs before and during the 2000 Olympic Games. By the end of 2007, an independent report on androgen use in professional baseball was released, which suggested that the use of androgens and other performance-enhancing drugs is a serious problem in professional baseball in the U.S.A. (360). Table 3 provides a time line of the history of androgen use.
Research on Androgens as a Performance-Enhancing Drug
Studies investigating the performance-enhancing effects of androgen administration have yielded conflicting findings. Although athletes were making significant gains with androgen use since the mid-1950s (with a possibility athletes may have began to experiment with androgens prior to this period of time), early research did not corroborate the anabolic and ergogenic effects experienced by athletes. Thus, academia decried their efficacy citing a lack of evidence. In fact, the ACSM between 1976 and 1984 regarded androgens as being ineffective until they revised their position in 1984 (9,10). Several important factors must be considered when interpreting results of these studies. For example, some early studies that have shown limited effects were plagued by poor scientific design (i.e., nonrandomized, not double-blind, no-placebo trials used) and issues that contrasted with how athletes were using androgens in real-world settings. In these studies, researchers oftentimes administered too low a dose of androgens (e.g., a clinical dose or lower typically prescribed for androgen deficiency, which is far exceeded by athletes), and this study did not have subjects train in conjunction with androgen use (e.g., whereas athletes were training at a high level), did not examine “stacking” of androgens or the compounding effects of multiple-drug use (e.g., most androgen users stack multiple drugs), used untrained subjects (which undergo an extend neural phases initially that may mask potential increases from androgens), and failed to examine dietary interventions such as increased protein intake coinciding with androgen use (e.g., many androgen users increase protein and kilocalories consumption greatly). This information notwithstanding, androgen research before 1980 was inconsistent regarding its efficacy.
Androgen Studies Before 1980
An early performance study was performed by Samuels and colleagues (434) who reported that 50 mg·d−1 of methyltestosterone (plus 250 mg of creatine hydrate) for 3 weeks did not enhance grip strength in untrained subjects. Nearly a quarter of a century had passed before androgen ergogenicity studies resurfaced with greater frequency predominantly in non-resistance-trained subjects. Several studies did not report ergogenic effects of anabolic steroids on muscle strength or performance. Fowler et al. (190) administered 20 mg·d−1 of methenolone acetate (Nibal) for 16 weeks to untrained subjects who either did not exercise or exercised 30 min·d−1, 5 d·wk−1 and reported that androgen use did not enhance muscle size, body weight, or isometric strength. Weiss and Muller (527) also did not report any greater enhancement of grip strength or body weight after administration of 10 mg of Dianabol for 17 days in high school students. Casner et al. (104) administered 6 mg·d−1 of Winstrol in some subjects' weight training 3 d·wk−1 and reported no ergogenic effects of androgens on isometric strength, although body weight gains were greater in the androgen/lifting group. Fahey and Brown (174) administered 1 mg·kg−1 body mass of Deca-Durabolin every second or third week for 9 weeks in college students' weight training 3 d·wk−1 (3-5 sets of 1-5 repetitions) and reported statistically similar increases in strength compared with a control group (13-15 kg compared with 6-10 kg). Stromme et al. (486) administered 75 mg·d−1 of mesterolone (Mestoranum) for 4 weeks and 150 mg·d−1 for the subsequent 4-week period in college students taking a weight training class and reported similar increases in isometric strength to a control group. Hervey and colleagues (237,238) administered 100 mg of Dianabol (or placebo) for 6 weeks in a crossover design and reported greater gains in body weight and girth measurements with androgen use, but no significant difference was observed in lifting performance between androgen and placebo conditions. Loughton and Ruhling (329) administered 10 mg·d−1 of Dianabol for 3 weeks and 5 mg·d−1 for 3 more weeks concomitant with weight training and running program and reported greater weight gains in the androgen group but nonsignificant interactions in strength performance.
Several early studies in lesser trained individuals did show ergogenic potential of androgens. Johnson and O'Shea (273) weight trained subjects for 6 weeks but administered 10 mg of Dianabol (plus protein) daily the last 3 weeks to half of the subjects and reported significantly greater gains in isometric strength and 1 repetition maximum (1RM) squat (although other strength measures did not reach statistical significance) in the steroid group. In a follow-up study, Johnson et al. (272) reported similar findings where androgens enhanced muscle strength and girth to a greater extent. Win-May and Mya-Tu (533) administered 5 mg·d−1 of Dianabol to university students over 3 months (little was known about their physical activity) and reported greater gains in grip strength, push-up, and pull-up performance in the steroid group.
Most early studies examining androgen use in trained subjects demonstrated ergogenic potential in muscular strength and performance. O'Shea and Winkler (379) administered 10 mg·d−1 of Anavar (plus protein) to swimmers and weightlifters for 6 weeks and reported large improvements in strength, although no control group was used for comparison. O'Shea (377) administered 10 mg·d−1 of Dianabol for 4 weeks to weightlifters (half consumed anabolic steroids, half consumed a placebo) and reported greater strength gains in bench press in the steroid group (but 30% greater increase in squat strength in the steroid group was not significant). Bowers and Reardon (78) administered 10 mg·d−1 of Dianabol (plus 30 g of protein per day) to resistance-trained men for 3 weeks and reported greater strength increases in the steroid group. Ariel (20) administered 10 mg·d−1 of Dianabol for 4 weeks to resistance-trained varsity athletes and reported that rate of strength gains was greater with steroid use than with placebo. In 2 other studies, Ariel (21,22) administered 15 mg·d−1 of Dianabol for 4 weeks in a crossover design and reported greater strength gains with androgen use. Interestingly, subjects who consumed a placebo first made greater gains than subjects who consumed a placebo the last 4 weeks, indicating that strength gains were attenuated when androgens were discontinued. In the second study, Ariel (22) reported that strength gains from androgen use did not deteriorate as fast as gains made during placebo consumption in subjects following a protocol similar to that followed in the previous study over a subsequent 15-week period of detraining. Ward (524) administered 10 mg·d−1 of Dianabol (or placebo) for 4 weeks to weight-trained college men during training (3 d·wk−1, 4 sets of 5 repetitions) and reported significantly greater gains in bench press and squat strength in the androgen group than in group receiving placebo. Stamford and Moffatt (473) administered 20 mg·d−1 of Dianabol (plus 30 g of protein) for 4 weeks in resistance-trained men and reported accelerated strength gains in the androgen group compared with placebo. O'Shea (378) administered 8 mg·d−1 of Winstrol (plus 0.5 g·kg−1 of protein) to weight-trained men (1-2 years of experience) for 5 weeks and reported that only the androgen group increased maximal bench press and squat strength. Freed et al. (193) administered 10 or 25 mg·d−1 of Dianabol to trained lifters for 6 weeks and reported greater strength improvements in the androgen groups but no dose-response relationship was found. However, Golding et al. (207) administered 10 mg·d−1 of Dianabol (3 weeks on, 1 off) for 12 weeks to trained lifters and reported no significant greater strength gains in the androgen group compared with placebo. Thus, most of these studies have shown greater strength and performance gains in trained lifters using androgens compared with a placebo.
Androgen Studies: 1980-1990
Considerably less research was conducted investigating ergogenic effects of androgens during this time. However, study designs improved and in some cases were more realistic. Hervey et al. (239) administered 100 mg·d−1 of Dianabol (or placebo) to resistance-trained individuals for 6 weeks in a crossover design and reported significant increases in lower- and upper-body strength (but not grip strength) in the androgen group, with no changes during control (placebo) training period. In addition, the androgen group increased body weight and muscle circumferences to a greater extent. These differences were quite substantial between steroid and placebo conditions. It is important to note that in a randomized, crossover design, those who consumed Dianabol initially had difficulty improving in a subsequent placebo condition. Crist et al. (126) administered testosterone cypionate or nandrolone decanoate (100 mg·wk−1) or placebo to strength-trained men for 3 weeks (plus supplemental protein) and reported nonsignificant differences in peak isokinetic torque and lean body mass. Although subjects in this study reported feelings of greater strength, isokinetic testing did not reveal significant differences. Alen et al. (4,5) examined elite power athletes self-administering anabolic steroids (∼31.0 ± 14.3 mg·d−1 of methanedienone, stanozolol, and nandrolone, and 178.4 ± 82.7 mg·wk−1 of testosterone) for 24 weeks and reported greater increases in muscle fiber area, fat-free mass (FFM), maximal isometric force, and squat strength with androgen use. The increases continued for 6 weeks after the experimental period where no drugs were consumed in the steroid group. In a case study, Häkkinen and Alen (223) reported similar findings where an elite bodybuilder increased FFM, muscle force, and fiber area substantially during a 6-month polydrug regimen and heavy training.
Anabolic Steroid Studies: 1990 to Present
Some studies further examined androgen use in athletes (76). These studies continued to report that cross-sectionally, androgen users had greater strength and muscle mass than nonusers (76), and longitudinally, androgens increased lean body mass, muscle strength, and performance (63,196,203,309). However, a large increase in the number of investigations examining the clinical use of androgens with resistance training occurred during this period, for example, in hypogonadal men, elderly men, and diseased populations. In the U.S.A., most institutional review boards regarded the administration of androgens in nonclinical settings as unethical. Thus, the number of clinical studies rose dramatically while most studies investigating athletic ramifications were performed outside of the U.S.A.
Friedl et al. (196) examined androgen administration of (a) 100 or 300 mg·wk−1 of testosterone enanthate or (b) 100 or 300 mg·wk−1 of nandrolone for 6 weeks in physically active men. They reported dose-response relationships where the largest gains in body weight and isokinetic muscle strength were seen in most cases with 300 mg·wk−1 of testosterone enanthate. Smaller increases in strength were observed with nandrolone administration, although some did not reach statistical significance. Bhasin et al. (63) administered a high dose (600 mg·wk−1) of testosterone enanthate to weight-trained men concomitant with resistance training and reported that the combination of androgen administration plus resistance training produced the largest increases in lean body mass and muscle strength than training with a placebo or just androgen administration alone with no resistance training. Maximum squat and bench press strength increased 38 and 22%, respectively, in the combination group compared with ∼20 and 10% increases in the group receiving placebo plus resistance training and group administered androgen only. Bhasin et al. (67), Sinha-Hikim et al. (460), and Storer et al. (482) administered 25, 50, 125, 300, or 600 mg·wk−1 of testosterone enanthate (with no resistance training) to resistance-trained men over 20 weeks and reported that increases in lean body mass, type I and II muscle fiber area, and thigh muscle volume were greatest at higher doses, for example, at least 125 mg·wk−1. A positive relationship was seen between lean body mass increases and dose of androgen administered. In addition, muscle strength increased mostly when 50, 300, and 600 mg·wk−1 of testosterone enanthate were administered and androgen dose was significantly related to changes in leg press strength. In a follow-up study, Woodhouse et al. (535) reported that changes in muscle size were strongly related to androgen dose. Androgen dose was the best predictor of the anabolic response accounting for 61-65% of the variance in the anabolic response. Kuipers et al. (309) administered 200 mg·wk−1 (week 1) and 100 mg·wk−1 of nandrolone decanoate (or placebo) to bodybuilders for 8 weeks (along with training) and reported that muscle fiber area increased substantially only in the bodybuilders using steroids. Hartgens et al. (230) also showed a dose-response relationship where they reported that a supraclinical stack of androgens increased deltoid muscle fiber area by 12.6%, whereas administration of a more therapeutic dose (200 mg·d−1 of nandrolone decanoate) did not increase fiber area in strength-trained athletes. In a series of studies Hartgens et al. (229), Kuipers et al. (310), and Van Marken Lichtenbelt et al. (512) demonstrated that administration of 100-200 mg·wk−1 of nandrolone decanoate for 8 weeks to bodybuilders significantly increased lean tissue mass more than a placebo. Forbes et al. (188) administered ∼42 mg·kg−1 body mass of testosterone enanthate for 12 weeks in untrained men and reported a large increase in lean body mass. Kouri et al. (304) reported steroid users to have greater body weight and muscle mass. Interestingly, they developed an equation to attempt to predict steroid use based on FFM index. They reported that androgen users had a larger FFM index (e.g., > 25.0). Giorgi et al. (203) administered 3.5 mg·kg−1 body mass of testosterone enanthate (or placebo) concomitant to 12 weeks of periodized resistance training and reported greater increases in body weight and bench press strength (22 vs. 9%) in the testosterone group. Much of the gains were lost during a subsequent 12-week period where androgens were not administered. Using a similar administration protocol for 6 weeks, Rogerson et al. (424) reported greater increases in 1 repetition maximum (1RM) bench press strength and cycle sprint performance in the androgen group compared with placebo.
Several studies have investigated androgen administration and performance in elderly (e.g., testosterone replacement), hypogonadal men, and clinical populations. In general, these populations tend to be very responsive as their testosterone concentrations are low and subsequently even low-dose testosterone replacement could have a significant impact. Testosterone replacement has occurred mostly in the forms of oral tablets, intramuscular injections, transdermal patches and gels, and buccal delivery (373). In hypogonadal young men, several studies have shown that low-dose testosterone replacement of 50-100 mg·wk−1 increased lean body mass mostly with minimal strength augmentations (64,69). A meta-analysis in middle-aged men showed that testosterone replacement produced significant increases in lean body mass (2.7%) but only sporadic increases in muscle strength (255). In the elderly, data have been inconsistent as some studies have shown testosterone replacement (typically low dose) alone to increase lean body mass and muscular performance modestly, but others have reported limited effects of testosterone replacement (57,77,85,383). However, there appears to be a dose-response relationship. Bhasin et al. (68) administered 25, 50, 125, 300, or 600 mg·wk−1 of testosterone enanthate to elderly men over 20 weeks and reported that increases in lean body mass correlated to the dose administered. In addition, muscle strength increased mostly when at least 125 mg·wk−1 of testosterone enanthate was administered, and testosterone dose was significantly related to changes in leg press strength. Schroeder et al. (439) administered 50 or 100 mg·d−1 of oxymetholone in elderly men for 12 weeks and reported significant increases in lean body mass and muscle strength. Although the increases in the group receiving 100 mg·d−1 of oxymetholone were greater, these data did not reach statistical significance. Limited effects have been shown in some studies with lower doses. Lambert et al. (314) administered 100 mg·wk−1 of testosterone enanthate to elderly men over 12 weeks (combined with resistance training) and reported that testosterone replacement did not augment gains in muscle strength and lean body mass.
The effect of androgens on strength and body mass gains has not been lost on the medical community. Many diseases result in weight loss and skeletal muscle atrophy, and the use of androgens to offset these reductions has been suggested. Androgen therapy has been used in patients with human immunodeficiency virus (HIV) infection/AIDS, pulmonary disorders, liver failure, severe burns, renal failure, and spinal cord injuries, and during postoperative recovery. Body mass gains have been common in these studies as a result of androgen therapy (38,112). For example, Casaburi et al. (102) administered 100 mg·wk−1 of testosterone enanthate or placebo for 10 weeks in patients with chronic obstructive lung disease (COPD) who were undergoing resistance training simultaneously, and they reported significantly greater increases in lower-body strength and endurance in the testosterone group compared with the placebo group. Interestingly, lean body mass increased similarly in both groups receiving the androgens (e.g., 1 sedentary and 1 resistance training). Strawford et al. (485) investigated the combination of testosterone replacement (100 mg·wk−1) plus resistance training with either a placebo or an additional 20 mg·d−1 of oxandrolone for 8 weeks in patients with HIV infection, and they reported the oxandrolone group increased lean tissue mass and several measures of muscle strength to a greater extent than the placebo group. Storer et al. (483) and Bhasin et al. (65) also reported greater increases in lean body mass and strength in HIV-positive men after 12 and 16 weeks of nandrolone (150 mg·wk−1) and 100 mg·wk−1 of testosterone enanthate administration, respectively. Interestingly, the addition of resistance training did not augment muscle strength or lean body mass gains when 100 mg·wk−1 of testosterone enanthate was administered (65). Bhasin et al. (62) showed 12 weeks of testosterone administration via transdermal patch (2.5 mg every 24 hours) in the absence of resistance training increased lean tissue mass (but not muscle strength) to a greater extent than a placebo in HIV-positive men.
Clinical Applications of Androgens
Testosterone is approved for the treatment of hypogonadism in adult men. The reader is referred to the guidelines for the use of testosterone therapy in hypogonadal men developed by an expert panel of the Endocrine Society (59). Substantial pharmaceutical effort is currently focused on exploiting the anabolic effects of androgens on the skeletal muscle for the prevention and treatment of sarcopenia and functional limitations associated with aging and chronic illness (57), although androgens are currently not approved for these indications.
Testosterone Therapy of Androgen-Deficient Men
Testosterone replacement therapy has been approved by the Food and Drug Administration for the treatment of androgen deficiency syndromes in adult men (59). In young androgen-deficient men, testosterone therapy has many benefits and is associated with a low risk of serious adverse events. Consequently, an expert Panel of the Endocrine Society recommended testosterone therapy for symptomatic men with classical androgen deficiency syndromes who have low testosterone levels (59).
In a systematic review of mostly open-label trials in healthy, androgen-deficient men, testosterone therapy was associated with significant gains in FFM and maximal voluntary strength and a significant decrease in whole-body fat mass (57). Testosterone administration in hypogonadal men also increases vertebral bone mineral density (59). However, its effects on fracture risk are unknown.
Testosterone improves many domains of sexual function in hypogonadal men (60). Testosterone therapy increases spontaneous sexual thoughts and fantasies, overall sexual activity scores and sexual desire (7,24,311,462,476), and attentiveness to erotic stimuli (6). Testosterone administration in healthy, hypogonadal men increases the frequency and duration of nocturnal penile erections (127). Testosterone therapy does not alter the erectile response to visual erotic stimulus (311) or frequency of orgasms in hypogonadal men (59), although it increases the volume of the ejaculate.
The effects of testosterone on mood and sense of well-being have not been well studied. Anecdotally, androgen-deficient men report improvements in sense of well-being and energy after initiation of testosterone therapy. Testosterone replacement in hypogonadal men improves positive aspects and reduces negative aspects of mood (522). However, randomized clinical trial data on the effects of testosterone therapy on mood are limited and have not shown significantly greater improvements in mood with testosterone therapy than with placebo (476). Some studies have reported small and inconsistent effects of testosterone on visuospatial cognition and verbal memory and verbal fluency (106,261).
Studies of the effects of testosterone therapy on insulin sensitivity have yielded conflicting results (249,281,343,344,456). Although low testosterone levels in cross-sectional studies of community-dwelling men have been associated with increased risk of insulin resistance and type 2 diabetes mellitus, testosterone therapy has not been shown consistently to improve insulin sensitivity or risk of diabetes mellitus in randomized clinical trials.
Adverse Events Associated With Testosterone Replacement Therapy
There is an agreement that testosterone therapy of young hypogonadal men is associated with a low frequency of adverse events (59). Acne and oiliness of skin are common in young hypogonadal men. Erythrocytosis is the most frequent and dose-limiting adverse event associated with testosterone therapy in testosterone trials (59). The increments in hematocrit during testosterone therapy are related to testosterone dose and age (122); older men experience greater increments in hemoglobin and hematocrit than young men (122).
The frequency of the development of gynecomastia in testosterone-treated men is low. Testosterone has been reported to induce and worsen obstructive sleep apnea. Patients with obstructive sleep apnea have a high frequency of low testosterone levels and testosterone therapy has also been reported to improve sleep apnea.
Testosterone therapy in young hypogonadal men increases prostate-specific antigen (PSA) levels by an average 0.3 ng·mL−1 and in older hypogonadal men by 0.43 ng·mL−1 (95). However, PSA levels do not increase progressively during continued testosterone therapy (46,350). Similarly, hypogonadal men have smaller prostate volumes than age-matched eugonadal controls (46,350). After initiation of testosterone therapy, prostate volume increases to that seen in age-matched eugonadal controls. There is no evidence that testosterone therapy worsens lower urinary tract symptoms or causes prostate cancer. However, testosterone administration might promote the growth of metastatic prostate cancer. Many older men harbor subclinical prostate cancers in their prostate; there is concern that testosterone therapy of older men might induce these subclinical cancers to grow and become clinically overt (59,61). Testosterone therapy is associated with increased risk of prostate biopsy and detection of prostate events (59,61).
Contraindications for Testosterone Therapy
Testosterone therapy is contraindicated in men with prostate and breast cancer (59). Testosterone is associated with high risk of serious adverse events in men with erythrocytosis, untreated severe sleep apnea, severe lower urinary tract symptoms as indicated by AUA/IPSS symptom score greater than 19, or class III or IV congestive heart failure. Testosterone therapy should not be initiated in individuals with undiagnosed prostate nodule or induration or PSA more than 3 ng·mL−1 without appropriate urological evaluation (59).
Monitoring of Testosterone Therapy
The goal of testosterone therapy is to raise testosterone levels into the mid-normal range for healthy young men, correct symptoms of androgen deficiency, induce and maintain secondary sex characteristics, and maintain sexual function (59). Testosterone levels should be measured 3 months after initiating testosterone therapy and the dose and/or regimen adjusted to achieve testosterone levels in the mid-normal range.
To minimize risks and for early detection of adverse events, the Endocrine Society Expert Panel recommended that patients receiving testosterone therapy should have their hematocrit and serum PSA, and AUA/IPSS prostate symptoms score measured before initiating therapy, 3 months after starting therapy, and annually thereafter (59). The patients should also undergo digital prostate examination at baseline, after 3 months of therapy, and annually thereafter. Androgen-deficient men should undergo a dual x-ray absoriptiometry (DEXA) scan to measure baseline bone mineral density; patients deemed osteoporotic should have their bone mineral density measured again by DEXA scan 1 or 2 years after initiating testosterone therapy.
Testosterone Therapy for Sexual Dysfunction
Many domains of male sexual function are regulated by testosterone (60). Pioneering investigations have demonstrated that androgen-deficient men can achieve penile erections in response to erotic stimuli, but their overall sexual activity is decreased (332,476). Testosterone increases sexual thoughts, desire (311), arousal, and attentiveness to erotic stimuli (6). Testosterone administration increases the frequency, fullness, and duration of nocturnal penile tumescence (96). Maximum rigidity may require a threshold level of androgen activity (92): testosterone regulates nitric oxide synthase (NOS) in the cavernosal smooth muscle (332) and exerts trophic effects on cavernosal smooth muscle (446) and ischiocavernosus and bulbospongiosus muscles, and is necessary for the veno-occlusive response. However, testosterone does not improve erectile response to visual erotic stimulus (311) or erectile function in men with erectile dysfunction who have normal testosterone levels or orgasms (258).
Androgen deficiency and erectile dysfunction are 2 independently distributed disorders that coexist in 6-10% of middle-aged and older men (300). Testosterone trials among sildenafil failures have been inconclusive (26,447). There is insufficient evidence to support the proposal that testosterone improves therapeutic response to selective phosphodiesterase inhibitors (26,59,447).
Table 4 provides the domains of sexual function that are improved by androgen therapy in hypogonadal men. Systematic reviews of randomized trials have shown that testosterone therapy improves sexual activity and libido in men with sexual dysfunction who have unequivocally low testosterone levels but not in men with normal testosterone levels. These considerations led the Endocrine Society Expert Panel to “suggest (that) clinicians offer testosterone therapy to men with low testosterone levels and low libido in order to improve libido and to men with erectile function (ED) who have unequivocally low testosterone levels after evaluation of underlying causes of ED and consideration of established therapies for ED)” (59). However, the expert panel noted the low-quality evidence supporting this suggestion.
Anabolic Applications of Androgens for the Prevention and Treatment of Sarcopenia and Functional Limitations Associated With Aging and Chronic Illness
Administration of supraphysiologic doses of testosterone increases skeletal muscle cross-sectional area, lean body mass, and maximal voluntary muscle strength in eugonadal young men (Figure 3) (63). Subsequent research has shown that the anabolic effects of testosterone on appendicular skeletal muscle mass, muscle size, and maximal voluntary strength are correlated with the administered dose and circulating testosterone concentrations (Figure 4) (68). This section will review possible clinical applications of testosterone therapy to treat the muscle wasting and functional limitations associated with aging and chronic diseases.
Mechanisms of Testosterone Effects on the Skeletal Muscle
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).
Testosterone also inhibits preadipocyte differentiation into adipocytes (458). The effects of testosterone on myogenic differentiation in vitro are blocked by the AR antagonist, bicalutamide, indicating that these effects are mediated through an AR pathway (458). It is possible that androgens might exert additional effects through nongenomic mechanisms. Testosterone increases fractional muscle protein synthesis and improves the reutilization of amino acids by the muscle (180-182,447).
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.
Androgen Therapy in Chronic Diseases
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).
Testosterone Therapy for HIV-Infected Men With Weight Loss
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.
Chronic Obstructive Pulmonary Disease
Patients with COPD have weak muscles (55,209,480) with smaller cross-sectional area (55) than age- and gender-matched healthy individuals. Mid-arm area (468), mid-thigh cross-sectional area (345), and quadriceps strength (490) have been shown to be predictors of mortality in patients with COPD. Peripheral muscle weakness in patients with COPD is associated with increased utilization of health care resources (131). Proposed mechanisms of skeletal muscle dysfunction in COPD are numerous and include disuse atrophy, systemic inflammation, oxidative stress, blood gas abnormalities, and use of glucocorticosteroids (11,100,101,421,521). Several studies have reported higher prevalence of low testosterone in men with COPD than in healthy older men (100,101,513), although a study reported frequency of low testosterone levels to be no greater than healthy age-matched controls (312).
Resistance exercise training improves skeletal muscle strength (56,102,400,455,480) and leg extensor power in patients with COPD (245). Only scant evidence (400), however, suggests that these changes result in improvement of physical function. Recent evidence-based guidelines for pulmonary rehabilitation (371,422) have emphasized the value of resistance exercise training for increasing muscle strength and muscle mass for both upper and lower extremities.
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.
Casaburi et al. (102) were the first to demonstrate significant increases in muscle performance, as well as increases in lean body mass after androgen administration in men with COPD. Using a 2-by-2 factorial design, 47 men with moderate to severe COPD (mean forced expiratory volume in the first second of expiration = 40% of predicted) and low testosterone (mean = 320 ng·dL−1) were randomized to one of 4 groups in a 10-week study: resistance exercise training only, resistance training + placebo, resistance training + 100 mg·wk−1 testosterone enanthate, or 100 mg·wk−1 testosterone enanthate only. Men receiving testosterone had mean nadir levels within the mid-range of young healthy men. Leg press strength increased 17% in the men receiving testosterone alone and in the resistance training plus placebo groups; leg press strength improved 27% in the combined group. Leg press fatigability (repetitions to failure at 80% 1RM) increased by 2, 7, and 11 repetitions, in the testosterone only, resistance training + placebo, and combined groups, respectively. Lean body mass increased 2.3 kg in the testosterone-only group and 3.3 kg in the group receiving testosterone + resistance exercise training. No changes in lean body mass were noted in the men who only performed resistance training only. Thus, 10 weeks of a replacement dose of testosterone in men with moderate to severe COPD yielded significant improvements in lean body mass, muscle strength, and resistance to fatigue. Resistance training of the legs resulted in benefits similar to testosterone and the combination of the interventions proved to be additive.
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.
Testosterone Therapy in Glucocorticoid-Treated Men
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).
End-Stage Renal Disease
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.
Johansen et al. (269) demonstrated that 6 months of weekly injections of 100 mg nandrolone decanoate significantly increased lean body mass by 4.5 ± 2.3 kg compared with the 1.9 ± 0.6 kg change in the placebo group. Muscle mass increases were observed only in the nandrolone-treated men. Combined times for completing walking and stair climbing tasks decreased by 3.8 seconds in the treated group compared with a 3.4-second increase in control subjects; these differences were statistically significant. There were no differences in the change in grip strength between the 2 groups.
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.
Eiam-Ong et al. (162) randomized 29 predialysis patients with CKD in a 3-month investigation of the anabolic effects of nandrolone decanoate. Subjects received either conventional treatment for CKD or conventional treatment plus weekly injections of 100 mg nandrolone. Lean body mass increased significantly greater in the nandrolone-treated group as compared with controls, 2.1 ± 2.2 vs. 0.4 ± 1.4 kg, respectively. The authors concluded that 100 mg·wk−1 nandrolone decanoate significantly improved lean body mass without altering renal function or producing serious adverse effects in these patients.
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.
Testosterone Therapy for Older Men With Sarcopenia and Functional Limitations
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.
In epidemiological studies (44,45,354,361,376,382,394,428,436,510), low total or bioavailable testosterone levels are associated with low appendicular skeletal muscle mass and muscle strength and self-reported physical function. Low testosterone levels have also been associated with decreased self-reported and performance-based physical function in a number of epidemiologic studies (130,361,376,382,436,510). The data on the association of testosterone levels with sexual dysfunction have been inconsistent (17,275,300,341,502,549). In general, serum total and bioavailable testosterone levels are not significantly different between men who report erectile dysfunction and those who do not (275,300). In the Massachusetts Male Aging Study (MMAS), decreased libido, as assessed by a single question, was associated only with very low testosterone levels (502). In another study of men older than 50 years who had benign prostatic hyperplasia, sexual dysfunction, assessed by the Sexual Function Inventory, was reported only in men with serum total testosterone levels less than 225 ng·dL−1 (341).
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 epidemiologic studies of older men (12,165,214,317,354), including MrOS (165), the Rancho Bernardo Study (214), the Framingham Heart Study (12), and the Olmsted County Study (354), have found bioavailable testosterone levels to be associated with bone mineral density, bone geometry, and bone quality (317); the associations are stronger with bioavailable testosterone and estradiol levels than with total testosterone levels. In the MrOS Study, the odds of osteoporosis in men with a total testosterone less than 200 ng·dL−1 were 3.7-fold higher than in men with normal testosterone level (165); free testosterone was an independent predictor of prevalent osteoporotic bone fractures (352).
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).
In a systematic review of randomized trials (57), testosterone therapy was associated with a significantly greater increase in FFM (contrast 2.5 kg, 95% CI 1.5-3.4) and right hand grip strength (contrast 3.3 kg, 95% CI 0.7-5.8 kg) (Figure 5). Whole-body fat mass showed a greater reduction in androgen groups (contrast −2.1 kg, 95% CI −3.1, −1.1) than in placebo (163,182,290,364,383,465,497,534).
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).
Dosing and Use Patterns of Androgens in Athletic Populations
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).
Masking Agents and Drugs Commonly Used with Androgens
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.
Some athletes have also used epitestosterone as a masking agent (2). Epitestosterone is 17α epimer of testosterone found in urine in similar concentrations to testosterone. Although its physiological role is unclear (e.g., possible antiandrogenic activity) (474), some athletes have administered epitestosterone (in similar doses to their testosterone regimen) to reduce the T:E ratio to within legal limits (i.e., a 4:1 ratio). Reports from athletes have indicated that epitestosterone injections 1 hour before testing have resulted in a “passed” drug test. Although epitestosterone administration can be detected (2), it could result in an athlete passing a drug test unless it is specifically tested for. Epitestosterone is difficult to obtain commercially so it is mostly used by elite athletes. Last, other masking procedures such as urine substitution, catheterization, use of adulterants, and other tampering methods have been reported (257). These procedures are banned, and stricter enforcement policies have been used in an attempt to decrease their use among athletes.
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.
Central Nervous System Stimulants
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 Chorionic Gonadotropin (hCG)
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
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.
Frequency of Androgen Use
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.
Medical Issues Associated with Androgen Use and Abuse
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).
Table 5 lists the adverse events that have been reported in association with androgen abuse, including mood and psychiatric disorders (406); increased risk of suicidal or homicidal death (389); deleterious changes in the cardiovascular risk factors, including a marked decrease in plasma HDL cholesterol level (204,391) and changes in clotting factors (15); suppression of the hypothalamic-pituitary-testicular axis and spermatogenesis resulting in infertility; and increase in liver enzymes (144,397,467). Individuals abusing androgens often also concomitantly abuse other accessory drugs, including stimulants, such as amphetamines and cocaine; these accessory drugs may have serious adverse effects of their own. Also, individuals who abuse androgens may engage in high-risk behaviors that may increase the risks of HIV infection, injury, or violence.
Androgen Abuse and Mortality
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.
Thiblin et al. (498) investigated the cause and manner of death among 34 androgen users whose deaths were investigated medicolegally: 32% committed suicide, 26% were victims of homicide, and 35% of deaths were deemed accidental (498). Use of multiple drugs, cardiac causes, and impulsive and uncontrolled violent behaviors were among the contributory causes of accidental deaths (498).
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).
Cardiovascular Effects of Androgens
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.
Psychiatric and Behavioral Effects of Androgens in Athletes
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).
Kanayama et al. (279) have reported a high frequency of prior androgen abuse among male substance abusers. In a sample of 223 male substance abusers, who were hospitalized for the treatment of alcohol, cocaine, and opioid dependence, 13% reported prior androgen use, leading those investigators to speculate that AAS use may predispose some individuals to substance abuse.
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).
The Suppression of Hypothalamic-Pituitary-Testicular Axis
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.
Androgen Abuse and Insulin Resistance
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).
Risks Associated With Intramuscular Injections of Androgens
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.
Risks Associated With Excessive Muscle Hypertrophy
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).
Risks Associated With the Use of Accessory Drugs
It has been reported that 90% of androgen users abuse additional drugs (171,388). Almost one-quarter of androgen users also take hGH or insulin (388). Some of these additional drugs of abuse, such as cocaine, amphetamine, and ephedra, may be associated with potentially serious medical complications.
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.
Medical Issues Associated With Androgen Use Among Women
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).
Medical Issues Associated with Androgen Use Among Children and Adolescents
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.
Testing of Androgens
Current Analytical Methods of Detection
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.
High-Resolution Mass Spectrometry for Low-Level Androgen Detection
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.
Isotope Ratio Mass Spectrometry for Androgen Detection
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.
Criteria for Detection
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).
Effect of Genotype on Testing Results
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.
A recent study by Schulze et al. (440) examined 55 male subjects who were genotyped for the UGT2B17 deletion. Of these subjects, 31% were homozygous for the gene deletion, 44% were heterozygous for the gene deletion, and 25% had 2 copies of the gene. Subjects had originated from different ethnicities. After a single injection of 500 mg of testosterone enanthate, urine samples were collected for 15 days. Results demonstrated that the rate of increase in testosterone glucuronide excretion was highly dependent on the genotype of UGT2B17. Forty percent of the subjects who were homozygous for the gene deletion never reached the T:E cutoff of 4 during the 15 days of the study. Interestingly, in the group that had both copies of the gene, 14% of the individuals had baseline T:E ratios above 4, resulting in a false-positive test. However, by changing the ratio to 1.0 in the homozygous group and to 6.0 in the group that had both copies of the gene, the sensitivity of the test increases to 100% within 6 days from injection. Thus consideration of the genetic variation of testosterone glucuronidation enzymes appears to be important in developing appropriate doping tests.
Legal Issues Associated With Androgens
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.
Direction of Future Research
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.
What Is Growth Hormone?
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).
What Is the Physiological Role of Growth Hormone?
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).
Hayashi and Proud (232) reported that GH also stimulates dephosphorylation of eEF2 and activates S6K, thus playing a role in translation, initiation, and elongation of the proteins synthesized. These downstream effects are thought to be a result of the GH-mediated stimulation of phosphatidylinositol 3-kinase and protein kinase B (PKB, also called AKT) (232).
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).
History of the Use of Human Growth Hormone as an Ergogenic Aid in Athletes
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).
What Is the Clinical Role of Growth Hormone?
Growth hormone is administered to promote linear growth in short children. The following are the Food and Drug Administration (FDA)-approved indications for GH:
* GH deficiency
* Turner syndrome
* Small-for-gestational-age infants who fail to catch-up to the normal growth percentiles
* Prader-Willi syndrome
* Idiopathic short stature
* SHOX gene haploinsufficiency
* Noonan syndrome
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.
What Types of Clinical Research Are Being Done With GH?
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:
1. Growth hormone deficiency to note the changes in well-being, body composition as noted above, and the psychosocial issues of well-being because the major indication for GH treatment in GH-deficient adults is to favorably alter the sense of health-related well-being (244).
2. Growth hormone excess (acromegaly) to note the changes in body composition and health-related well-being, but especially the alteration of cardiovascular risk factors noted with diminishing the GH values by surgery, radiotherapy, and pharmacologic agents (93).
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.
Liu et al. (324) have systematically reviewed the effects of hGH on athletic performance. Using proper and stringent criteria for a meta-analysis, they reviewed 7,599 titles from the largest databases, reviewed 252 abstracts in detail, and retrieved 56 articles for full-text evaluation. Following their review, just 44 articles representing only 27 unique studies met the strict inclusion criteria. The majority of the 303 participants received hGH for an average of 20 days, with a number having received hGH for only 1 injection. They were mainly young men (average age 27 years) and were recreational not elite athletes. The average dose was 36 μg·kg−1·day−1, approximately 5- to 10-fold the therapeutic dose in adults with GH deficiency.
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.
Recently, hGH (19 μg·kg·d−1) of 1 week's duration was noted to increase strength, peak power output, and IGF-1 levels in a group of abstinent dependent users of anabolic-androgenic steroids (211). Great care was taken to be certain that no anabolic steroids were detected in appropriately obtained urine samples. Body weight increased (likely water retention) as did peak power output. This is a very special group of athletes and is a single study, but it was quite carefully performed.
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.”
Detection of GH Abuse
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.
Direction of Future Research
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)].
The precise language of the FDCA under section 303  follows:
(f) (1) Except as provided in paragraph (2), whoever knowingly distributes, or possesses with intent to distribute, human growth hormone for any use in humans other than the treatment of a disease or other recognized medical condition, where such use has been authorized by the Secretary of Health and Human Services under section 505 and pursuant to the order of a physician, is guilty of an offense punishable by not more than 5 years in prison, such fines authorized by title 18, or both.
(2) Whoever commits any offense set forth in paragraph (1) and such offense involves an individual under 18 years of age is punishable by not more than 10 years imprisonment, such fines as are authorized by title 18 or both.
(3) Any conviction for a violation of paragraphs (1) and (2) of this subsection shall be considered a felony violation of the Controlled Substances Act for the purposes of forfeiture under section 413 of such Act.
(4) As used in this subsection the term “human growth hormone” means somatrem, somatropin, or an analogue of either of them.
(5) The Drug Enforcement Administration (DEA) is authorized to investigate offenses punishable by this subsection.
1. Aguilera, R, Chapman, TE, Starcevic, B, Hatton, CK, and Catlin, DH. Performance characteristics of a carbon isotope ratio method for detecting doping with testosterone based on urine diols: Controls and athletes with elevated testosterone/epitestosterone ratios. Clin Chem
47: 292-300, 2001.
2. Aguilera, R, Hatton, CK, and Catlin, DH. Detection of epitestosterone by isotope ratio mass spectrometry. Clin Chem
48: 629-636, 2002.
3. Albaaj, F, Sivalingham, M, Haynes, P, Mckinnon, G, Foley, RN, Waldek, S, O'donoghue, DJ, and Kalra, PA. Prevalence of hypogonadism in male patients with renal failure. Postgrad Med J
82: 693-696, 2006.
4. Alen, M and Häkkinen, K. Androgenic steroid effects on serum hormones and on maximal force development in strength athletes. J Sports Med Phys Fitness
27: 38-46, 1987.
5. Alen, M, Häkkinen, K, and Komi, PV. Changes in neuromuscular performance and muscle fiber characteristics of elite power athletes self-administering androgenic and anabolic steroids. Acta Physiol Scand
122: 535-544, 1984.
6. Alexander, GM and Sherwin, BB The association between testosterone, sexual arousal, and selective attention for erotic stimuli in men. Horm Behav
25: 367-381, 1991.
7. Alexander, GM, Swerdloff, RS, Wang, C, Davidson, T, Mcdonald, V, Steiner, B, and Hines, M. Androgen-behavior correlations in hypogonadal men and eugonadal men. II. Cognitive abilities. Horm Behav
33: 85-94, 1998.
8. Alexandersen, P, Haarbo, J, and Christiansen, C. The relationship of natural androgens to coronary heart disease in males: A review. Atherosclerosis
125: 1-13, 1996.
9. American College of Sports Medicine. Position statement on the use and abuse of anabolic-androgenic steroids in sports. Med Sci Sports
9: xi-xiii, 1977.
10. American College of Sports Medicine. Position stand: The use of anabolic-androgenic steroids in sports. Med Sci Sports Exerc
19: 534-539, 1987.
11. American Thoracic Society. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. A statement of the American Thoracic Society and European Respiratory Society. Am J Respir Crit Care Med
159: S1-S40, 1999.
12. Amin, S, Zhang, Y, Felson, DT, Sawin, CT, Hannan, MT, Wilson, PW, and Kiel, DP. Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham study. Am J Med
119: 426-433, 2006.
13. Amory, JK, Watts, NB, Easley, KA, Sutton, PR, Anawalt, BD, Matsumoto, AM, Bremner, WJ, and Tenover, JL. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab
89: 503-510, 2004.
14. Anderson, WA, Albrecht, MA, and McKeag, DB. Second Replication of a National Study of the Substance use/Abuse Habits of College Student Athletes
. Report to NCAA. Mission, KS: National Collegiate Athletic Association, 1993.
15. Ansell, JE, Tiarks, C, and Fairchild, VK. Coagulation abnormalities associated with the use of anabolic steroids. Am Heart J
125: 367-371, 1993.
16. Antonio, J, Wilson, JD, and George, FW. Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles. J Appl Physiol
87: 2016-2019, 1999.
17. Araujo, AB, Esche, GR, Kupelian, V, O'donnell, AB, Travison, TG, Williams, RE, Clark, RV, and Mckinlay, JB. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab
92: 4241-4247, 2007.
18. Araujo, AB, Kupelian, V, Page, ST, Handelsman, DJ, Bremner, WJ, and Mckinlay, JB. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med
167: 1252-1260, 2007.
19. Argetsinger, LS, Campbell, GS, Yang, X, Witthuhn, BA, Silvennoinen, O, Ihle, JN, and Carter-Su, C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell
74: 237-244, 1993.
20. Ariel, G. The effect of anabolic steroid upon skeletal muscle contractile force. J Sports Med Phys Fitness
13: 187-190, 1973.
21. Ariel, G. Prolonged effects of anabolic steroid upon muscular contractile force. Med Sci Sports
6: 62-64, 1974.
22. Ariel, G. Residual effect of an anabolic steroid upon isotonic muscular force. J Sports Med Phys Fitness
14: 103-111, 1974.
23. Armstrong, LE. Diuretics. In: Performance-Enhancing Substances in Sport and Exercise
. Bahrke, MS and Yesalis, CE eds. Champaign, IL: Human Kinetics, 2002. pp. 109-116.
24. Arver, S, Dobs, AS, Meikle, AW, Allen, RP, Sanders, SW, and Mazer, NA. Improvement of sexual function in testosterone deficient men treated for 1 year with a permeation enhanced testosterone transdermal system. J Urol
155: 1604-1608, 1996.
25. Arver, S, Sinha-Hikim, I, Beall, G, Guerrero, M, Shen, R, and Bhasin S. Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss. J Androl
20: 611-618, 1999.
26. Aversa, A, Mazzilli, F, Rossi, T, Delfino, M, Isidori, AM, and Fabbri, A. Effects of sildenafil (viagra) administration on seminal parameters and post-ejaculatory refractory time in normal males. HumReprod
15: 131-134, 2000.
27. Avois, L, Robinson, N, Saudan, C, Baume, N, Mangin, P, and Saugy, M. Central nervous system stimulants and sport practice. Br J Sports Med
40: 16-20, 2006.
28. Babigian, A and Silverman, RT. Management of gynecomastia due to use of anabolic steroids in bodybuilders. Plast Reconstr Surg
107: 240-242, 2001.
29. Bagatell, CJ, Heiman, JR, Matsumoto, AM, Rivier, JE, and Bremner, WJ. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab
79: 561-567, 1994.
30. Bahrke, MS and Yesalis, CE. Weight training. A potential confounding factor in examining the psychological and behavioural effects of anabolic-androgenic steroids. Sports Med
18: 309-318, 1994.
31. Bamman, MM, Shipp, JR, Jiang, J, Gower, BA, Hunter, GR, Goodman, A, Mc Lafferty, CL, and Urban, RJ. Mechanical load increases muscle IGF-1 and androgen receptor mRNA concentrations in humans. Am J Physiol
280: E383-E390, 2001.
32. Barnea, N, Drory, Y Iaina, A, Lapidot, C, Reisin, E, Eliahou, H, and Kellermann, JJ. Exercise tolerance in patients on chronic hemodialysis. Isr J Med Sci
16: 17-21, 1980.
33. Barr, SI. Effects of dehydration on exercise performance. Can J Appl Physiol
24: 164-172, 1999.
34. Barrett-Connor, E and Khaw, KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation
78: 539-545, 1988.
35. Barrett-Connor, E, Goodman-Gruen, D, and Patay, B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab
84: 3681-3685, 1999.
36. Barrett-Connor, E, Von Muhlen, DG, and Kritz-Silverstein, D. Bioavailable testosterone and depressed mood in older men: The Rancho Bernardo study. J Clin Endocrinol Metab
84: 573-577, 1999.
37. Barton-Davis, ER, Shoturma, DI, Musaro, A, Rosenthal, N, and Sweeney, HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci U S A
95: 15603-15607, 1998.
38. Basaria, S, Wahlstrom, JT, and Dobs, AS. Anabolic-androgenic steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab
86: 5108-5117, 2001.
39. Basu, R, Dalla Man, C, Campioni, M, Basu, A, Nair, KS, Jensen, MD, Khosla, S, Klee, G, Toffolo, G, Cobelli, C, and Rizza, RA. Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women. Diabetes
56: 753-766, 2007.
40. Baumann, CK and Castiglione-Gertsch, M. Estrogen receptor modulators and down regulators: Optimal use in postmenopausal women with breast cancer. Drugs
67: 2335-2353, 2007.
41. Baumann, G. Growth hormone heterogeneity: Genes, isohormones, variants, and binding proteins. Endocr Rev
12: 424-449, 1991.
42. Baumann, G, MacCart, JG, and Amburn, K. The molecular nature of cirgulating growth hormone in normal and acromegalic man: Evidence for a principal and minor monomeric forms. J Clin Endocrinol Metab
56: 946-952, 1983.
43. Baumann, G, Shaw, M, Amburn, K, Jan, T, Davila, N, Mercado, M, Stolar, M, and MacCart, J. Heterogeneity of circulating growth hormone. Nucl Med Biol
21: 369-379, 1994.
44. Baumgartner, RN, Koehler, KM, Gallagher, D, Romero, L, Heymsfield, SB, Ross, RR, Garry, PJ, and Lindeman, RD. Epidemiology of sarcopenia among the elderly in new Mexico. Am J Epidemiol
147: 755-763, 1998.
45. Baumgartner, RN, Waters, DL, Gallagher, D, Morley, JE, and Garry, PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev
107: 123-136, 1999.
46. Behre, HM, Bohmeyer, J, and Nieschlag, E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf)
40: 341-349, 1994.
47. Behre, HM, von Eckardstein, S, Kliesch, S, and Nieschlag, E. Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7-10 years. Clin Endocrinol (Oxf)
50: 629-635, 1999.
48. Belanger, A, Pelletier, G, Labrie, F, Barbier, O, and Chouinard, S. Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol Metab
14: 473-479, 2003.
49. Bell, DG and Jacobs, I. Combined caffeine and ephedrine ingestion improves run times of Canadian Forces Warrior Test. Aviat Space Environ Med
70: 325-329, 1999.
50. Bell, DG, Jacobs, I, and Ellerington, K. Effect of caffeine and ephedrine ingestion on anaerobic exercise performance. Med Sci Sports Exerc
33: 1399-1403, 2001.
51. Bell, DG, Jacobs, I, and Zamecnik, J. Effects of caffeine, ephedrine and their combination on time to exhaustion during high-intensity exercise. Eur J Appl. Physiol
77: 427-433, 1998.
52. Bents, RT, Tokish, JM, and Goldberg, L. Ephedrine, pseudoephedrine, and amphetamine prevalence in college hockey players. Phys Sports Med
32: 54-59, 2004.
53. Benzi, G. Pharmacoepidemiology of the drugs used in sports as doping agents. Pharmacol Res
29: 13-26, 1994.
54. Berger, JR, Pall, L, and Winfield, D. Effect of anabolic steroids on HIV-related wasting myopathy. South Med J
86: 865-866, 1993.
55. Bernard, S, Leblanc, P, Whittom, F, Carrier, G, Jobin, J, Belleau, R, and Maltais, F. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
158: 629-634, 1998.
56. Bernard, S, Whittom, F, Leblanc, P, Jobin, J, Belleau, R, Berube, C, Carrier, G, and Maltais, F. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
159: 896-901, 1999.
57. Bhasin, S, Calof, OM, Storer, TW, Lee, ML, Mazer, NA, Jasuja, R, Montori, VM, Gao, W, and Dalton, JT. Drug insights: Anabolic applications of testosterone and selective androgen receptor modulators in aging and chronic illness. Nat Clin Pract Endocrinol Metab
2: 133-140, 2006.
58. Bhasin, S, Calof, OM, Storer, TW, Lee, ML, Mazer, NA, Jasuja, R, Montori, VM, Gao, W, and Dalton, JT. Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab
2: 146-159, 2006.
59. Bhasin, S, Cunningham, GR, Hayes, FJ, Matsumoto, AM, Snyder, PJ, Swerdloff, RS, and Montori, VM. Testosterone therapy in adult men with androgen deficiency syndromes: An endocrine society clinical practice guideline. J Clin Endocrinol Metab
91: 1995-2010, 2006.
60. Bhasin, S, Enzlin, P, Coviello, A, and Basson, R. Sexual dysfunction in men and women with endocrine disorders. Lancet
369: 597-611, 2007.
61. Bhasin, S, Singh, AB, Mac, RP, Carter, B, Lee, MI, and Cunningham, GR. Managing the risks of prostate disease during testosterone replacement therapy in older men: Recommendations for a standardized monitoring plan. J Androl
24: 299-311, 2003.
62. Bhasin, S, Storer, TW, Asbel-Sethi, N, Kilbourne, A, Hays, R, Sinha-Hikim, I, Shen, R, Arver, S, and Beall, G. Effects of testosterone replacement with a nongenital, transdermal system, androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab
83: 3155-3162, 1998.
63. Bhasin, S, Storer, TW, Berman, N, Callegari, C, Clevenger, B, Phillips, J, Bunnell, TJ, Tricker, R, Shirazi, A, and Casaburi, R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med
335: 1-7, 1996.
64. Bhasin, S, Storer, TW, Berman, N, Yarasheski, KE, Clevenger, B, Phillips, J, Lee, WP, Bunnell, TJ, and Casaburi, R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin. Endocrinol Metab
82: 407-413, 1997.
65. Bhasin, S, Storer, TW, Javanbakht, M, Berman, N, Yarasheski, KE, Phillips, J, Dike, M, Sinha-Hikim, I, Shen, R, Hays, RD, and Beall, G. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA
283: 763-770, 2000.
66. Bhasin, S, Taylor, WE, Singh, R, Artaza, J, Sinha-Hikim, I, Jasuja, R, Choi, H, and Gonzalez-Cadavid, NF. The mechanisms of androgen effects on body composition: Mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci
58: M1103-M1110, 2003.
67. Bhasin, S, Woodhouse, L, Casaburi, R, Singh, AB, Bhasin, D, Berman, N, Chen, X, Yarasheski, KE, Magliano, L, Dzekov, C, Dzekov, J, Bross, R, Phillips, J, Sinha-Hikim, I, Shen, R, and Storer, TW. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab
281: E1172-E1181, 2001.
68. Bhasin, S, Woodhouse, L, Casaburi, R, Singh, AB, Mac, RP, Lee, M, Yarasheski, KE, Sinha-Hikim, I, Dzekov, C, Dzekov, J, Migliano, L, and Storer, TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab
90: 678-688, 2005.
69. Bhasin, S, Woodhouse, L, and Storer, TW. Proof of the effect of testosterone on skeletal muscle. J Endocrinol
170: 27-38, 2001.
70. Bidlingmaier, M and Strasburger, CJ. Technology insight: Detecting growth hormone abuse in athletes. Nat Clin Pract Endocinol Metab
3: 769-777, 2007.
71. Bjoe, O. Doping. Bull Health Organ League Nations
8: 439-496, 1939.
72. Blackman, MR, Sorkin, JD, Munzer, T, Bellantoni, MF, Busby-Whitehead, J, Stevens, TE, Jayme, J, O'connor, KG, Christmas, C, Tobin, JD, Stewart, KJ, Cottrell, E, St. Clair, C, Pabst, KM, and Harman, SM. Growth hormone and sex steroid administration in healthy aged women and men: A randomized controlled trial. JAMA
288: 2282-2292, 2002.
73. Bohannon, RW, Smith, J, and Barnhard, R. Grip strength in end stage renal disease. Percept Mot Skills
79: 1523-1526, 1994.
74. Bolona, ER, Uraga, MV, Haddad, RM, Tracz, MJ, Sideras, K, Kennedy, CC, Caples, SM, Erwin, PJ, and Montori, VM. Testosterone use in men with sexual dysfunction: A systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc
82: 20-28, 2007.
75. Bonetti, A, Tirelli, F, Catapano, A, Dazzi, D, Dei Cas, A, Solito, F, Ceda, G, Reverberi, C, Monica, C, Pipitone, S, Elia, G, Spattini, M, and Magnati, G. Side effects of anabolic androgenic steroids abuse. Int J Sports Med
29: 679-687, 2008.
76. Boone, JB, Lambert, CP, Flynn, MG, Michaud, TJ, Rodriguez-Zayas, A, and Andres, FF. Resistance exercise effects on plasma cortisol, testosterone and creatine kinase activity in anabolic-androgenic steroid users. Int J Sports Med
11: 293-297, 1990.
77. Borst, SE Interventions for sarcopenia and muscle weakness in older people. Age Ageing
33: 548-555, 2004.
78. Bowers, RW and Reardon, JP. Effects of methandrostenolone (Dianabol) on strength development and aerobic capacity. Med Sci Sports
4: 54, 1972.
79. Brahm, H, Piehl-Aulin, K, Saltin, B, and Ljunghall, S. Net fluxes over working thigh of hormones, growth factors and biomarkers of bone metabolism during short lasting dynamic exercise. Calcif Tissue Int
60: 175-180, 1997.
80. Brater, DC. Clinical pharmacology of loop diuretics in health and disease. Eur Heart J
13(Suppl. G): 10-14, 1992.
81. Braunstein, GD. Clinical practice. Gynecomastia. N Engl J Med
357: 1229-1237, 2007.
82. Brenta, G, Danzi, S, and Klein, I. Potential therapeutic applications of thyroid hormone analogs. Nat Clin Pract Endocrinol Metab
3: 632-640, 2007.
83. Bricout, VA, Germain, PS, Serrurier, BD, and Guezennec, CY. Changes in testosterone muscle receptors: Effects of an androgen treatment on physically trained rats. Cell Mol Biol
40: 291-294, 1994.
84. Bricout, VA, Serrurier, BD, Bigard, AX, and Guezennec, CY. Effects of hindlimb suspension and androgen treatment on testosterone receptors in rat skeletal muscles. Eur J Appl Physiol
79: 443-448, 1999.
85. Brill, KT, Weltman, AL, Gentili, A, Patrie, JT, Fryburg, DA, Hanks, JB, Urban, RJ, and Veldhuis, JD. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab
87: 5649-5657, 2002.
86. Brockenbrough, AT, Dittrich, MO, Page, ST, Smith, T, Stivelman, JC, and Bremner, WJ. Transdermal androgen therapy to augment epo in the treatment of anemia of chronic renal disease. Am J Kidney Dis
47: 251-262, 2006.
87. Brooks, R, Jeremiah, G, Webb, W, and Wheeler, M. Detection of anabolic steroid administration to athletes. J Steroid Biochem
11: 913-917, 1979.
88. Brower, KJ. Anabolic steroid abuse and dependence. Curr Psychiatry Rep
4: 377-387, 2002.
89. Brower, KJ, Blow, FC, Young, JP, and Hill, EM. Symptoms and correlates of anabolic-androgenic steroid dependence. Br J Addict
86: 759-768, 1991.
90. Brower, KJ, Eliopulos, GA, Blow, FC, Catlin, DH, and Beresford, TP. Evidence for physical and psychological dependence on anabolic androgenic steroids in eight weight lifters. Am J Psychiatry
147: 510-512, 1990.
91. Buckley, WE, Yesalis, CE, Friedl, KE, Anderson, WA, Streit, AL, and Wright, JE. Estimated prevalence of anabolic steroid use among male high school seniors. JAMA
260: 3441-3445, 1988.
92. Buena, F, Swerdloff, RS, Steiner, BS, Lutchmansingh, P, Peterson, MA, Pandian, MR, Galmarini, M, and Bhasin, S. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertil Steril
59: 1118-1123, 1993.
93. Bush, ZM and Vance, ML. Management of acromegaly: Is there a role for primary medical therapy? Rev Endocr Metab Disord
9: 83-94, 2008.
94. Cabasso, A. Peliosis hepatis in a young adult bodybuilder. Med Sci Sports Exerc
26: 2-4, 1994.
95. Calof, O, Singh, AB, Lee, ML, Urban, RJ, Kenny, AM, Tenover, JL, and Bhasin, S. Adverse events associated with testosterone supplementation of older men. J Greontol Med Sci
60: 1451-1457, 2005.
96. Carani, C, Bancroft, J, Granata, A, Del Rio, G, and Marrama, P. Testosterone and erectile function, nocturnal penile tumescence and rigidity, and erectile response to visual erotic stimuli in hypogonadal and eugonadal men. Psychoneuroendocrinology
17: 647-654, 1992.
97. Cardone, A, Angelini, F, Esposito, T, Comitato, R, and Varriale, B. The expression of androgen receptor messenger RNA is regulated by tri-iodothyronine in lizard testis. J Steroid Biochem Mol Biol
72: 133-141, 2000.
98. Carpenter, PC. Performance-enhancing drugs in sport. Endocrinol Metab Clin North Am
36: 481-495, 2007.
99. Carter, WJ, Dang, AQ, Faas, FH, and Lynch, ME. Effects of clenbuterol on skeletal muscle mass, body composition, and recovery from surgical stress in senescent rats. Metabolism
40: 855-860, 1991.
100. Casaburi, R. Rationale for anabolic therapy to facilitate rehabilitation in chronic obstructive pulmonary disease. Baillieres Clin Endocrinol Metab
12: 407-418, 1998.
101. Casabur, R. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Med Sci Sports Exerc
33: S662-S670, 2001.
102. Casaburi, R, Bhasin, S, Cosentino, L, Porszasz, J, Somfay, A, Lewis, MI, Fournier, M, and Storer, TW. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
170: 870-878, 2004.
103. Casavant, MJ, Blake, K, Griffith, J, Yates, A, and Copley, LM, Consequences of use of anabolic androgenic steroids. Pediatr Clin North Am
54: 677-690, 2007.
104. Casner, SW, Early, RG, and Carlson, BR. Anabolic steroid effects on body composition in normal young men. J Sports Med Phys Fitness
11: 98-103, 1971.
105. Catlin, DH, Sekera, MH, Ahrens, BD, Starcevic, B, Chang, YC, and Hatton, CK. Tetrahydrogestrinone: Discovery, synthesis, and detection in urine. Rapid Commun Mass Spectrom
18: 1245-1249, 2004.
106. Cherrier, MM, Asthana, S, Plymate, S, Baker, L, Matsumoto, AM, Peskind, E, Raskind, MA, Brodkin, K, Bremner, W, Petrova, A, Latendresse, S, and Craft, S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology
57: 80-88, 2001.
107. Chester, N, Mottram, DR, Reilly, T, and Powell, M. Elimination of ephedrines in urine following multiple dosing: The consequences for athletes, in relation to doping control. Br J Clin Pharmacol
57: 62-67, 2004.
108. Chester, N, Reilly, T, and Mottram, DR. Physiological, subjective and performance effects of pseudoephedrine and phenylpropanolamine during endurance running exercise. Int J Sports Med
24: 3-8, 2003.
109. Christiansen, K. Sex hormone-related variations of cognitive performance in !Kung san hunter-gatherers of Namibia. Neuropsychobiology
27: 97-107, 1993.
110. Chu, KS, Doherty, TJ, Parise, G, Milheiro, JS, and Tarnopolsky, MA. A moderate dose of pseudoephedrine does not alter muscle contraction strength or anaerobic power. Clin J Sport Med
12: 387-390, 2002.
111. Churchill, DN, Torrance, GW, Taylor, DW, Barnes, CC, Ludwin, D, Shimizu, A, and Smith, EK. Measurement of quality of life in end-stage renal disease: The time trade-off approach. Clin Invest Med
10: 14-20, 1987.
112. Clark, MJ, Petroski, GF, Mazurek, MO, Hagglund, KG, Sherman, AK, Lammy, AB, Childers, MK, and Acuff, ME. Testosterone replacement therapy and motor function in men with spinal cord injury: A retrospective analysis. Am J Phys Med Rehabil
87: 281-284, 2008.
113. Clarke, N and Kabadi, UM, Optimizing treatment of hypothyroidism. Treat Endocrinol
3: 217-221, 2004.
114. Cohen, J, Collins, R, Darkes, J, and Gwartney, D. A league of their own: demographics, motivations and patterns of use of 1,955 male adult non-medical anabolic steroid users in the United States. J Int Soc Sports Nutr
11: 4-12, 2007.
115. Cohen, JC and Hickman, R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab
64: 960-963, 1987.
116. Cole, CL and Mobley, A. American steroids: Using race and gender. J Sport Soc Issues
29: 3-8, 2005.
117. Collins, RD and Fledstein, AH. Special legal review: The androstenedione ban and the criminalization of steroid precursors-Implications for the sports nutritional supplement market. In: Essentials of Sports Nutrition and Supplements
. Antonio, J, Kalman, D, Stout, JR, Greenwood, M, Willoughby, DS, and Haff, GG, eds. Totowa, NJ: Humana Press, 2008. pp. 567-579.
118. Contoreggi, CS, Blackman, MR, Andres, R, Muller, DC, Lakatta, EG, Fleg, JL, and Harman, SM. Plasma levels of estradiol, testosterone, and DHEA do not predict risk of coronary artery disease in men. J Androl
11: 460-470, 1990.
119. Coodley, GO, and Coodley, MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS
11: 1347-1352, 1997.
120. Coodley, GO, Loveless, MO, Nelson, HD, and Coodley, MK. Endocrine function in the HIV wasting syndrome. J Acquir Immune Defic Syndr
7: 46-51, 1994.
121. Copeland, KC and Nair, KS. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab
78: 1040-1047, 1994.
122. Coviello, AD, Kaplan, B, Lakshman, KM, Chen, T, Singh, AB, and Bhasin, S. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab
93: 914-919, 2008.
123. Cowan, DA, Kicman, AT, Walker, CJ, and Wheeler, MJ. Effect of administration of human chorionic gonadotrophin on criteria used to assess testosterone administration in athletes. J Endocrinol
131: 147-154, 1991.
124. Crawford, BA, Liu, PY, Kean, MT, Bleasel, JF, and Handelsman, DJ. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab
88: 3167-3176, 2003.
125. Creutzberg, EC, Wouters, EF, Mostert, R, Pluymers, RJ, and Schols, AM. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest
124: 1733-1742, 2003.
126. Crist, DM, Stackpole, PJ, and Peake, GT. Effects of androgenic-anabolic steroids on neuromuscular power and body composition. J Appl Physiol
54: 366-370, 1983.
127. Cunningham, GR, Hirshkowitz, M, Korenman, SG, and Karacan, I. Testosterone replacement therapy and sleep-related erections in hypogonadal men. J Clin Endocrinol Metab
70: 792-797, 1990.
128. Dai, WS, Kuller, LH, Laporte, RE, Gutai, JP, Falvo-Gerard, L, and Caggiula, A. The epidemiology of plasma testosterone levels in middle-aged men. Am J Epidemiol
114: 804-816, 1981.
129. Daly, RC, Su, TP, Schmidt, PJ, Pagliaro, M, Pickar, D, and Rubinow, DR. Neuroendocrine and behavioral effects of high-dose anabolic steroid administration in male normal volunteers. Psychoneuroendocrinology
28: 317-331, 2003.
130. David, KG, Dingemanse, E, Freud J, and Laqueur, E. On crystalline male hormone from testicles (testosterone). Hoppe Seylers Z Physiol Chem
233: 281, 1935.
131. Decramer, M, Gosselink, R, Troosters, T, Verschueren, M, and Evers, G. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J
10: 417-423, 1997.
132. Defay, R, Papoz, L, Barny, S, Bonnot-Lours, S, Caces, E, and Simon, D. Hormonal status and NIDDM in the European and Melanesian populations of New Caledonia: a case-control study. The CALedonia DIAbetes Mellitus (CALDIA) Study Group. Int J Obes Relat Metab Disord
22: 927-934, 1998.
133. Dehennin, L. On the origin of physiologically high ratios of urinary testosterone to epitestosterone: Consequences for reliable detection of testosterone administration by male athletes. J Endocrinol
142: 353-360, 1994.
134. Dehennin, L and Matsumoto, A. Long-term administration of testosterone enanthate to normal men: Alterations of the urinary profile of androgen metabolites potentially useful for detection of testosterone misuse in sport. J Steroid Biochem Mol Biol
44: 179-189, 1993.
135. de Kruif, P. The Male Hormone
. Garden City, NY: Garden City, 1945.
136. de la Torre, X, Segura, J, Yang, Z, Li, Y, and Wu, M. Testosterone detection in different ethnic groups. In: Recent Advances in Doping Analysis
. S.W.A. Gotzman and U. Mareck-Engelke, eds. Koln, Germany: Sport Und Buch Strauss, 1997. pp. 71-90.
137. Delhez, M, Hansenne, M, and Legros, JJ. Andropause and psychopathology: Minor symptoms rather than pathological ones. Psychoneuroendocrinology
28: 863-874, 2003.
138. Deligiannis, A. Exercise rehabilitation and skeletal muscle benefits in hemodialysis patients. Clin Nephrol
61(Suppl. 1): S46-S50, 2004.
139. de Luis, DA, Aller, R, Cuellar, LA, Terroba, C, and Romero, E. Anabolic steroids and gynecomastia. Review of the literature. An Med Interna
18: 489-491, 2001.
140. De Piccoli, B, Giada, F, Benettin, A, Sartori, F, and Piccolo, E. Anabolic steroid use in body builders: An echocardiographic study of left ventricle morphology and function. Int J Sports Med
12: 408-412, 1991.
141. Derman, RJ. Effects of sex steroids on women's health: Implications for practitioners. Am J Med
98(Suppl.): 137S-143S, 1995.
142. Deyssig, R, Frisch, H, Blum, WF, and Waldhor, T. Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Acta Endocrinol (Copenh)
128: 313-318, 1993.
143. Dhar, R, Stout, CW, Link, MS, Homoud, MK, Weinstock, J, and Estes, NA. Cardiovascular toxicities of performance-enhancing substances in sports. Mayo Clin Proc
80: 1307-1315, 2005.
144. Dickerman, RD, McConathy, WJ, Schaller, F, and Zachariah, NY. Cardiovascular complications and anabolic steroids. Eur Heart J
17: 1912, 1996.
145. Dickerman, RD, Pertusi, RM, Zachariah, NY, Dufour, DR, and McConathy, WJ. Anabolic steroid-induced hepatotoxicity: Is it overstated? Clin J Sport Med
9: 34-39, 1999.
146. Dickerman, RD, Schaller, F, Prather, I, and McConathy, WJ. Sudden cardiac death in a 20-year-old bodybuilder using anabolic steroids. Cardiology
86: 172-173, 1995.
147. Diel, P, Friedel, A, Geyer, H, Kamber, M, Laudenbach-Leschowsky, U, Schanzer, W, Thevis, M, Vollmer, G, and Zierau, O. Characterisation of the pharmacological profile of desoxymethyltestosterone (Madol), a steroid misused for doping. Toxicol Lett
169: 64-71, 2007.
148. Dimick, DF, Heron, M, Baulieu, EE, and Jayle, MF. A comparative study of the metabolic fate of testosterone, 17 alpha-methyl-testosterone. 19-nor-testosterone. 17 alpha-methyl-19-nor-testosterone and 17 alpha-methylestr-5(10)-ene-17 beta-ol-3-one in normal males. Clin Chim Acta
6: 63-71, 1961.
149. Ding, EL, Song, Y, Malik, VS, and Liu, S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis. JAMA
295: 1288-1299, 2006.
150. Di Paolo, M, Agozzino, M, Toni, C, Luciani, AB, Molendini, L, Scaglione, M, Inzani, F, Pasotti, M, Buzzi, F, and Arbustini, E. Sudden anabolic steroid abuse-related death in athletes. Int J Cardiol
114: 114-117, 2007.
151. Dobs, AS, Bachorik, PS, Arver, S, Meikle, AW, Sanders, SW, Caramelli, KE, and Mazer, NA. Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system. J Clin Endocrinol Metab
86: 1026-1033, 2001.
152. Dobs, AS, Cofrancesco, J, Nolten, WE, Danoff, A, Anderson, R, Hamilton, CD, Feinberg, J, Seekins, D, Yangco, B, and Rhame, F. The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Am J Med
107: 126-132, 1999.
153. Dobs, AS, Few, WL III, Blackman, MR, Harman, SM, Hoover, DR, and Graham, NM. Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab
81: 4108-4112, 1996.
154. Dodge, TL and Jaccard, JJ. The effect of high school sports participation on the use of performance-enhancing substances in young adulthood. J Adolesc Health
39: 367-272, 2006.
155. Dorlochter, M, Astrow, SH, and Herrera, AA. Effects of testosterone on a sexually dimorphic frog muscle: Repeated in vivo observations and androgen receptor distribution. J Neurobiol
25: 897-916, 1994.
156. Dotson, JL and Brown, RT. The history of the development of anabolic-androgenic steroids. Pediatr Clin North Am
54: 761-769, 2007.
157. Dotzlaw, H, Moehren, U, Mink, S, Cato, AC, Iniguez Lluhi, JA, and Baniahmad, A. The amino terminus of the human AR is a target for corepressor action and antihormone agonism. Mol Endocrinol
16: 661-673, 2002.
158. Downie, D, Delday, MI, Maltin, CA, and Sneddon, AA. Clenbuterol increases muscle fiber size and GATA-2 protein in rat skeletal muscle in utero. Mol Reprod Dev
75: 785-794, 2008.
159. DuRant, RH, Escobedo, LG, and Heath, GW. Anabolic-steroid use, strength training, and multiple drug use among adolescents in the United States. Pediatrics
96: 23-28, 1995.
160. DuRant, RH, Middleman, AB, Faulkner, AH, Emans, SJ, and Woods, ER. Adolescent anabolic-androgenic steroid use, multiple drug use, and high school sports participation. Ped Exerc Sci
9: 150-158, 1997.
161. Eder, IE, Culig, Z, Putz, T, Menardi, CN, Bartsch, G, and Klocker, H. Molecular biology of the androgen receptor: From molecular understanding to the clinic. Eur Urol
40: 241-251, 2001.
162. Eiam-Ong, S, Buranaosot, S, Wathanavaha, A, and Pansin, P. Nutritional effect of nandrolone decanoate in predialysis Patients with chronic kidney disease. J Ren Nutr
17: 173-178, 2007.
163. Emmelot-Vonk, MH, Verhaar, HJ, Nakhai Pour, HR, Aleman, A, Lock, TM, Bosch, JL, Grobbee, DE, and Van Der Schouw, YT. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: A randomized controlled trial. JAMA
299: 39-52, 2008.
164. Endre, T, Mattiasson, I, Berglund, G, and Hulthen, UL. Low testosterone and insulin resistance in hypertension-prone men. J Hum Hypertens
10: 755-761, 1996.
165. Ensrud, KE, Lewis, CE, Lambert, LC, Taylor, BC, Fink, HA, Barrett-Connor, E, Cauley, JA, Stefanick, ML, and Orwoll, E; O.F.I.M.M.S. Research Group. Endogenous sex steroids, weight change and rates of hip bone loss in older men: The MrOS study. Osteoporos Int
17: 1329-1336, 2006.
166. Erotokrito-Mulligan, I, Bassett, EE, Kniess, A, Sonksen, PH, and Holt, RI. Validation of the growth hormone (GH)-dependent marker method of detecting GH abuse in sport through the use of independent data sets. Growth Horm IGF Res
17: 416-423, 2007.
167. Escobar-Morreale, HF, Botella-Carretero, JI, Escobar del Rey, F, and Morreale de Escobar, G. Review: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab
90: 4946-4954, 2005.
169. Esposito, T, Astore, E, Cardone, A, Angelini, F, and Varriale, B. Regulation of androgen receptor mRNA expression in primary culture of Hardesian gland cells: Cross-talk between steroid hormones. Comp Biochem Physiol B
132: 97-105, 2002.
170. Estrada, M, Espinosa, A, Muller, M, and Jaimovich, E. Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells. Endocrinology
144: 3586-3597, 2003.
171. Evans, NA. Gym and tonic: A profile of 100 male steroid users. Br J Sports Med
31: 54-58, 1997.
172. Evans, NA. Local complications of self administered anabolic steroid injections. Br J Sports Med
31: 349-350, 1997.
173. Evans, NA, Bowrey, DJ, and Newman, GR. Ultrastructural analysis of ruptured tendon from anabolic steroid users. Injury
29: 769-773, 1998.
174. Fahey, TD and Brown, CH. The effects of an anabolic steroid on the strength, body composition, and endurance of college males when accompanied by a weight training program. Med Sci Sports
5: 272-276, 1973.
175. Faigenbaum, AD, Zaichkowsky, LD, Gardner, DE, and Micheli, LJ. Anabolic steroid use by male and female middle school students. Pediatrics
101: 6-14, 1998.
176. Fair, JD. Olympic weightlifting and the introduction of steroids: A statistical analysis of world championship results, 1948-1972. Int J Hist Sport
5: 96-114, 1988.
177. Fales, CL, Knowlton, BJ, Holyoak, KJ, Geschwind, DH, Swerdloff, RS, and Gonzalo, IG. Working memory and relational reasoning in Klinefelter syndrome. J Int Neuropsychol Soc
9: 839-846, 2003.
178. Feldman, HA, Longcope, C, Derby, CA, Johannes, CB, Araujo, AB, Coviello, AD, Bremner, WJ, and Mckinlay, JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: Longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab
87: 589-598, 2002.
179. Ferenchick, GS. Anabolic/androgenic steroid abuse and thrombosis: Is there a connection? Med Hypothesis 35: 27-31, 1991.
180. Ferrando, AA, Sheffield-Moore, M, Paddon-Jones, D, Wolfe, RR, and Urban, RJ. Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab
88: 358-362, 2003.
181. Ferrando, AA, Sheffield-Moore, M, Wolf, SE, Herndon, DN, and Wolfe, RR. Testosterone administration in severe burns ameliorates muscle catabolism. Crit Care Med
29: 1936-1942, 2001.
182. Ferrando, AA, Sheffield-Moore, M, Yeckel, CW, Gilkison, C, Jiang, J, Achacosa, A, Lieberman, SA, Tipton, K, Wolfe, RR, and Urban, RJ. Testosterone administration to older men improves muscle function: Molecular and physiological mechanisms. Am J Physiol Endocrinol Metab
282: E601-E607, 2002.
183. Ferreira, IM, Verreschi, IT, Nery, LE, Goldstein, RS, Zamel, N, Brooks, D, and Jardim, JR. The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients. Chest
114: 19-28, 1998.
184. Ferrini, RL and Barrett-Connor, E. Sex hormones and age: A cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol
147: 750-754, 1998.
185. Fineschi, V, Baroldi, G, Monciotti, F, Paglicci Reattelli, L, and Turillazzi, E. Anabolic steroid abuse and cardiac sudden death: A pathologic study. Arch Pathol Lab Med
125: 253-255, 2001.
186. Fineschi, V, Riezzo, I, Centini, F, Silingardi, E, Licata, M, Beduschi, G, and Karch, SB. Sudden cardiac death during anabolic steroid abuse: Morphologic and toxicologic findings in two fatal cases of bodybuilders. Int J Legal Med
121: 48-53, 2007.
187. Forbes, GB. The effect of anabolic steroids on lean body mass: the dose responsive curve. Metabolism
34: 571-573, 1985.
188. Forbes, GB, Porta, CR, Herr, BE, and Griggs. RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA
267: 397-399, 1992.
189. Fouque, D, Guebre-Egziabher, F, and Laville, M. Advances in anabolic interventions for malnourished dialysis patients. J Ren Nutr
13: 161-165, 2003.
190. Fowler, WM, Gardner, GW, and Egstrom, GH. Effect of an anabolic steroid on physical performance of young men. J Appl Physiol
20: 1038-1040, 1965.
191. Franke, WW and Berendonk, B. Hormonal doping and androgenization of athletes: A secret program of the German Democratic Republic government. Clin Chem
43: 1262-1279, 1997.
192. Fraser, AD. Doping control from a global and national perspective. Ther Drug Monit
26: 171-174, 2004.
193. Freed, DL, Banks, AJ, Longson, D, and Burley, DM. Anabolic steroids in athletics: Crossover double-blind trial on weightlifters. Br Med J
2: 471-473, 1975.
194. Freeman, ER, Bloom, DA, and McGuire, EJ. A brief history of testosterone. J Urol
165: 371-373, 2001.
195. Friedel A, Geyer, H, Kamber, M, Laudenbach-Leschowsky, U, Schanzer, W, Thevis, M, Vollmer, G, Zierau, O, and Diel, P. Tetrahydrogestrinone is a potent but unselective binding steroid and affects glucocorticoid signalling in the liver. Toxicol Lett
164: 16-23, 2006.
196. Friedl, KE, Dettori, JR, Hannan, CJ, Patience, TH, and Plymate, SR. Comparison of the effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men. J Steroid Biochem Mol Biol
40: 607-612, 1991.
197. Fryburg, DA, Louard, RJ, Gerow, KE, Gelfand, RA, and Barrett, EJ. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans. Diabetes
41: 424-429, 1992.
198. Fujita, S, Abe, T, Drummond, MJ, Cadenas, JG, Dreyer, HC, Sato, Y, Volpi, E, and Rasmussen, BB. Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis. J Appl Physiol
103: 903-910, 2007.
199. Gelman, EP. Molecular biology of the androgen receptor. J Clin Oncol
20: 3001-3015, 2002.
200. Gill, GV. Anabolic steroid induced hypogonadism treated with human chorionic gonadotropin. Postgrad Med J
74: 45-46, 1998.
201. Gill, ND, Shield, A, Blazevich, AJ, Zhou, S, and Weatherby, RP. Muscular and cardiorespiratory effects of pseudoephedrine in human athletes. Br J Clin. Pharmacol
50: 205-213, 2000.
202. Gillies, H, Derman, WE, Noakes, TD, Smith, P, Evans, A, and Gabriels, G. Pseudoephedrine is without ergogenic effects during prolonged exercise. J Appl Physiol
81: 2611-2617, 1996.
203. Giorgi, A, Weatherby, RP, and Murphy, PW. Muscular strength, body composition and health responses to the use of testosterone enanthate: A double blind study. J Sci Med Sport
2: 341-355, 1999.
204. Glazer, G. Atherogenic effects of anabolic steroids on serum lipid levels. A literature review. Arch Intern Med
151: 1925-1933, 1991.
205. Gold, J, High, HA, Li, Y, Michelmore, H, Bodsworth, NJ, Finlayson, R, Furner, VL, Allen, BJ, and Oliver, CJ. Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS
10: 745-752, 1996.
206. Goldberg L, Elliot, D, Clarke, GN, MacKinnon, DP, Moe, E, Zoref, L, Green, C, Wolf, SL, Greffrath, E, Miller, DJ, and Lapin, A. Effects of a multidimensional anabolic steroid prevention intervention. The Adolescents Training and Learning to Avoid Steroids (ATLAS) Program. JAMA
276: 1555-1562, 1996.
207. Golding, LA, Freydinger, JE, and Fishel, SS. Weight, size, and strength-Unchanged with steroids. Phys Sports Med
2: 39-43, 1974.
208. Gosselink, KL, Grindeland, RE, Roy, RR, Zhong, H, Bigbee, AJ, and Edgerton, VR. Afferent input from rat slow skeletal muscle inhibits bioassayable growth hormone release. J Appl Physiol
88: 142-148, 2000.
209. Gosselink, R, Troosters, T, and Decramer, M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med
153: 976-980, 1996.
210. Gouchie, C and Kimura, D. The relationship between testosterone levels and cognitive ability patterns. Psychoneuroendocrinology
16: 323-334, 1991.
211. Graham, MR, Baker, JS, Evans, P, Kicman, A, Cowan, D, Hullin, D, Thomas, N, and Bavies, B. Physical effect of short-term recombinant human growth hormone administration in abstinent steroid dependency. Horm Res
69: 343-354, 2008.
212. Gray, A, Feldman, HA, Mckinlay, JB, and Longcope, C. Age, disease, and changing sex hormone levels in middle-aged men: Results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab
73: 1016-1025, 1991.
213. Green, GA, Uryasz, FD, Petr, TA, and Bray, CD. NCAA study of substance use and abuse habits of college student-athletes. Clin J Sport Nutr
11: 51-56, 2001.
214. Greendale, GA, Edelstein, S, and Barrett-Connor, E. Endogenous sex steroids and bone mineral density in older women and men: The Rancho Bernardo study. J Bone Miner Res
12: 1833-1843, 1997.
215. Grinspoon, S, Corcoran, C, Lee, K, Burrows, B, Hubbard, J, Katznelson, L, Walsh, M, Guccione, A, Cannan, J, Heller, H, Basgoz, N, and Klibanski, A. Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab
81: 4051-4058, 1996.
216. Grinspoon, S, Corcoran, C, Parlman, K, Costello, M, Rosenthal, D, Anderson, E, Stanley, T, Schoenfeld, D, Burrows, B, Hayden, D, Basgoz, N, and Klibanski, A. Effects of testosterone and progressive resistance training in eugonadal men with aids wasting. A randomized, controlled trial. Ann Intern Med
133: 348-355, 2000.
217. Grinspoon, S, Corcoran, C, Stanley, T, Baaj, A, Basgoz, N, and Klibanski, A. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab
85: 60-65, 2000.
218. Gruber, AJ and Pope, HG. Ephedrine use among 36 female weightlifters. Am J Addict
7: 256-261, 1998.
219. Gruber, AJ and Pope, HG. Psychiatric and medical effects of anabolic-androgenic steroid use in women. Psychother Psychosom
69: 19-26, 2000.
220. Haffner, SM. Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: Epidemiological and clinical correlation. Int J Obes Relat Metab Disord
24(Suppl. 2): S56-S58, 2000.
221. Haffner, SM, Katz, MS, Stern, MP, and Dunn, JF. The relationship of sex hormones to hyperinsulinemia and hyperglycemia. Metabolism
37: 683-688, 1988.
222. Hak, AE, Witteman, JC, De Jong, FH, Geerlings, MI, Hofman, A, and Pols, HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam study. J Clin Endocrinol Metab
87: 3632-3639, 2002.
223. Häkkinen, K and Alen, M. Physiological performance, serum hormones, enzymes and lipids of an elite power athlete during training with and without androgens and during prolonged detraining. A case study. J Sports Med Phys Fitness
26: 92-100, 1986.
224. Haller, CA, Jacob, P, and Benowitz, NL. Enhanced stimulant and metabolic effects of combined ephedrine and caffeine. Clin Pharmacol Ther
75: 259-273, 2004.
225. Hammes, A, Andreassen, TK, Spoelgen, R, Raila, J, Hubner, N, Schulz, H, Metzger, J, Schweigert, FJ, Luppa, PB, Nykjaer, A, and Willnow, TE. Role of endocytosis in cellular uptake of sex steroids. Cell
122: 751-762, 2005.
226. Handelsman, DJ. Clinical review: The rationale for banning human chorionic gonadotropin and estrogen blockers in sport. J Clin Endocrinol Metab
91: 1646-1653, 2006.
227. Hansen, B. New images of a new medicine: Visual evidence for the widespread popularity of therapeutic discoveries in America after 1885. Bull Hist Med
73: 629-678, 1999.
228. Harman, SM, Metter, EJ, Tobin, JD, Pearson, J, and Blackman, MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab
86: 724-731, 2001.
229. Hartgens, F, Van Marken Lichtenbelt, WD, Ebbing, S, Vollaard, N, Rietjens, G, and Kuipers, H. Body composition and anthropometry in bodybuilders: Regional changes due to nandrolone decanoate administration. Int J Sports Med
22: 235-241, 2001.
230. Hartgens, F, van Straaten, H, Fideldij, S, Rietjens, G, Keizer, HA, and Kuipers, H. Misuse of androgenic-anabolic steroids and human deltoid muscle fibers: Differences between polydrug regimens and single drug administration. Eur J Appl Physiol
86: 233-239, 2002.
231. Hausmann, R, Hammer, S, and Betz, P. Performance enhancing drugs (doping agents) and sudden death-A case report and review of the literature. Int J Legal Med
111: 261-264, 1998.
232. Hayashi, AA and Proud, CG. The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. Am J Physiol Endocrinol Metab
292: E1647-E1655, 2007.
233. Healy, ML, Dall, R, Gibney, J, Bassett, E, Ehrnborg, C, Pentecost, C, Rosen, T, Cittadini, A, Baxter, RC, and Sonksen, PH. Toward the development of a test for growth hormone (GH) abuse: A study of extreme physiological ranges of GH-dependent markers in 813 elite athletes in the postcompetition setting. J Clin Endocrinol Metab
90: 641-649, 2005.
234. Hendershott, J. Steroids: Breakfast of champions. Track and Field News
22: 3, 1969.
235. Hengge, UR, Baumann, M, Maleba, R, Brockmeyer, NH, and Goos, M. Oxymetholone promotes weight gain in patients with advanced human immunodeficiency virus (HIV-1) infection. Br J Nutr
75: 129-138, 1996.
236. Herman-Bonert, VS and Melmed, S. Growth hormone. In: The Pituitary
. Melmed, S. ed. Malden, MA: Blackwell Publishing, 2002.
237. Hervey, GR. Are athletes wrong about anabolic steroids? Br J Sports Med
9: 74-77, 1975.
238. Hervey, GR, Hutchinson, I, Knibbs, AV, Burkinshaw, L, Jones, PRM, Norgan, MG, and Levell, MJ. “Anabolic” effects of methandienone in men undergoing athletic training. Lancet
2: 699-702, 1976.
239. Hervey, GR, Knibbs, AV, Burkinshaw, L, Morgan, DB, Jones, PRM, Chettle, DR, and Vartsky, D. Effects of methanedienone on the performance and body composition of men undergoing athletic training. Clin Sci
60: 457-461, 1981.
240. Hier, DB and Crowley, WF Jr. Spatial ability in androgen-deficient men. N Engl J Med
306: 1202-1205, 1982.
241. Higgins, B and Williams, B. Pharmacological management of hypertension. Clin Med
7: 612-616, 2007.
242. Ho, KK, on behalf of the 2007 GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: A statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol
157: 695-700, 2007.
243. Hoberman, J. Testosterone Dreams: Rejuvenation, Aphrodisia, Doping
. Berkeley: University of California Press, 2005.
244. Hoberman, JM and Yesalis, CE. The history of synthetic testosterone. Sci Am
272: 76-81, 1995.
245. Hoff, J, Tjonna, AE, Steinshamn, S, Hoydal, M, Richardson, RS, and Helgerud, J. Maximal strength training of the legs in COPD: A therapy for mechanical inefficiency. Med Sci Sports Exerc
39: 220-226, 2007.
246. Hoffman, JR, Faigenbaum, AD, Ratamess, NA, Ross, R, Kang, J, and Tenenbaum, G. Nutritional and anabolic steroid use in adolescents. Med Sci Sports Exerc
40: 15-24, 2008.
247. Hoffman, JR and Ratamess, NA. Medical issues associated with anabolic steroid use: Are they exaggerated? J Sports Sci Med
5: 182-193, 2006.
248. Hoffman, JR and Ratamess, NA. A Practical Guide to Developing Resistance Training Programs
(2nd ed). Monterey, CA: Coaches Choice/Healthy Learning, 2008.
249. Holmang, A and Bjorntorp, P. The effects of testosterone on insulin sensitivity in male rats. Acta Physiol Scand
146: 505-510, 1992.
250. Holt, RIG and Sonksen, PH. Growth hormone, IGF-I and insulin and their abuse in sport. Br J Pharmacol
154: 1-15, 2008.
251. Hymer, WC, Grindeland, RE, Nindl, BC, and Kraemer, WJ. Growth hormone variants and human exercise. In: The Endocrine System in Sports and Exercise
. Kraemer, WJ and Rogol, AD, eds. Malden, MA: Blackwell Publishing, 2005.
252. Ifudu, O, Paul, H, Mayers, JD, Cohen, LS, Brezsnyak, WF, Herman, AI, Avram, MM, and Friedman, EA. Pervasive failed rehabilitation in center-based maintenance hemodialysis patients. Am J Kidney Dis
23: 394-400, 1994.
253. Irving, LM, Wall, M, Neumark-Sztainer, D, and Story, M. Steroid use among adolescents: Findings from Project EAT. J Adolescent Health
30: 243-252, 2002.
254. Isidori, AM, Giannetta, E, Gianfrilli, D, Greco, EA, Bonifacio, V, Aversa, A, Isidori, A, Fabbri, A, and Lenzi, A. Effects of testosterone on sexual function in men: Results of a meta-analysis. Clin Endocrinol (Oxf)
63: 381-394, 2005.
255. Isidori, AM, Giannetta, E, Greco, EA, Gianfrilli, D, Bonifacio, V, Isidori, A, Lenzi, A, and Fabbri, A. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: A meta-analysis. Clin Endocrinol
63: 280-293, 2005.
256. Jacobs, I, Pasternak, H, and Bell, DG. Effects of ephedrine, caffeine, and their combination on muscular endurance. Med Sci Sports Exerc
35: 987-994, 2003.
257. Jaffee, WB, Trucco, E, Levy, S, and Weiss, RD. Is this urine really negative? A systematic review of tampering methods in urine drug screening and testing. J Subst Abuse Treat
33: 33-42, 2007.
258. Jain, P, Rademaker, AW, and Mcvary, KT. Testosterone supplementation for erectile dysfunction: Results of a meta-analysis [in process citation]. J Urol
164: 371-375, 2000.
259. Jakobsson, J, Ekstrom, L, Inotsume, N, Garle, M, Lorentzon, M, Ohlsson, C, Roh, HK, Carlstrom, R, and Rane, A. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism. J Clin Endocrinol Metab
91: 687-693, 2006.
260. Janowsky, JS, Chavez, B, and Orwoll, E. Sex steroids modify working memory. J Cogn Neurosci
12: 407-414, 2000.
261. Janowsky, JS, Oviatt, SK, and Orwoll, ES. Testosterone influences spatial cognition in older men. Behav Neurosci
108: 325-332, 1994.
262. Jarow, JP and Lipshultz, LI. Anabolic steroid-induced hypogonadotropic hypogonadism. Am J Sports Med
18: 429-431, 1990.
263. Jette, M, Posen, G, and Cardarelli, C. Effects of an exercise programme in a patient undergoing hemodialysis treatment. J Sports Med Phys Fitness
17: 181-186, 1977.
264. Jezova, D, Komadel, L, and Mikulaj, L. Plasma testosterone response to repeated human chorionic gonadotropin administration is increased in trained athletes. Endocrinol Exp
21: 143-147, 1987.
265. Jockenhovel, F, Bullmann, C, Schubert, M, Vogel, E, Reinhardt, W, Reinwein, D, Muller-Wieland, D, and Krone, W. Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men. Metabolism
48: 590-596, 1999.
266. Johansen, KL. Physical functioning and exercise capacity in patients on dialysis. Adv Ren Replace Ther
6: 141-148, 1999.
267. Johansen, KL. The role of nandrolone decanoate in patients with end stage renal disease in the erythropoietin era. Int J Artif Organs
24: 183-185, 2001.
268. Johansen, KL, Chertow, GM, Ng, AV, Mulligan, K, Carey, S, Schoenfeld, PY, and Kent-Braun, JA. Physical activity levels in patients on hemodialysis and healthy sedentary controls. Kidney Int
57: 2564-2570, 2000.
269. Johansen, KL, Mulligan, K, and Schambelan, M. Anabolic effects of nandrolone decanoate in patients receiving dialysis: A randomized controlled trial. JAMA
281: 1275-1281, 1999.
270. Johansen, KL, Painter, PL, Sakkas, GK, Gordon, P, Doyle, J, and Shubert, T. Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: A randomized, controlled trial. J Am Soc Nephrol
17: 2307-2314, 2006.
271. Johansen, KL, Shubert, T, Doyle, J, Soher, B, Sakkas, GK, and Kent-Braun, JA. Muscle atrophy in patients receiving hemodialysis: Effects on muscle strength, muscle quality, and physical function. Kidney Int
63: 291-297, 2003.
272. Johnson, LC, Fisher, G, Silvester, LJ, and Hofheins, CC. Anabolic steroid: Effects on strength, body weight, oxygen uptake and spermatogenesis upon mature males. Med Sci Sports
4: 43-45, 1972.
273. Johnson, LC and O'Shea, JP. Anabolic steroid: Effects on strength development. Science
164: 957-959, 1969.
274. Johnson, MD, Jay, MS, Shoup, B, and Rickert, VI. Anabolic steroid use by male adolescents. Pediatrics
83: 921-924, 1989.
275. Kaiser, FE, Viosca, SP, Morley, JE, Mooradian, AD, Davis, SS, and Korenman, SG. Impotence and aging: Clinical and hormonal factors. J Am Geriatr Soc
36: 511-519, 1988.
276. Kalyani, RR, Gavini, S, and Dobs, AS. Male hypogonadism in systemic disease. Endocrinol Metab Clin North Am
36: 333-348, 2007.
277. Kamalakkannan, G, Petrilli, CM, George, I, LaManca, J, McLaughlin, BT, Shane, E, Mancini, DM, and Maybaum, S. Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure. J Heart Lung Transplant
27: 457-461, 2008.
278. Kamischke, A, Kemper, DE, Castel, MA, Luthke, M, Rolf, C, Behre, HM, Magnussen, H, and Nieschlag, E. Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy. Eur Respir J
11: 41-45, 1998.
279. Kanayama, G, Cohane, GH, Weiss, RD, and Pope, HG. Past anabolic-androgenic steroid use among men admitted for substance abuse treatment: An underrecognized problem? J Clin Psychiatry
64: 156-160, 2003.
280. Kanayama, G, Gruber, AJ, Pope, HG, Borowiecki, JJ, and Hudson, JI. Over-the-counter drug use in gymnasiums: An unrecognized substance abuse problem? Psychother Psychosom
70: 137-140, 2001.
281. Kapoor, D, Goodwin, E, Channer, KS, and Jones, TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol
154: 899-906, 2006.
282. Karakitsos, D, Patrianakos, AP, De Groot, E, Boletis, J, Karabinis, A, Kyriazis, J, Samonis, G, Parthenakis, FI, Vardas, PE, and Daphnis, E. Androgen deficiency and endothelial dysfunction in men with end-stage kidney disease receiving maintenance hemodialysis. Am J Nephrol
26: 536-543, 2006.
283. Karch, SB. Amphetamines. In: Performance-Enhancing Substances in Sport and Exercise
. Bahrke, MS, and Yesalis, CE, eds. Champaign, IL: Human Kinetics, 2002. pp. 257-265.
284. Karila, TA, Karjalainen, JE, Mantysaari, MJ, Viitasalo, MT, and Seppala, TA. Anabolic androgenic steroids produce dose-dependant increase in left ventricular mass in power athletes, and this effect is potentiated by concomitant use of growth hormone. Int J Sports Med
24: 337-343, 2003.
285. Kawada, S, Okuno, M, and Ishii, N. Testosterone causes decrease in the content of skeletal muscle myostatin. Int J Sport Health Sci
4: 44-48, 2006.
286. Kearns, B, Harkness, R, Hobson, V, and Smith, A. Testosterone pellet implantation in the gleding. J Am Vet Med Assoc
C/780: 197-201, 1942.
287. Kemppainen, JA, Lane, MV, Sar, M, and Wilson, EM. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem
267: 968-974, 1992.
288. Kennedy, MC and Lawrence, C. Anabolic steroid abuse and cardiac death. Med J Aust
158: 346-348, 1993.
289. Kenny, AM, Prestwood, KM, Gruman, CA, Fabregas, G, Biskup, B, and Mansoor, G. Effects of transdermal testosterone on lipids and vascular reactivity in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci
57: M460-M465, 2002.
290. Kenny, AM, Prestwood, KM, Gruman, CA, Marcello, KM, and Raisz, LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci
56: M266-M272, 2001.
291. Kicman, AT, Brooks, RV, Collyer, SC, Cowan, DA, Nanjee, MN, Southan, GJ, and Wheeler, MJ. Criteria to indicate testosterone administration. Br J Sports Med
24: 253-264, 1990.
292. Kicman, AT, Brooks, RV, and Cowan, DA. Human chorionic gonadotrophin and sport. Br J Sports Med
25: 73-80, 1991.
293. Kicman, A, Oftebro, H, Walker, C, Norman, N, and Cown, D. Potential use of ketoconazole in a dynamic endocrine test to differentiate between biological outliers and testosterone use by athletes. Clin Chem
39: 1798-1803, 1993.
294. Kierzkowska, B, Stanczyk, J, and Kasprzak, JD. Myocardial infarction in a 17-year-old body builder using clenbuterol. Circ J
69: 1144-1146, 2005.
295. Klotz, F, Garle, M, Granath, F, and Thiblin, I. Criminality among individuals testing positive for the presence of anabolic androgenic steroids. Arch Gen Psychiatry
63: 1274-1279, 2006.
296. Knight, J. Drugs bust reveals athletes' secret steroid. Nature
425: 752, 2003.
297. Knobil, E and Hotchkiss, J. Growth hormone. Ann Rev Physiology
26: 47-74, 1964.
298. Kondro, W. Athletes' “designer steroid” leads to widening scandal. Lancet
362: 1466, 2003.
299. Kopple, JD, Storer, T, and Casburi, R. Impaired exercise capacity and exercise training in maintenance hemodialysis patients. J Ren Nutr
15: 44-48, 2005.
300. Korenman, SG, Morley, JE, Mooradian, AD, Davis, SS, Kaiser, FE, Silver, AJ, Viosca, SP, and Garza, D. Secondary hypogonadism in older men: Its relation to impotence. J Clin Endocrinol Metab
71: 963-969, 1990.
301. Kosaka, A, Takahashi, H, Yajima, Y, Tanaka, M, Okamura, K, Mizumoto, R, and Katsuta, K. Hepatocellular carcinoma associated with anabolic steroid therapy: Report of a case and review of the Japanese literature. J Gastroenterol
31: 450-454, 1996.
302. Kouidi, E, Albani, M, Natsis, K, Megalopoulos, A, Gigis, P, Guiba-Tziampiri, O, Tourkantonis, A, and Deligiannis, A. The effects of exercise training on muscle atrophy in haemodialysis patients. Nephrol Dial Transplant
13: 685-699, 1998.
303. Kouri, EM, Lukas, SE, Pope, HG, and Oliva, PS. Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug Alcohol Depend
40: 73-79, 1995.
304. Kouri, EM, Pope, HG, Katz, DL, and Oliva, P. Fat-free mass index in users and nonusers of anabolic-androgenic steroids. Clin J Sports Med
5: 223-228, 1995.
305. Kraemer, WJ and Ratamess, NA. Fundamentals of resistance training: Progression and exercise prescription. Med Sci Sports Exerc
36: 674-688, 2004.
306. Kraemer, WJ and Ratamess, NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med
35: 339-361, 2005.
307. Kraemer, WJ, Spiering, BA, Volek, JS, Ratamess, NA, Sharman, MJ, Rubin, MR, French, DN, Silvestre, R, Hatfield, DL, Van Heest, JL, Vingren, JL, Judelson, DA, Deschenes, MR, and Maresh, CM. Androgenic responses to resistance exercise: Effects of feeding and L-carnitine. Med Sci Sports Exerc
38: 1288-1296, 2006.
308. Krongrad, A, Wilson, CM, Wilson, JD, Allman, DR, and McPhaul, MJ. Androgen increases androgen receptor protein while decreasing receptor mRNA in LNCaP cells. Mol Cell Endocrinol
76: 79-88, 1991.
309. Kuipers, H, Peeze Binkhorst, FM, Hartgens, F, Wijnen, JAG, and Keizer, HA. Muscle ultrastructure after strength training with placebo or anabolic steroid. Can J Appl Physiol
18: 189-196, 1993.
310. Kuipers, H, Wijnen, JAG, Hartgens, F, and Willems, SM. Influence of anabolic steroids on body composition, blood pressure, lipid profile and liver functions in body builders. Int J Sports Med
12: 413-418, 1991.
311. Kwan, M, Greenleaf, WJ, Mann, J, Crapo, L, and Davidson, JM. The nature of androgen action on male sexuality: A combined laboratory-self-report study on hypogonadal men. J Clin Endocrinol Metab
57: 557-562, 1983.
312. Laghi, F, Antonescu-Turcu, A, Collins, E, Segal, J, Tobin, DE, Jubran, A, and Tobin, MJ. Hypogonadism in men with chronic obstructive pulmonary disease: Prevalence and quality of life. Am J Respir Crit Care Med
171: 728-733, 2005.
313. La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, and Fischbeck, KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature
352: 77-79, 1991.
314. Lambert, CP, Sullivan, DH, Freeling, SA, Lindquist, DM, and Evans, WJ. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: A randomized controlled trial. J Clin Endocrinol Metab
87: 2100-2106, 2002.
315. Landis, J and Ziegenfuss, TN. Hormonal supplements: legal and illegal. In: Essentials of Sports Nutrition and Supplements
. Antonio, J, Kalman, D, Stout, JR, Greenwood, M, Willoughby, DS, and Haff, GG, eds. Totowa, NY: Humana Press, 2008. pp. 541-564.
316. Laughlin, GA, Barrett-Connor, E, and Bergstrom, J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab
93: 68-75, 2008.
317. Lauretani, F, Bandinelli, S, Russo, CR, Maggio, M, Di Iorio, A, Cherubini, A, Maggio, D Ceda, GP, Valenti, G, Guralnik, JM, and Ferrucci, L. Correlates of bone quality in older persons. Bone
39: 915-921, 2006.
318. Leikis, MJ, Mckenna, MJ, Petersen, AC, Kent, AB, Murphy, KT, Leppik, JA, Gong, X, and Mcmahon, LP. Exercise performance falls over time in patients with chronic kidney disease despite maintenance of hemoglobin concentration. Clin J Am Soc Nephrol
1: 488-495, 2006.
319. Leung, DW, Spencer, SA, Cachianes, G, Hammonds, RG, Collins, C, Henzel, WJ, Bernard, R, Waters, MJ, and Wood, WI. Growth hormone receptor and serum binding protein: Purification, cloning and expression. Nature
330: 537-543, 1987.
320. Lewis, UJ, Singh, RN, Bonewald, LF, Lewis, LJ, and Vanderlaan, WP. Human growth hormone: Additional members of the complex. Endocrinology
104: 1256-1265, 1979.
321. Li, CH and Papkoff, H. Preparation and properties of growth hormone from human and monkey pituitary glands. Science
124: 1293-1294, 1956.
322. Lin, MC, Rajfer, J, Swerdloff, RS, and Gonzalez-Cadavid, NF. Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens. J Steroid Biochem Mol Biol
45: 333-343, 1993.
323. Litman, HJ, Bhasin, S O'leary, MP, Link, CL, Mckinlay, JB, and BACH Survey Investigators. An investigation of the relationship between sex-steroid levels and urological symptoms: Results from the Boston area community health survey. BJU Int
100: 321-326, 2007.
324. Liu, H, Bravata, DM, Okin, I, Friedlander, A, Liu, V, Roberts, B, Bendavid, E, Saynina, O, Salpeter, SR, Garber, AM, and Hoffman, AR. Systematic review: The effects of growth hormone on athletic performance. Ann Intern Med
148: 747-758, 2008.
325. Liverman, CT, Blazer, DG, and National Research Council (U.S.); Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. Testosterone and Aging Clinical Research Directions
. National Academies Press: Washington, D.C. Vol 71. 2004. pp. 219.
326. Llewellyn, W. William Llewellyn's Anabolics 2007
(6th ed). Jupiter, FL: Body of Science, 2007.
327. Lloyd, FH, Powell, P, and Murdoch, AP. Anabolic steroid abuse by body builders and male subfertility. BMJ
313: 100-101, 1996.
328. Logothetis, P. Dick Pound Believes Operation Puerto not Limited to Cycling. International Herald Tribune
. November 14, 2007.
329. Loughton, SJ and Ruhling, RO. Human strength and endurance responses to anabolic steroid and training. J Sports Med Phys Fitness
17: 285-296, 1977.
330. Lowrie, EG, Curtin, RB, Lepain, N, and Schatell, D. Medical outcomes study short form-36: A consistent and powerful predictor of morbidity and mortality in dialysis patients. Am J Kidney Dis
41: 1286-1292, 2003.
331. Lu, S, Simon, NG, Wang, Y, and Hu, S. Neural androgen receptor regulation: Effects of androgen and antiandrogen. J Neurobiol
41: 505-512, 1999.
332. Lugg, JA, Rajfer, J, and Gonzalez-Cadavid, NF. Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat. Endocrinology
136: 1495-1501, 1995.
333. Luke, JL, Farb, A, Virmani, R, and Sample, RH. Sudden cardiac death during exercise in a weight lifter using anabolic androgenic steroids: Pathological and toxicological findings. J Forensic Sci
35: 1441-1447, 1990.
334. Lynch, GS. Beta-2 agonists. In: Performance-Enhancing Substances in Sport and Exercise
. Bahrke, MS, and Yesalis, CE, eds. Champaign, IL: Human Kinetics, 2002. pp. 47-64.
335. Ma, L, Chen, Z, Erdjument-Bromage, H, Tempst, P, and Pandolfi, PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell
121: 179-193, 2005.
336. Macadams, MR, White, RH, and Chipps, BE, Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med
104: 648-651, 1986.
337. MacIndoe, JH, Perry, PJ, Yates, WR, Holman, TL, Ellingrod, VL, and Scott, SD. Testosterone suppression of the HPT axis. J Investig Med
45: 441-447, 1997.
338. MacKenzie, SJ, Yarwood, SJ, Peden, AH, Bolger, GB, Vernon, RG, and Houslay, MD. Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. Proc Natl Acad Sci U S A
95: 3549-3554, 1998.
339. Malone, DA Jr, Dimeff, RJ, Lombardo, JA, and Sample, RH. Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sport Med
5: 25-31, 1995.
340. Maravelias, C, Dona, A, Stefanidou, M, and Spiliopoulou, C. Adverse effects of anabolic steroids in athletes. A constant threat. Toxicol Lett
158: 167-175, 2005.
341. Marberger, M, Roehrborn, CG, Marks, LS, Wilson, T, and Rittmaster, RS. Relationship among serum testosterone, sexual function, and response to treatment in men receiving dutasteride for benign prostatic hyperplasia. J Clin Endocrinol Metab
91: 1323-1328, 2006.
342. Margolese, HC. The male menopause and mood: Testosterone decline and depression in the aging male-Is there a link? J Geriatr Psychiatry Neurol
13: 93-101, 2000.
343. Marin, P, Holmang, S, Jonsson, L, Sjostrom, L, Kvist, H, Holm, G, Lindstedt, G, and Bjorntorp, P. The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int J Obes Relat Metab Disord
16: 991-997, 1992.
344. Marin, P, Krotkiewski, M, and Bjorntorp, P. Androgen treatment of middle-aged, obese men: Effects on metabolism, muscle and adipose tissues. Eur J Med
1: 329-336, 1992.
345. Marquis, K, Debigare, R, Lacasse, Y, Leblanc, P, Jobin, J, Carrier, G, and Maltais, F. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med
166: 809-813, 2002.
346. Martikainen, H, Alen, M, Rahkila, P, and Vihko, R. Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogonadism induced by androgenic/anabolic steroids in power athletes. J Steroid Biochem
25: 109-112, 1986.
347. Matsumoto, AM, Paulsen, CA, Hopper, BR, Rebar, RW, and Bremner, WJ. Human chorionic gonadotropin and testicular function: Stimulation of testosterone, testosterone precursors, and sperm production despite high estradiol levels. J Clin Endocrinol Metab
56: 720-728, 1983.
348. McCabe, SE, Bower, KJ, West, BT, Nelson, TF, and Wechsler, H. Trends in non-medical use of anabolic steroids by U.S. college students: Results from four national surveys. Drug Alcohol Depend
90: 243-251, 2007.
349. McCarthy, K, Tang, AT, Dalrymple-Hay, MJ, and Haw, MP. Ventricular thrombosis and systemic embolism in bodybuilders: Etiology and management. Ann Thorac Surg
70: 658-660, 2000.
350. Meikle, AW, Arver, S, Dobs, AS, Adolfsson, J, Sanders, SW, Middleton, RG, Stephenson, RA, Hoover, DR, Rajaram, L, and Mazer, NA. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology
49: 191-196, 1997.
351. Melchert, RB and Welder, AA. Cardiovascular effects of androgenic-anabolic steroids. Med Sci Sports Exerc
27: 1252-1262, 1995.
352. Mellström, D, Johnell, O, Ljunggren, O, Eriksson, AL, Lorentzon, M, Mallmin, H, Holmberg, A, Redlund-Johnell, I, Orwoll, E, and Ohlsson, C. Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MROS Sweden. J Bone Miner Res
21: 529-535, 2006.
353. Melmed, S and Kleinberg, D. Anterior pituitary. In: Williams Textbook of Endocrinology
(11th ed.). H.M. Kronenberg, S. Melmed, K.S. Polonsky, and P.R. Larsen, eds. New York, NY: Elsevier, 2008. pp. 155-261.
354. Melton, LJR, Khosla, S, Crowson, CS, O'connor, MK, O'Fallon, WM, and Riggs, BL. Epidemiology of sarcopenia. J Am Geriatr Soc
48: 625-630, 2000.
355. Menard, CS, and Harlan, RE. Up-regulation of androgen receptor immunoreactivity in the rat brain by androgenic-anabolic steroids. Brain Res
622: 226-236, 1993.
356. Mendel, CM. The free hormone hypothesis: A physiologically based mathematical model. Endocr Rev
10: 232-274, 1989.
357. Midgley, SJ, Heather, N, and Davies, JB. Levels of aggression among a group of anabolic-androgenic steroid users. Med Sci Law
41: 309-314, 2001.
358. Mihailescu, R, Aboul-Enein, HY, and Efstatide, MD. Identification of tamoxifen and metabolites in human male urine by GC/MS. Biomed Chromatogr
14: 180-183, 2000.
359. Miller, KE, Hoffman, JH, Barnes, GM, Sabo, D, Melnick, MJ, and Farrell, MP. Adolescent anabolic steroid use, gender, physical activity, and other problem behaviors. Subst Use Misuse
40: 1637-1657, 2005.
360. Mitchell, GJ. Report to the Commissioner of Baseball of an Independent Investigation into the Illegal Use of Steroids and Other Performance Substances by Players in Major League Baseball 2007
361. Mohr, BA, Bhasin, S, Kupelian, V, Araujo, AB, O'donnell, AB, and Mckinlay, JB. Testosterone, sex hormone-binding globulin, and frailty in older men. J Am Geriatr Soc
55: 548-555, 2007.
362. Moller, N, Copeland, KC, and Nair, KS. Growth hormone effects on protein metabolism. Endocrinol Metab Clin North Am
36: 89-100, 2007.
363. Morley, JE, Kaiser, FE, Perry, HM III, Patrick, P, Morley, PM, Stauber, PM, Vellas, B, Baumgartner, RN, and Garry, PJ. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism
46: 410-413, 1997.
364. Morley, JE, Perry, HM, III, Kaiser, FE, Kraenzle, D, Jensen, J, Houston, K, Mattammal, M, and Perry, HM Jr. Effects of testosterone replacement therapy in old hypogonadal males: A preliminary study. J Am Geriatr Soc
41: 149-152, 1993.
365. Nair, KS, Rizza, RA, O'brien, P, Dhatariya, K, Short, KR, Nehra, A, Vittone, JL, Klee, GG, Basu, A, Basu, R, Cobelli, C, Toffolo, G, Dalla Man, C, Tindall, DJ, Melton, LJ, III, Smith, GE, Khosla, S, and Jensen, MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med
355: 1647-1659, 2006.
366. Nakao A, Sakagami, K, Nakata, Y, Komazawa, K, Amimoto, T, Nakashima, K, Isozaki, H, Takakura, N, and Tanaka, N. Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. J Gastroenterol
35: 557-562, 2000.
367. Nakhla, AM and Rosner, W. Stimulation of prostate cancer growth by androgens and estrogens through the intermediacy of sex hormone-binding globulin. Endocrinology
137: 4126-4129, 1996.
368. National Collegiate Athletic Association (NCAA). NCAA Study of Substance Use Habits of College Student Athletes
. 2001. (http://www.ncaa.org
369. National Science Foundation (NSF). 2003 College Graduates in the U.S. Workforce: A Profile. NSF 06-304. 2005.
370. Naylor, AH, Gardner, D, and Zaichokowsky, L. Drug use patterns among high school athletes and nonathletes. Adolescence
36: 627-639, 2001.
371. Nici, L, Donner, C, Wouters, E, Zuwallack, R, Ambrosino, N, Bourbeau, J, Carone, M, Celli, B, Engelen, M, Fahy, B, Garvey, C, Goldstein, R, Gosselink, R, Lareau, S, Macintyre, N, Maltais, F, Morgan, M, O'Donnell, D, Prefault, C, Reardon, J, Rochester, C, Schols, A, Singh, S, and Troosters, T. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med
173: 1390-1413, 2006.
372. Nieminen, MS, Ramo, MP, Viitasalo, M, Heikkila, P, Karjalainen, J, Mantysaari, M, and Heikkila, J. Serious cardiovascular side effects of large doses of anabolic steroids in weight lifters. Eur Heart J
17: 1576-1583, 1996.
373. Nieschlag, E, Behre, HM, Bouchard, P, Corrales, JJ, Jones, TH, Stalla, GK, Webb, SM, and Wu, FC. Testosterone replacement therapy: Current trends and future directions. Hum Reprod Update
10: 409-419, 2004.
374. Nindl, BC, Hymer, WC, Deaver, DR, and Kraemer, WJ. Growth hormone pulsatility profile characteristics following acute heavy resistance exercise. J Appl Physiol
91: 163-172, 2001.
375. Nitsche, EM and Hiort, O. The molecular basis of androgen insensitivity. Horm Res
54: 327-333, 2000.
376. O'Donnell, AB, Travison, TG, Harris, SS, Tenover, JL, and Mckinlay, JB. Testosterone, dehydroepiandrosterone, and physical performance in older men: Results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab
91: 425-431, 2006.
377. O'Shea, JP. The effects of anabolic steroids on dynamic strength levels in weightlifters. Nutr Rep Int
4: 363-370, 1971.
378. O'Shea, JP. Biochemical evaluation of the effects of stanozolol on adrenal, liver, and muscle function in man. Nutr Rep Int
10: 381-388, 1974.
379. O'Shea, JP and Winkler, W. Biochemical and physical effects of an anabolic steroid in competitive swimmers and weightlifters. Nutr Rep Int
2: 351-362, 1970.
380. Oettel, M. Testosterone metabolism, dose-response relationships and receptor polymorphisms: Selected pharmacological/toxicological considerations on benefits versus risks of testosterone therapy in men. Aging Male
6: 230-256, 2003.
381. Omwancha, J and Brown, TR. Selective androgen receptor modulators: In pursuit of tissue-selective androgens. Curr Opin Invest Drugs
7: 873-881, 2006.
382. Orwoll, E, Lambert, LC, Marshall, LM, Blank, J, Barrett-Connor, E, Cauley, J, Ensrud, K, and Cummings, SR. Endogenous testosterone levels, physical performance, and fall risk in older men. Arch Intern Med
166: 2124-2131, 2006.
383. Page, ST, Amory, JK, Bowman, FD, Anawalt, BD, Matsumoto, AM, Bremner, WJ, and Tenover, JL. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab
90: 1502-1510, 2005.
384. Painter, P, Messer-Rehak, D, Hanson, P, Zimmerman, SW, and Glass, NR. Exercise capacity in hemodialysis, CAPD, and renal transplant patients. Nephron
42: 47-51, 1986.
385. Palmer, BF. Sexual dysfunction in men and women with chronic kidney disease and end-stage kidney disease. Adv Ren Replace Ther
10: 48-60, 2003.
386. Palonek, E, Gottlieb, C, Garle, M, Bjorkhem, I, and Carlstrom, K. Serum and urinary markers of exogenous testosterone administration. J Steroid Biochem Mol Biol
55: 121-127, 1995.
387. Park, J, Park, S, Lho, D, Choo, HP, Chung, B, Yoon, C, Min, H, and Choi, MJ. Drug testing at the 10th Asian games and 24th Seoul Olympic games. J Anal Toxicol
14: 66-72, 1990.
388. Parkinson, AB and Evans, NA. Anabolic androgenic steroids: A survey of 500 users. Med Sci Sports Exerc
38: 644-651, 2006.
389. Parssinen, M, Kujala, U, Vartiainen, E, Sarna, S, and Seppala, T. Increased premature mortality of competitive powerlifters suspected to have used anabolic agents. Int J Sports Med
21: 225-227, 2000.
390. Pavlatos, AM, Fultz, O, Monberg, MJ, and Vootkur, A. Review of oxymetholone: A 17α-alkylated anabolic-androgenic steroid. Clin Ther
23: 789-801, 2001.
391. Payne, AH, Quinn, PG, and Rani, CS. Regulation of microsome cytochrome P-450 enzymes and testosterone production in Leydig cells. Recent Prog Horm Res
41: 153-197, 1985.
392. Payne, JR, Kotwinski, PJ, and Montgomery, HE. Cardiac effects of anabolic steroids. Heart
90: 473-475, 2004.
393. Pelletier, G. Localization of androgen and estrogen receptors in rat and primate tissues. Histol Histopathol
15: 1261-1270, 2000.
394. Perry, HM III, Miller, DK, Patrick, P, and Morley, JE. Testosterone and leptin in older African-American men: Relationship to age, strength, function, and season. Metabolism
49: 1085-1091, 2000.
395. Perry, PJ, Lund, BC, Deninger, MJ, Kutscher, BC, and Schneider, J. Anabolic steroid use in weightlifters and bodybuilders. An Internet survey of drug utilization. Clin J Sport Med
15: 326-330, 2005.
396. Perry, PJ, MacIndoe, JH, Yates, WR, Scott, SD, and Holman, TL. Detection of anabolic steroid administration: Ratio of urinary testosterone to epitestosterone vs the ratio of urinary testosterone to luteinizing hormone. Clin Chem
43: 731-735, 1997.
397. Pertusi, R, Dickerman, RD, and McConathy, WJ. Evaluation of aminotransferases elevations in a bodybuilder using anabolic steroids: Hepatitis or rhabdomyolysis. J Am Osteopath Assoc
101: 391-394, 2001.
398. Petersson, A, Garle, M, Granath, F, and Thiblin, I. Morbidity and mortality in patients testing positively for the presence of anabolic androgenic steroids in connection with receiving medical care. A controlled retrospective cohort study. Drug Alcohol Depend
81: 215-220, 2006.
399. Petersson, A, Garle, M, Holmgren, P, Druid, H, Krantz, P, and Thiblin, I. Toxicological findings and manner of death in autopsied users of anabolic androgenic steroids. Drug Alcohol Depend
81: 241-249, 2006.
400. Phillips, WT, Benton, MJ, Wagner, CL, and Riley, C. The effect of single set resistance training on strength and functional fitness in pulmonary rehabilitation patients. J Cardiopulm Rehabil
26: 330-337, 2006.
401. Pirke, KM and Doerr, P. Age related changes and interrelationships between plasma testosterone, oestradiol and testosterone-binding globulin in normal adult males. Acta Endocrinol (Copenh)
74: 792-800, 1973.
402. Pitteloud, N, Hardin, M, Dwyer, AA, Valassi, E, Yialamas, M, Elahi, D, and Hayes, FJ. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab
90: 2636-2641, 2005.
403. Pitteloud, N, Mootha, VK, Dwyer, AA, Hardin, M, Lee, H, Eriksson, KF, Tripathy, D, Yialamas, M, Groop, L, Elahi, D, and Hayes, FJ. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care
28: 1636-1642, 2005.
404. Pollanen, P, Harkonen, K, Makinen, J, Irjala, K, Saad, F, Hubler, D, Oettel, M, Koskenuo, M, and Huhtaniemi, I. Facts and fictions of andropause: Lessons from the Turku Male Ageing Study. 1st International Congress on Male Health in Vienna, November 2001. pp. 222.
405. Pope, HG Jr and Katz, DL. Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry
51: 28-31, 1990.
406. Pope, HG Jr and Katz, DL. Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry
51: 375-382, 1994.
407. Pope, HG Jr, Kouri, EM, and Hudson, JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: A randomized controlled trial. Arch Gen Psychiatry
57: 133-140; discussion 155-156, 2000.
408. Porcerelli, JH and Sandler, BA. Anabolic-androgenic steroid abuse and psychopathology. Psychiatr Clin North Am
21: 829-833, 1998.
409. Prather, ID, Brown, DE, North, P, and Wilson, JR. Clenbuterol: A substitute for anabolic steroids? Med Sci Sports Exerc
27: 1118-1121, 1995.
411. Pye, M, Quinn AC, and Cobbe, SM. QT interval dispersion: A non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias? Br Heart J
71: 511-514, 1994.
412. Rabkin, JG, Wagner, GJ, Mcelhiney, MC, Rabkin, R, and Lin, SH. Testosterone versus fluoxetine for depression and fatigue in HIV/AIDS: A placebo-controlled trial. J Clin Psychopharmacol
24: 379-385, 2004.
413. Rabkin, JG, Wagner, GJ, and Rabkin, R. Testosterone therapy for human immunodeficiency virus-positive men with and without hypogonadism. J Clin Psychopharmacol
19: 19-27, 1999.
414. Rahman, F and Christian, HC. Non-classical actions of testosterone: An update. Trends Endocrinol Metab
18: 371-378, 2007.
415. Ratamess, NA, Kraemer, WJ, Volek, JS, Maresh, CM, Van Heest, JL, Sharman, MJ, Rubin, MR, French, DN, Vescovi, JD, Silvestre, R, Hatfield, DL, Fleck, SJ, and Deschenes, MR. Effects of heavy resistance exercise volume on post-exercise androgen receptor content in resistance-trained men. J Steroid Biochem Mol Biol
93: 35-42, 2005.
416. Reid, IR. Serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med
106: 639-640, 1987.
417. Reid, IR, Ibbertson, HK, France, JT, and Pybus, J. Plasma testosterone concentrations in asthmatic men treated with glucocorticoids. Br Med J (Clin Res Ed)
291: 574, 1985.
418. Reid, IR, Wattie, DJ, Evans, MC, and Stapleton, JP. Testosterone therapy in glucocorticoid-treated men. Arch Intern Med
156: 1173-1177, 1996.
419. Reiter, E, Bonnet, P, Sente, B, Dombrowicz, D, de Leval, J, Closset, J, and Hennen, G. Growth hormone and prolactin stimulate androgen receptor, insulin-like growth factor-1 (IGF-1) and IGF-1 receptors levels in the prostate of immature rats. Mol Cell Endocrinol
88: 77-87, 1992.
420. Reiter, EO and Rosenfeld, RG. Normal and aberrant growth. In: Williams Textbook of Endocrinology
(11th ed.). Kronenberg, HM, Melmed, S, Polonsky, KS, and Larsen, PR, eds. New York, NY: Elsevier, 2008. pp. 849-968.
421. Richardson, RS. Skeletal muscle dysfunction vs. muscle disuse in patients with COPD. J Appl Physiol
86: 1751-1753, 1999.
422. Ries, AL, Bauldoff, GS, Carlin, BW, Casaburi, R, Emery, CF, Mahler, DA, Make, B, Rochester, CL, Zuwallack, R, and Herrerias, C. Pulmonary rehabilitation: Joint ACCP/AACVPR evidence-based clinical practice guidelines. Chest
131: 4S-42S, 2007.
423. Rietschel, P, Corcoran, C, Stanley, T, Basgoz, N, Klibanski, A, and Grinspoon, S. Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis
31: 1240-1244, 2000.
424. Rogerson, S, Weatherby, RP, Deakin, GB, Meir, RA, Coutts, RA, Zhou, S, and Marshall-Gradisnick, SM. The effect of short-term use of testosterone enanthate on muscular strength and power in healthy young men. J Strength Cond Res
425. Rogol, AD. Sex steroid and growth hormone supplementation to enhance performance in adolescent athletes. Curr Opin Pediatr
12: 382-387, 2000.
426. Rolfe, M, McLeod, LE, Pratt, PF, and Proud, CG. Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem J
388: 973-984, 2005.
427. Roy, AK, Tyagi, RK, Song, CS, Lavrovsky, Y, Ahn, SC, Oh, TS, and Chatterjee, B. Androgen receptor: Structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci
949: 44-57, 2001.
428. Roy, TA, Blackman, MR, Harman, SM, Tobin, JD, Schrager, M, and Metter, EJ. Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men. Am J Physiol Endocrinol Metab
283: E284-E294, 2002.
429. Ruzicka, L and Wettstein, A. Sexualhormone VII. Uber die kunstliche Herstellung des Testikelhormons. Testosteron (Androsten-3-on-17-ol). Helv Chim Acta
18: 1264, 1935.
430. Saez, JM and Forest, MG. Kinetics of human chorionic gonadotropin-induced steroidogenic response of the human testis. I. Plasma testosterone: Implications for human chorionic gonadotropin stimulation test. J Clin Endocrinol Metab
49: 278-283, 1979.
431. Sahraian, MA, Mottamedi, M, Azimi, AR, and Moghimi, B. Androgen-induced cerebral venous sinus thrombosis in a young body builder: Case report. BMC Neurol
4: 22, 2004.
432. Sakiyama, R, Pardridge, WM, and Musto, NA. Influx of testosterone-binding globulin (TeBG) and TeBG-bound sex steroid hormones into rat testis and prostate. J Clin Endocrinol Metab
67: 98-103, 1988.
433. Salehian, B, Jacobson, D, Swerdloff, RS, Grafe, MR, Sinha-Hikim, I, and Mccutchan, JA. Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection. Endocr Pract
5: 1-9, 1999.
434. Samuels, LT, Henschel, AF, and Keys, A. Influence of methyl testosterone on muscular work and creatine metabolism in normal young men. J Clin Endocrinol
2: 649-654, 1942.
435. Saugy, M, Roginson, N, Saudan, C, Baume, N, Avois, L, and Mangin, P. Human growth hormone doping in sport. Br J Sports Med
40: 35-39, 2006.
436. Schaap, LA, Pluijm, SM, Smit, JH, Van Schoor, NM, Visser, M, Gooren, LJ, and Lips, P. The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women. Clin Endocrinol (Oxf)
63: 152-160, 2005.
437. Schanzer, W. Metabolism of anabolic androgenic steroids. Clin Chem
42: 1001-1020, 1996.
438. Schols, AM, Soeters, PB, Mostert, R, Pluymers, RJ, and Wouters, EF. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. Am J Respir Crit Care Med
152: 1268-1274, 1995.
439. Schroeder, ET, Singh, A, Bhasin, S, Storer, TW, Azen, C, Davidson, T, Martinez, C, Sinha-Hikim, I, Jaque, SV, Terk, M, and Sattler, FR. Effects of an oral androgen on muscle and metabolism in older, community-dwelling men. Am J Physiol Endocrinol Metab
284: E120-E128, 2003.
440. Schulze, JJ, Lundmark, J, Garle, M, Skilving, I, Ekstrom, L, and Rane, A. Doping test results dependent on genotype of UGT2B17 uridine diphospho-glucuronosyl transferase 2B17 the major enzyme for testosterone glucuronidation. J Clin Endocrinol Metab
93: 2500-2506, 2008.
441. Scott, DM, Wagner, JC, and Barlow, TW. Anabolic steroid use among adolescents in Nebraska Schools. Am J Health-Syst Pharm
53: 2068-2072, 1996.
442. Segal, S, Narayanan, R, and Dalton, JT. Therapeutic potential of the SARMs: Revisiting the androgen receptor for drug discovery. Expert Opin Investig Drugs
15: 377-387, 2006.
443. Seidman, SN, Araujo, AB, Roose, SP, Devanand, DP, Xie, S, Cooper, TB, and Mckinlay, J. Low testosterone levels in elderly men with dysthymic disorder. Am J Psychiatry
159: 456-459, 2002.
444. Seidman, SN, Araujo, AB, Roose, SP, and Mckinlay, JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry
50: 371-376, 2001.
445. Sekera, MH, Ahrens, BD, Chang, YC, Starcevic, B, Georgakopoulos, C, and Catlin, DH. Another designer steroid: Discovery, synthesis, and detection of ‘madol’ in urine. Rapid Commun Mass Spectrom
19: 781-784, 2005.
446. Shabsigh, R. The effects of testosterone on the cavernous tissue and erectile function. World J Urol
15: 21-26, 1997.
447. Shabsigh, R, Kaufman, JM, Steidle, C, and Padma-Nathan, H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol
172: 658-663, 2004.
448. Sheffield-Moore, M, Urban, RJ, Wolf, SE, Jiang, J, Catlin, DH, Herndon, DN, Wolfe, RR, and Ferrando, AA. Short-term oxandrolone administration stimulates net muscle protein synthesis in young men. J Clin Endocrinol Metab
84: 2705-2711, 1999.
449. Shekelle, PG, Hardy, ML, Morton, SC, Maglione, M, Mojica, WA, Suttorp, MJ, Rhodes, SL, Jungvig, L, and Gagne, J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. JAMA
289: 1537-1545, 2003.
450. Shores, MM, Matsumoto, AM, Sloan, KL, and Kivlahan, DR. Low serum testosterone and mortality in male veterans. Arch Intern Med
166: 1660-1665, 2006.
451. Shores, MM, Moceri, VM, Gruenewald, DA, Brodkin, KI, Matsumoto, AM, and Kivlahan, DR. Low testosterone is associated with decreased function and increased mortality risk: A preliminary study of men in a geriatric rehabilitation unit. J Am Geriatr Soc
52: 2077-2081, 2004.
452. Shute, VJPJ, Hubert, L, and Reynolds, RW. The relationship between androgen levels and human spatial abilities. Bull Psychonomic Soc
21: 465-468, 1983.
453. Sih, R, Morley, JE, Kaiser, FE, Perry, HM III, Patrick, P, and Ross, C. Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J Clin Endocrinol Metab
82: 1661-1667, 1997.
454. Simon, D, Preziosi, P, Barrett-Connor, E, Roger, M, Saint-Paul, M, Nahoul, K, and Papoz, L. The influence of aging on plasma sex hormones in men: The telecom study. Am J Epidemiol
135: 783-791, 1992.
455. Simpson, K, Killian, K, Mccartney, N, Stubbing, DG, and Jones, NL. Randomised controlled trial of weightlifting exercise in patients with chronic airflow limitation. Thorax
47: 70-75, 1992.
456. Singh, AB, Hsia, S, Alaupovic, P, Sinha-Hikim, I, Woodhouse, L, Buchanan, TA, Shen, R, Bross, R, Berman, N, and Bhasin, S. The effects of varying doses of t on insulin sensitivity, plasma lipids, apolipoproteins, and c-reactive protein in healthy young men. J Clin Endocrinol Metab
87: 136-143, 2002.
457. Singh, AB, Norris, K, Modi, N, Sinha-Hikim, I, Shen, R, Davidson, T, and Bhasin, S. Pharmacokinetics of a transdermal testosterone system in men with end stage renal disease receiving maintenance hemodialysis and healthy hypogonadal men. J Clin Endocrinol Metab
86: 2437-2445, 2001.
458. Singh, R, Artaza, JN, Taylor, WE, Braga, M, Yuan, X, Gonzalez-Cadavid, NF, and Bhasin, S. Testosterone inhibits adipogenic differentiation in 3t3-l1 cells: Nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical wnt signaling to down-regulate adipogenic transcription factors. Endocrinology
147: 141-154, 2006.
459. Singh, R, Artaza, JN, Taylor, WE, Gonzalez-Cadavid, NF, and Bhasin, S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in c3h 10t1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology
144: 5081-5088, 2003.
460. Sinha-Hikim, I, Artaza, J, Woodhouse, L, Gonzalez-Cadavid, N, Singh, AB, Lee, MI, Storer, TW, Casaburi, R, Shen, R, and Bhasin, S. Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab
283: E154-E164, 2002.
461. Sinha-Hikim, I, Roth, SM, Lee, MI, and Bhasin, S. Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men. Am J Physiol Endocrinol Metab
285: E197-E205, 2003.
462. Snyder, PJ and Lawrence, DA. Treatment of male hypogonadism with testosterone enanthate. J Clin Endocrinol Metab
51: 1335-1339, 1980.
463. Snyder, PJ, Peachey, H, Berlin, JA, Hannoush, P, Haddad, G, Dlewati, A, Santanna, J, Loh, L, Lenrow, DA, Holmes, JH, Kapoor, SC, Atkinson, LE, and Strom, BL. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab
85: 2670-2677, 2000.
464. Snyder, PJ, Peachey, H, Berlin, JA, Rader, D, Usher, D, Loh, L, Hannoush, P, Dlewati, A, Holmes, JH, Santanna, J, and Strom, BL. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med
111: 255-260, 2001.
465. Snyder, PJ, Peachey, H, Hannoush, P, Berlin, JA, Loh, L, Holmes, JH, Dlewati, A, Staley, J, Santanna, J, Kapoor, SC, Attie, MF, Haddad, JG Jr, and Strom, BL. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab
84: 1966-1972, 1999.
466. Socas, L, Zumbardo, M, Perez-Luzardo, O, Ramos, A, Perez, C, Hernandez, JR, and Boada, LD. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: A report of two cases and a review of the literature. Br J Sports Med
39: e27, 2005.
467. Soe, KL, Soe, M, and Gluud, C. Liver pathology associated with the use of anabolic-androgenic steroids. Liver
12: 73-79, 1992.
468. Soler-Cataluna, JJ, Sanchez-Sanchez, L, Martinez-Garcia, MA, Sanchez, PR, Salcedo, E, and Navarro, M. Mid-arm muscle area is a better predictor of mortality than body mass index in COPD. Chest
128: 2108-2115, 2005.
469. Sotiropoulos, A, Ohanna, M, Kedzia, C, Menon, RK, Kopchick, JJ, Kelly, PA, and Pende, M. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci U S A
103: 7315-7320, 2006.
470. Spiering, BA, Kraemer, WJ, Vingren, JL, Ratamess, NA, Anderson, JM, Armstrong, LE, Nindl, BC, Volek, JS, Hakkinen, K, and Maresh, CM. Elevated endogenous testerone concentrations potentiate muscle androgen receptor responses to resistance exercise. J Steroid Biochem Mol Biol
114: 195-199, 2009.
471. Spurlock, DM, McDaneld, TG, and McIntyre, LM. Changes in skeletal muscle gene expression following clenbuterol administration. BMC Genomics
7: 320, 2006.
472. Srinivas-Shankar, U and Wu, FCW. Drug insight: Testosterone preparations. Nat Clin Pract Urol
3: 653-665, 2006.
473. Stamford, BA and Moffatt, R. Anabolic steroid: Effectiveness as an ergogenic aid to experienced weight trainers. J Sports Med Phys Fitness
14: 191-197, 1974.
474. Starka, L, Epitestosterone. J Steroid Biochem Mol Biol
87: 27-34, 2003.
475. Steele, RE, Didato, F, and Steinetz, BG. Relative important of 5α reduction for the androgenic and LH-inhibiting activities of delta-4-3-ketosteroids. Steroids
29: 331-348, 1977.
476. Steidle, C, Schwartz, S, Jacoby, K, Sebree, T, Smith, T, and Bachand, R. Aa2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab
88: 2673-2681, 2003.
477. Steiner, AZ, Terplan, M, and Pauslon, RJ. Comparison of tamoxifen and clomiphene citrate for ovulation induction: A meta-analysis. Hum Reprod
20: 1511-1515, 2005.
478. Stilger, VG and Yesalis, CE. Anabolic-androgenic steroid use among high school football players. J Community Health
24: 131-145, 1999.
479. Stolt, A, Karila, T, Viitasalo, M, Mantysaari, M, Kujala, UM, and Karjalainen, J. QT interval and QT dispersion in endurance athletes and in power athletes using large doses of anabolic steroids. Am J Cardiol
84: 364-366, 1999.
480. Storer, TW. Exercise in chronic pulmonary disease: Resistance exercise prescription. Med Sci Sports Exerc
33: S680-S692, 2001.
481. Storer, TW, Casaburi, R, Sawelson, S, and Kopple, JD. Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients. Nephrol Dial Transplant
20: 1429-1437, 2005.
482. Storer, TW, Magliano, L, Woodhouse, L, Lee, ML, Dzekov, C, Dzekov, L, Casaburi, R, and Bhasin, S. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab
88: 1478-1485, 2003.
483. Storer, TW, Woodhouse, LJ, Sattler, F, Singh, AB, Schroeder, ET, Beck, K, Padero, M, Mac, P, Yarasheski, KE, Geurts, P, Willemsen, A, Harms, MK, and Bhasin, S. A randomized, placebo-controlled trial of nandrolone decanoate in human immunodeficiency virus-infected men with mild to moderate weight loss with recombinant human growth hormone as active reference treatment. J Clin Endocrinol Metab
90: 4474-4482, 2005.
484. Strauss, RH and Yesalis, CE. Anabolic steroids in the athlete. Annu Rev Med
42: 449-457, 1991.
485. Strawford, A, Barbieri, T, Van Loan, M, Parks, E, Catlin, D, Barton, N, Neese, R, Christiansen, M, King, J, and Hellerstein, MK. Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: A randomized controlled trial. JAMA
281: 1282-1290, 1999.
486. Stromme, SB, Meen, HD, and Aakvaag, A. Effects of an androgenic-anabolic steroid on strength development and plasma testosterone levels in normal males. Med Sci Sports
6: 203-208, 1974.
487. Su, TP, Pagliaro, M, Schmidt, PJ, Pickar, D, Wolkowitz, O, and Rubinow, DR. Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA
269: 2760-2764, 1993.
488. Sullivan, ML, Martinez, CM, Gennis, P, and Gallagher, EJ. The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis
41: 1-15, 1998.
489. Swain, RA, Harsha, DM, Baenziger, J, and Saywell, RM. Do pseudoephedrine or phenylpropanolamine improve maximum oxygen uptake and time to exhaustion? Clin J Sport Med
7: 168-173, 1997.
490. Swallow, EB, Reyes, D, Hopkinson, NS, Man, WD, Porcher, R, Cetti, EJ, Moore, AJ, Moxham, J, and Polkey, MI. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax
62: 115-120, 2007.
491. Takeda, H, Chodak, G, Mutchnik, S, Nakamoto, T, and Chang, C. Immunohistochemical localization of androgen receptors with mono- and polyclonal antibodies to androgen receptor. J Endocrinol
126: 17-25, 1990.
492. Tang, WH. Pharmacologic therapy for acute heart failure. Cardiol Clin
25: 539-551, 2007.
493. Tanner, SM, Miller, DW, and Alongi, C. Anabolic steroid use by adolescents: Prevalence, motives and knowledge of risks. Clin J Sports Med
5: 108-115, 1995.
494. Tattersall, RB. Charles-Edouard Brown-Sequard: Double-hyphenated neurologist and forgotten father of endocrinology. Diabet Med
11: 728-731, 1994.
495. Taylor, WN. Anabolic Steroids and the Athlete
(2nd ed.). Jefferson, NC: McFarland and Company, Inc., 2002.
496. Temple, CM and Sanfilippo, PM. Executive skills in Klinefelter's syndrome. Neuropsychologia
41: 1547-1559, 2003.
497. Tenover, JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab
75: 1092-1098, 1992.
498. Thiblin, I, Lindquist, O, and Rajs, J. Cause and manner of death among users of anabolic androgenic steroids. J Forensic Sci
45: 16-23, 2000.
499. Thiblin, I, Runeson, B, and Rajs, J. Anabolic androgenic steroids and suicide. Ann Clin Psychiatry
11: 223-231, 1999.
500. Todd, T. Anabolic steroids: The gremlins of sport. J Sport Hist
14: 87-107, 1987.
501. Toth, M and Zakar, T. Relative binding affinities of testosterone, 19-nortestosterone and their 5 alpha-reduced derivatives to the androgen receptor and to other androgen-binding proteins: A suggested role of 5 alpha-reductive steroid metabolism in the dissociation of “myotropic” and “androgenic” activities of 19-nortestosterone. J Steroid Biochem
17: 653-660, 1982.
502. Travison, TG, Morley, JE, Araujo, AB, O'donnell, AB, and Mckinlay, JB. The relationship between libido and testosterone levels in aging men. J Clin Endocrinol Metab
91: 2509-2513, 2006.
503. Tricker, R, Casaburi, R, Storer, TW, Clevenger, B, Berman, N, Shirazi, A, and Bhasin, S. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men-A clinical research center study. J Clin Endocrinol Metab
81: 3754-3758, 1996.
504. Tseng, YL, Han, HR, Kuo, FH, Shieh, MH, and Chang, CF. Ephedrines in over-the-counter cold medicines and urine specimens collected during sport competitions. J Anal Toxicol
27: 359-365, 2003.
505. Ungerleider, S. Faust Gold: Inside the East German Doping Machine
. New York, NY: Thomas Dunne Books, 2001.
506. Urban, RJ, Bodenburg, YH, Gilkison, C, Foxworth, J, Coggan, AR, Wolfe, RR, and Ferrando, A. Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis. Am J Physiol
269: E820-E826, 1995.
507. Urhausen, A, Albers, T, and Kindermann, W. Are the cardiac effects of anabolic steroid abuse in strength athletes reversible? Heart
90: 496-501, 2004.
508. Urhausen, A, Torsten, A, and Wilfried, K. Reversibility of the effects on blood cells, lipids, liver function and hormones in former anabolic-androgenic steroid abusers. J Steroid Biochem Mol Biol
84: 369-375, 2003.
509. Uzych, L. Anabolic-androgenic steroids and psychiatric-related effects: A review. Can J Psychiatry
37: 23-28, 1992.
510. Van Den Beld, AW, De Jong, FH, Grobbee, DE, Pols, HA, and Lamberts, SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab
85: 3276-3282, 2000.
511. Van Honk, J, Tuiten, A, Verbaten, R, Van Den Hout, M, Koppeschaar, H, Thijssen, J, and De Haan, E. Correlations among salivary testosterone, mood, and selective attention to threat in humans. Horm Behav
36: 17-24, 1999.
512. Van Marken Lichtenbelt, WD, Hartgens, F, Vollaard, NB, Ebbing, S, and Kuipers, H. Bodybuilders' body composition: Effect of nandrolone decanoate. Med Sci Sports Exerc
36: 484-489, 2004.
513. Van Vliet, M, Spruit, MA, Verleden, G, Kasran, A, Van Herck, E, Pitta, F, Bouillon, R, and Decramer, M. Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
172: 1105-1111, 2005.
514. Vandenberg, P, Neumark-Sztainer, D, Cafri, G, and Wall, M. Steroid use among adolescents: Longitudinal findings from Project EAT. Pediatrics
119: 476-486, 2007.
515. Vicencio, JM, Ibarra, C, Estrada, M, Chiong, M, Soto, D, Parra, V, Diaz-Araya, G, Jaimovich, E, and Lavandero, S. Testosterone induces an intracellular calcium increase by a nongenomic mechanism in cultured rat cardiac myocytes. Endocrinology
147: 1386-1395, 2006.
516. Volek, JS. Strength nutrition. Curr Sports Med Rep
2: 189-193, 2003.
517. Volek, JS. Influence of nutrition on responses to resistance training. Med Sci Sports Exerc
36: 689-696, 2004.
518. Volek, JS, Forsythe, CE, and Kraemer, WJ. Nutritional aspects of women strength athletes. Br J Sports Med
40: 742-748, 2006.
519. Wade, N. Anabolic Steroids: Doctors denounce them, but athletes aren't listening. Science
176: 1399-1403, 1972.
520. Wagman, DF, Curry, LA, and Cook, DL. An investigation into anabolic androgenic steroid use by elite U.S. powerlifters. J Strength Cond Res
9: 149-154, 1995.
521. Wagner, PD. Skeletal muscles in chronic obstructive pulmonary disease: Deconditioning, or myopathy? Respirology
11: 681-686, 2006.
522. Wang, C, Alexander, G, Berman, N, Salehian, B, Davidson, T, Mcdonald, V, Steiner, B, Hull, L, Callegari, C, and Swerdloff, RS. Testosterone replacement therapy improves mood in hypogonadal men-A clinical research center study. J Clin Endocrinol Metab
81: 3578-3583, 1996.
523. Wang, L, Hsu, CL, and Chang, C. Androgen receptor corepressors: An overview. Prostrate
63: 117-130, 2005.
524. Ward, P. The effect of an anabolic steroid on strength and lean body mass. Med Sci Sports
5: 277-282, 1973.
525. Watson, G, Judelson, DA, Armstrong, LE, Yeargin, SW, Casa, DJ, and Maresh, CM. Influence of diuretic-induced dehydration on competitive sprint and power performance. Med Sci Sports Exerc
37: 1168-1174, 2005.
526. Weinbauer, GF, Partsch, CJ, Zitzmann, M, Schlatt, S, and Nieschlag, E. Pharmacokinetics and degree of aromatization rather than total dose of different preparations determine the effects of testosterone: A nonhuman primate study in Macaca fascicularis
. J Androl
24: 765-774, 2003.
527. Weiss, U and Muller, H. On the problem of influencing strength training with anabolic hormones. Schweiz Z Sportsmed
16: 79-89, 1968.
528. Wexler, JA and Sharretts, J. Thyroid and bone. Endocrinol Metab Clin North Am
36: 673-705, 2007.
529. Whitsel, EA, Boyko, EJ, Matsumoto, AM, Anawalt, BD, and Siscovick, DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: A meta-analysis. Am J Med
111: 261-269, 2001.
530. Wiersinga, WM. Thyroid hormone replacement therapy. Horm Res
56(Suppl. 1): 74-81, 2001.
531. Wight, JN Jr and Salem, D. Sudden cardiac death and the ‘athlete's heart'. Arch Intern Med
155: 1473-1480, 1995.
532. Wilson, CM and McPhaul, MJ. A and B forms of the androgen receptor are expressed in a variety of human tissues. Mol Cell Endocrinol
120: 51-57, 1996.
533. Win-May, M and Mya-Tu, M. The effect of anabolic steroids on physical fitness. J Sports Med Phys Fitness
15: 266-271, 1975.
534. Wittert, GA, Chapman, IM, Haren, MT, Mackintosh, S, Coates, P, and Morley, JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci
58: 618-625, 2003.
535. Woodhouse, LJ, Reisz-Porszasz, S, Javanbakht, M, Storer, TW, Lee, M, Zerounian, H, and Bhasin, S. Development of models to predict anabolic response to testosterone administration in healthy young men. Am J Physiol Endocrinol Metab
284: E1009-E1017, 2003.
536. World Anti-Doping Agency. World Anti-Doping Program: Guideline Reporting and Management of Elevated T/E Ratios
. WADA Standards and Harmonization/Science and Research: Montreal, Quebec, Canada. 2006. pp. 9.
538. World Health Organization. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet
336: 955-959, 1990.
539. Yarasheski, KE, Campbell, JA, Smith, K, Rennie, ML, Holloszy, JO, and Bier, DM. Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol
262: E261-E267, 1992.
540. Yarnell, JW, Beswick, AD, Sweetnam, PM, and Riad-Fahmy, D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb
13: 517-520, 1993.
541. Yates, WR, Perry, PJ, MacIndoe, J, Holman, T, and Ellingrod, V. Psychosexual effects of three doses of testosterone cycling in normal men. Biol Psychiatry
45: 254-260, 1999.
542. Yeh, SS, Deguzman, B, and Kramer, T. Reversal of COPD-associated weight loss using the anabolic agent oxandrolone. Chest
122: 421-428, 2002.
543. Yesalis, CE, Courson, SP, and Wright, J. History of anabolic steroid use in sport and exercise. In: Anabolic Steroids in Sport and Exercise
(2nd ed.). C.E. Yesalis, ed. Champaign, IL: Human Kinetics, 2000. pp. 51-71.
544. Yesalis, CE, Kennedy, NJ, Kopstein, AN, and Bahrke, MS. Anabolic-androgenic steroid use in the United States. JAMA
270: 1217-1221, 1993.
545. Zgliczynski, S, Ossowski, M, Slowinska-Srzednicka, J, Brzezinska, A, Zgliczynski, W, Soszynski, P, Chotkowska, E, Srzednicki, M, and Sadowski, Z. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men. Atherosclerosis
121: 35-43, 1996.
546. Zhao, J, Bauman, WA, Huang, R, Caplan, AJ, and Cardozo, C. Oxandrolone blocks glucocorticoid signaling in an androgen receptor-dependent manner. Steroids
69: 357-366, 2004.
547. Zhou, ZX, Lane, MV, Kemppainen, JA, French, FS, and Wilson, EM. Specificity of ligand-dependent androgen receptor stabilization: Receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol
9: 208-218, 1995.
548. Zhou, ZX, Wong, C, Sar, M, and Wilson, EM. The androgen receptor: An overview. Rec Prog Horm Res
49: 249-274, 1994.
549. Zitzmann, M, Faber, S, and Nieschlag, E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab
91: 4335-4343, 2006.
550. Zmuda, JM, Cauley, JA, Kriska, A, Glynn, NW, Gutai, JP, and Kuller, LH. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former multiple risk factor intervention trial participants. Am J Epidemiol
146: 609-617, 1997.
This article has been cited 7 time(s).
Pharmacological ResearchGLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophyPharmacological Research
European Journal of Applied PhysiologySupra-physiological doses of testosterone affect membrane oxidation of human neutrophils monitored by the fluorescent probe C-11-BODIPY581/591European Journal of Applied Physiology
Pediatric AnnalsStrength Training for the Young AthletePediatric Annals
Journal of the International Society of Sports NutritionISSN exercise & sport nutrition review: research & recommendationsJournal of the International Society of Sports Nutrition
Current Sports Medicine ReportsGrowth Hormone, Exercise, and Athletic Performance: A Continued Evolution of ComplexityCurrent Sports Medicine Reports
The Journal of Strength & Conditioning ResearchEffects of a Whole Body Compression Garment on Markers of Recovery After a Heavy Resistance Workout in Men and WomenThe Journal of Strength & Conditioning Research
The Journal of Strength & Conditioning ResearchErratumThe Journal of Strength & Conditioning Research
© 2009 National Strength and Conditioning Association
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read