The term "anabolic steroids" refers to testosterone derivatives that are used either clinically or by athletes for their anabolic properties. However, scientists have questioned the anabolic effects of testosterone and its derivatives in normal men for decades. Most scientists concluded that anabolic steroids do not increase muscle size or strength in people with normal gonadal function and have discounted positive results as unduly influenced by positive expectations of athletes, inferior experimental design, or poor data analysis. There has been a tremendous disconnect between the conviction of athletes that these drugs are effective and the conviction of scientists that they aren’t. In part, this disconnect results from the completely different dose regimens used by scientists to document the correction of deficiency states and by athletes striving to optimize athletic performance. Recently, careful scientific study of suprapharmacologic doses in clinical settings - including aging, human immunodeficiency virus, and other disease states - supports the efficacy of these regimens. However, the mechanism by which these doses act remains unclear. "Anabolism" is defined as any state in which nitrogen is differentially retained in lean body mass, either through stimulation of protein synthesis and/or decreased breakdown of protein anywhere in the body. Testosterone, the main gonadal steroid in males, has marked anabolic effects in addition to its effects on reproduction that are easily observed in developing boys and when hypogonadal men receive testosterone as replacement therapy. However, its efficacy in normal men, as during its use in athletes or in clinical situations in which men are eugonadal, has been debated. A growing literature suggests that use of suprapharmacologic doses can, indeed, be anabolic in certain situations; however, the clear identification of these situations and the mechanism by which anabolic effects occur are unclear. Furthermore, the pharmacology of "anabolism" is in its infancy: no drugs currently available are "purely" anabolic but all possess androgenic properties as well. The present review briefly recapitulates the historic literature about the androgenic/anabolic steroids and describes literature supporting the anabolic activity of these drugs in normal people, focusing on the use of suprapharmacologic doses by athletes and clinicians to achieve anabolic effects in normal humans. We will present the emerging literature that is beginning to explore more specific mechanisms that might mediate the effects of suprapharmacologic regimens. The terms anabolic/androgenic steroids will be used throughout to reflect the combined actions of all drugs that are currently available.
I. Use of Suprapharmacologic Doses of Anabolic/Androgenic Steroids (AAS)
People have been taking testosterone to restore "vitality" since the efficacy of some hormonal component of the testes was first described by Brown-Sequard in 1889. He reported the reversal of his own aging by self-injection of a testicular extract, thereby stimulated a flurry of experimentation into the putative anti-aging effects of testicular hormones long before the identity of testosterone was confirmed. The first use to improve athletic performance occurred shortly thereafter, in 1896. A contemporary of Brown-Sequard self-administered testicular extract, then measured his finger strength. Athletes have been using purified testosterone since it was first available (see a review of this early history in Yesalis et al., 2000). The modern use of anabolic steroids in athletic competition dates from the Olympic competitions during the Cold War era. Russian athletes were putatively the first to use anabolic steroids to improve athletic performance in international competitions. Although the International Olympic Committee banned use of anabolic agents in 1964, the practice spread and probably reached its pinnacle in the athletic programs in Germany during the 1970s (Yesalis et al., 2000). Medical use of testicular extract began in the late 1800s. Clinical use of supraphysiological doses of AAS in eugonadal patients for anabolic benefit started in the 1940s. High-dose AAS regimens have been used to promote muscle deposition after burns, surgery, radiation therapy, and aging-related sarcopenia (muscle wasting). Recent uses include treating wasting in human immunodeficiency virus (HIV) and contraception (Bhasin et al., 1996,1997; Amory and Bremner, 2000).
II. Anabolic Steroids
ll steroids that are anabolic are derivatives of testosterone and are androgenic as well as anabolic, as they stimulate growth and function of male reproductive tract. Individual drugs vary in their balance of anabolic:androgen activity but none of the currently available drugs are purely anabolic. All the anabolic steroids currently used are derivatives of testosterone or are structural modifications of testosterone that influence its pharmacokinetics, bioavailability, or balance of androgenic to anabolic activity. These include testosterone itself, all of the derivatives that are used clinically, as well as numerous plant products that at least claim to possess anabolic actions.
The testosterone derivatives available in the United States comprise several groups: 1) endogenously produced androgens or their precursors, including testosterone and androstenedione; 2) synthetic derivatives of testosterone with altered metabolic or receptor-binding characteristics; and 3) various uncharacterized plant or animal materials. Testosterone actions represent the combination of several activities. First, it binds to the androgen receptor to exert its androgenic activity. Second, it is 5 reduced in some target tissues (including the male urogenital tract, skin, liver, and sebaceous glands) to dihydrotestosterone (DHT), which also acts on the androgen receptor. Finally, it can be aromatized to estradiol and exert estrogenic activities. The latter two actions are highly undesirable in anabolic drugs, 5 reduction because it decreases the ratio of anabolic:androgenic activity and aromatization because of the feminizing side effects.
Structural and pharmacokinetic properties have been reviewed extensively (Wilson, 1988,1996) and are abstracted briefly here.
FIG. 1. Model testosterone structure. [Reprinted with permission from Wilson JD 1998 Androgen abuse by athletes. Endocr Rev 9:181–191. Copyright The Endocrine Society.]
FIG. 2. Structures of several anabolic steroids. [Reprinted with permission from Wilson JD 1998 Androgen abuse by athletes. Endocr Rev 9:181–191. Copyright The Endocrine Society.]
1. Testosterone as an injectable form, a transdermal patch, skin cream, and a micronized oral preparation
2. 17-ß esters of testosterone:testosterone cypionate, propionate, enanthate, and undecanoate. Esterification at this site renders the steroid more fat soluble and delays absorption into the circulation. All but the undecanoate must be injected. Nandrolone 17-ß esters also exist.
3. 17- derivatives (methyltestosterone, methandrostenolone, norethandrolone, fluoxymesterone, danazol, oxandrolone, stanozol). These derivatives resist metabolism in the liver, so are orally active. This modification is associated with significant hepatic toxicities.
4. Modifications of the A, B, or C rings (mesterolone, nortestosterone, methenolone, fluoxymesterone, methandrostenolone, northandrolone, danazol, nandrolone, stanozol). These modifications achieve a number of goals, including a) slow metabolism; b) enhanced affinity for the androgen receptor (19-nortestosterone); c) resistance to aromatization to estradiol (fluoxymesterone, 19 nortestosterone); and d) decreased binding of metabolites to androgen receptor (5 -reduced metabolites of 19-nortestosterone, 7-19- nortestosterone).
Structure:activity modifications that limit either conversion to DHT and/or to estradiol partially target specific testosterone derivatives to specific activities. Agents such as fluoxymesterone and 19-nortestosterone (nandrolone) that resist aromatization lack the feminizing side effects of testosterone. 19-nortestosterone possesses another characteristic that increases its anabolic activity because its 5 -reduced metabolite has poor affinity for the androgen receptor. Similarly, alpha-methyl-19-nortestosterone is not a substrate for 5 reductase (Sundaram et al., 1995).
Finally, a number of "natural products" that are purported to exhibit anabolic qualities are marketed freely in the United States due to the exemption of "natural products" from U.S. Food and Drug Administration regulation. Most of these are steroid precursors. Androstenedione and norandrostenedione are two widely marketed precursors. Marketers claim that they are converted into testosterone and nortestosterone (nandrolone). While a small percentage is, indeed, converted, the total amount produced is likely far below that which would have any anabolic activity in a eugonadal male. Finally, there are undefined mixtures with catchy names like "Horny Goat Weed" and "Testicular Extract" that are derived from both plant and animal materials and contain absolutely unknown ingredients.
All of the drugs listed above possess both anabolic and androgenic activities; none are absolutely selective. However, this ratio varies across a broad range. Table I shows the approximate anabolic:androgenic ratio of a number of clinically used AAS. The range is fairly narrow by clinical standards. All anabolic steroids are virilizing if administered for long enough at high enough doses.
These values are based on data collected in the 1950s and 1960s from bioassays of varying degrees of specificity and accuracy (see excellent historical review in Kochakian, 1976). Typically, the ability of a test drug to stimulate growth of a skeletal muscle and a reproductive target (prostate gland) was assessed. Two classic methods for establishing anabolic efficacy were the stimulation of growth of the levator ani muscle in the castrated rodent and stimulation of whole-body nitrogen retention in a castrated animal. Neither of these are ideal measures. The levator ani muscle may actually reflect androgenic efficacy of AAS because it can be viewed as part of the reproductive system. Its use as a bioassay for "anabolic" activity has been questioned. While the nitrogen-retention assay is better, it provides an extremely indirect measure of muscle deposition. There has been virtually no investigation of the relative anabolic and androgenic properties of AAS since the mid-1970s and none using more modern tools to assess androgen receptor activity. One major goal of this chapter is to summarize recent developments in the molecular pharmacology of androgen receptors that are opening this area up for pharmaceutical development.
In the summer of 1998, baseball player Mark McGwire revealed that he took regular androstenedione supplements during the season that he set a new home run record. The first scientific study of the anabolic efficacy of androstenedione appeared shortly thereafter (King et al., 1999). This study showed that giving modest doses to untrained men who were started on an exercise program increased testosterone only transiently at the higher (i.e., 300-mg) dose but did not improve strength. However, it did increase plasma estradiol levels, a finding that was confirmed in a later study (Leder et al., 2000). That is, this study recapitulated the large number of negative studies in the literature that documented that such combinations of training and AAS were no more effective than training alone. This study has been replicated in older men using a similar design (Broeder et al., 2000). In this case, users took doses recommended by supplement manufacturers while they were engaged in resistance training. The results of both studies were similar: neither younger nor older subjects who received androstenedione showed greater increases in strength than those who received placebo, although circulating lipid profiles changed in the direction of greater cardiovascular risk (low-density to high-density lipoprotein/apolipoprotein A/apolipoprotein B) ratio. Since, at most, 10–15% of a dose is converted to testosterone, it is unlikely that regimens used by athletes will prove anabolic but the research has not been conducted. No published studies report effective anabolic activity of suprapharmacologic doses of androstenedione.
IV. Do Anabolic Steroids Increase Muscle Size and/or Strength in Eugonadal Men?
The anabolic effects of restoring normal physiologic levels of testosterone in hypogonadal men are uncontested. The rise in testosterone during puberty contributes to the increase in linear growth as well as muscle deposition at that time. Increased muscle deposition clearly results when hypogonadal men receive testosterone treatment (Kopera, 1985; Wilson, 1996; Bross et al., 1999). AAS also can be anabolic in men who are hypogonadal as a result of disease such as HIV or after burns (Bhasin et al., 1996,1999).
The anabolic effects of testosterone derivatives in women athletes are similarly explicable, as circulating testosterone levels of women are typically about 10% of those observed in men (Wilson, 1996). Therefore, raising female testosterone levels to those comparable to males provides supraphysiologic levels. Although there are very few published studies of muscle size and strength after AAS use in women, one report found elevations up to 30-fold of normal levels in women who were self-administering AAS (Malarkey et al., 1991). There are virtually no controlled studies of AAS effects on women for obvious ethical reasons but dramatic evidence of these effects derives from the recently released results of the East German sports program of the 1970s and 1980s (Franke and Berendonk, 1997). Figure 3 shows shotput performance of a female German athlete, with the bars below indicating the periods of AAS administration. Unfortunately, women receiving AAS inevitably experience the androgenization associated with these drugs.
FIG. 3. Shot-put performance of woman athlete from East Germany. [Redrawn from Franke WW, Berendonk B 1997 Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clin Chem 43:1262–1279.]
The benefit of anabolic steroid use for eugonadal men is far more controversial.
For decades, scientists argued that anabolic steroids do not increase muscle mass or strength in normal men. This was based first on clinical experience that suggested that the nitrogen-retaining effects of testosterone treatment to normal men were modest and transient (Wilson, 1996). The controversy between those who state that anabolic steroids do not increase muscle mass or strength and those who believe in their effectiveness derives in part from which body of research is cited. Many critics properly cite many negative studies in which addition of testosterone or another AAS to a training regimen failed to improve performance (see reviews in Wilson, 1988; Elashoff et al., 1991; O’Connor and Cicero, 1993; Friedl, 2000). They also critique the poor study design in studies conducted in athletes, including lack of placebo control, nonblinded study conditions, reliance on case studies or small study populations, lack of standardization of dose and training regimen, and the impact that expectation of benefit had on results.
These differences in study design might well play an important part in the different findings. First, nonfit people who are started on a training regimen generally experience such substantial benefit from the training regimen alone that it is difficult to show an additive benefit of AAS. The use of physiologic doses of AAS contributed to this problem. Little benefit of increasing testosterone within the physiologic range has been demonstrated in such studies. Furthermore, the dependent measure chosen to assess muscle strength is critical. Testosterone increases upper body mass differentially, so performance in tasks like weightlifting should improve more than lower-body tasks or tasks in which aerobic capacity rather than strength are assessed. As expected, the task in which increases have been reported most reliably are in the bench press (Friedl, 2000). Finally, the degree of improvement expected in such studies is generally small. Changes in performance of 1–5% are rarely statistically or clinically significant but they represent the margin of victory for elite athletes. Therefore, scientists, clinicians, and athletes all might interpret data from the same study quite differently.
Controversies about anabolic effects of AAS in animals have been similar but less intense. The same factors have entered into the outcome: gender of animals, conducting the study in trained vs. sedentary animals, dose regimen, and duration of exposure. AAS do effectively increase muscle size, protein content, and contractility in both male and female rats (Exner et al., 1973; Menschikowski et al., 1988; Lewis et al., 1999), although negative findings have been reported (Bates et al., 1987). Efficacy of AAS in trained animals has been established (Lubek et al., 1984; Elashoff et al., 1991; Lewis et al., 1999), although different muscle beds respond differentially and slow twitch muscles improve more than fast twitch (Sachs and Leipheimer, 1988; Lewis et al., 1999; Joumaa and Leoty, 2001).
V. Challenging the Conventional Wisdom: AAS Can Increase Muscle Size and Strength in Normal Men
Studies providing suprapharmacologic doses, using maximally trained athletes and testing performance in tasks like weightlifting, are mainly likely to show an effect of AAS. A recent study showing clear, statistically significant increases in muscle mass and strength after AAS administration in a proper placebo-controlled, blinded study may help put these controversies to rest. This complemented previous studies from the same laboratory demonstrating benefit in hypogonadal, HIV-infected men using the same strategy (Bhasin et al., 1996,1999,2001; Strawford et al., 1999).
Biochemical and anatomical studies show that AAS do significantly influence muscle morphology and biochemistry in humans. Body weight reliably increases after AAS use and part of the increase is in lean body mass, although part also reflects retention of water (see recent review in Friedl, 2000). Muscle biopsies in weightlifters reported that both the number of muscle fibers and average fiber size in the trapezius muscle were greater in AAS users than nonusers (Doumit et al., 1996; Kadi et al., 1999a). Controlled studies show that both the number of muscle fibers and the size of individual fibers increase with AAS treatment in animal models (Joubert and Tobin, 1989). Both of these processes depend upon activation of satellite cells within the muscle. Satellite cells contain androgen receptors (Doumit et al., 1996). AAS action within these cells to stimulate proliferation may represent an important mechanism of AAS action. The specific genes that are regulated by androgens in the muscle are unknown. Muscle biopsies in AAS-using powerlifters, in comparison to drug-free powerlifters, showed increased expression of embryonic forms of myosin and the Leu-19 antigen that is expressed in developing myotubes and newly formed myonuclei. This finding supports the hypothesis that AAS trigger both hypertrophy and hyperplasia but does not elucidate the specific genes that are activated (Kadi et al., 1999a,b,2000).
Increases in strength can also result not from hypertrophy or hyperplasia but from increased expression of specific elements of the contractile apparatus. Again, this has been little studied. However, a recent study (Joumaa and Leoty, 2001) began to address this phenomenon by evaluating potassium and caffeine-induced contractures. Both the magnitude of potassium-induced contractures and the rate of recovery were greater in slow-twitch muscles of animals that received training and nandrolone. The authors speculated that these results suggested changes in both the activation mechanism and recovery mechanisms that sequestrate calcium in the sarcoplasmic reticulum. Enhanced caffeine contractures could reflect enhanced calcium release from the sarcoplasmic reticulum or changes in the calcium sensitivity of the contractile proteins.
VI. Mechanism of Anabolic Effect in Eugonadal Men
A. ROLE OF SUPRAPHARMACOLOGIC DOSES
Steroid regimens favored by athletes differ markedly from those used clinically to provide replacement for hypogonadal men. Athletes use suprapharmacologic doses and typically "stack" multiple drugs at total androgen doses that range from 10–100-fold above normal levels (Wilson, 1988). Typically, they take androgens in cycles of weeks, with drug holidays interspersed of weeks or months. Many athletes use "stacking" regimens that involve taking multiple agents simultaneously, and/or a pyramiding dose regimen in which doses are started low, increased, then tapered back down.
A small but expanding literature suggests that suprapharmacologic doses are effective in eugonadal men. The active hormone is probably testosterone, since 5 reductase is not present in muscle (Wilson and Gloyna, 1970). Two older studies (Griggs et al., 1989; Forbes et al., 1992) have been supplemented by several recent findings demonstrating increased lean body mass, muscle protein synthesis, and/or positive nitrogen balance in normal men after high doses of AAS (Bhasin et al., 1996; Ferrando et al., 1998; Sheffield-Moore et al., 1999; Strawford et al., 1999; see also review in Sheffield-Moore, 2000). The most important recent finding is the dose-response study showing that androgenic effects of testosterone saturate at fairly low doses, in contrast to measurable anabolic effects, which require considerably higher doses (Bhasin et al., 1999).
B. ANDROGEN RECEPTOR IN AAS: EFFECTS ON EUGONADAL MEN
The finding that muscle hypertrophy associated with exercise is blocked by androgen antagonists (Inoue et al., 1994) supports a primary role for androgen receptors in exercise-induced muscle hypertrophy. One androgen receptor has been cloned (see review by Lamb et al., 2001) and while its expression varies quantitatively in muscle and reproductive tissues (Sar et al., 1990; Kimura et al., 1993), it is likely that this receptor mediates AAS effects in the muscle. The one study comparing the binding of a range of AAS to skeletal muscle and prostate reported, as expected, that little tissue specificity in binding affinity was observed across a broad range in binding affinities (Saartok et al., 1984). Androgen receptors are present in skeletal muscle of every mammalian species (Sar et al., 1990; Takeda et al., 1990). Levels of expression differ from muscle bed to muscle bed in a manner consistent with reported AAS effects on muscle strength in different tasks. For example, human muscle beds differ from each other, with expression higher in the muscles of the neck and chest girdle, in comparison to the limbs (Kadi et al., 2000).
Recent studies in multiple species show that androgen receptor can be upregulated by exposure to AAS (Bricout et al., 1994; Doumit et al., 1996; Sheffield-Moore et al., 1999; Kadi et al., 2000). The induction reported in humans (Sheffield-Moore et al., 1999) suggests that suprapharmacologic concentrations might be effective because they increase the population of androgen receptors upon which they can act. These findings suggest at least one potential mechanism by which high doses could elicit different effects than physiologic doses.
In summary, two aspects of androgen receptor expression can influence the magnitude of anabolic effects: variations from muscle bed to muscle bed in androgen receptor expression and induction of androgen receptor expression after treatment with AAS. These are shown schematically in Figure 4.
FIG. 4. Model cell containing nucleus with few (top) or more (bottom) androgen receptors. Top represents head and neck muscle relative to leg or normal individual compared to AAS-treated individual.
Recent insights into the organization of the steroid hormone receptor:DNA complex suggest an alternative explanation for the varying anabolic:androgenic ratio of AAS. Steroid hormone receptors form a "tripartite" complex between ligand, receptor, and effector that can have varying actions (Katzenellenbogen et al., 1996). When steroid hormones or their analogues bind to their receptor, they form a complex that binds to DNA. However, the receptor:DNA complex also binds a group of adaptor proteins that influence the transcriptional consequences of receptor binding to DNA. These proteins function as coactivators or co-repressors to enhance or prevent activation of transcription by the receptor (Torchia et al., 1998). Each drug that binds steroid hormone receptor induces a particular "shape" in the drug:receptor complex that permits a unique pattern of adapter protein association. The adapter proteins that associate influence the consequence of drug:receptor binding on transcription (Darimont et al., 1998). Selectivity can derive from the drug, the receptor, or the pattern of adaptor protein expression. This model has been exploited successfully in the development of tissue-selective estrogenic compounds. Different estrogenic compounds have specific actions, depending upon the coactivator and/or co-repressor environment (see McDonnell et al., this volume). A recent commentary (Negro-Vilar, 1999) suggests that a similar approach could be considered for androgens. Up to six different coactivators that are relatively specific for the androgen receptor have been described in the literature (Yeh and Chang, 1996; Fujimoto et al., 1999; Kang et al., 1999; Muller et al., 2000). Although tissue distribution is incompletely described, all are expressed in testis and prostate with widely varying levels of expression in other androgen target tissues. One, FHL2, is expressed highly in heart, slightly in prostate, but not elsewhere (Muller et al., 2000). This coactivator is the first described that is expressed more highly in a nonreproductive tissue than in reproductive tissues. Its existence suggests that tissue-specific distribution of coactivators could theoretically contribute to the ability of different AAS agonists to vary in their ratio of actions in different tissues due to the different tissue distribution of coactivators or co-repressors. Information from a different source supports the possibility that different agonists do induce different conformations of the drug:receptor complex. An NH2-terminal and carboxyl-terminal interaction of the androgen receptor occurs in the presence of agonist binding (Langley et al., 1995). In a co-transfection system, this interaction parallels agonist activity to a degree but weak agonists like medroxyprogesterone possess agonist activity in the absence of this interaction (Kemppainen et al., 1999). However, the study of androgen receptor interactions of this type is in its infancy. It suggests that nonselective steroids like testosterone might occupy the androgen receptor in a way that produces a receptor conformation that permits binding of both general and tissue-selective co-activators (Figure 5). Model drugs with selective actions would results in a ligand:receptor conformation that permitted association only of one set of tissue-selective ligands (Figure 6).
FIG. 5. Model of testosterone activation of androgen receptor (showing just one of the two ligand:receptor dimers that bind to DNA and activate transcription). HRE = hormone response element.
FIG. 6. Hypothetical ligand-occupied androgen receptor conformations that would allow an agonist to recruit coactivators in a tissue-specific way.
C. ANTICATABOLIC EFFECTS OF ANDROGENS
There is also evidence to support a role for anticatabolic mechanisms in the anabolic effects of suprapharmacologic AAS regimens. A recent case report of two patients with a point mutation in the androgen receptor that rendered it inactive showed that a suprapharmacologic steroid regimen was anabolic in both individuals (Tincello et al., 1997). Evidence from animal models also supports this possibility. These begin with binding studies that show that androgens can bind, albeit at low affinity, to glucocorticoid receptors (Danheive and Rousseau, 1986,1988). Such low-affinity binding would not be effective, unless extremely high doses of AAS were present. More directly, testosterone can block glucocorticoid-mediated induction of tyrosine amino transferase in liver just like the glucocorticoid antagonist RU486 (Danhaive and Rousseau 1986,1988). However, androgen blockade of glucocorticoid-induced muscle wasting is not observed consistently (see review by Hickson et al., 1990). Furthermore, in healthy young men as well as in burn patients, the anabolic steroid oxandrolone has been shown to increase net protein synthesis without slowing protein degradation (Sheffield-Moore et al., 1999; Hart et al., 2001). Therefore, the specific contribution of glucocorticoid antagonism in AAS-induced anabolic effects has not been demonstrated unequivocally.
D. COMPLEMENTARY EFFECTS ON GROWTH HORMONE SECRETION AND INSULIN-LIKE GROWTH FACTOR-1 PRODUCTION
The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is thought to contribute to the anabolic effects of testosterone, both through androgen-induced stimulation of GH secretion and direct stimulation of hepatic production of IGF-1 (Rosenfeld et al., 1994; Veldhuis and Iranmanesh, 1996). IGF-1 can stimulate skeletal muscle formation (Florini et al., 1991). Increases in IGF mRNA have been reported in rats following nandrolone administration and increases in both IGF mRNA and circulating IGF-1 occur in men after testosterone treatment (Urban et al., 1995; Gayan-Ramirez et al., 2000) and decreases in mRNA occur when gonadal function is suppressed (Mauras et al., 1998). However, none of these studies measured IGF-1 directly or established the relationship between IGF-1 and anabolic effects of the drugs.
E. COMPLEMENTARY EFFECTS OF TRAINING AND AAS
One of the challenges involved in understanding the effects of AAS in normal athletes is that many of the endpoints (e.g., muscle size, strength) are enhanced by training. Most studies of AAS action involve administration of AAS to sedentary animals, which presents a clear picture of what isolated AAS administration can achieve. Furthermore, comparing the benefits of beginning an exercise regimen and/or AAS in an unfit person provides a model for potential treatment of patient populations such as patients with HIV or the elderly. It does not replicate the environment in which AAS are most often used, which is in a highly trained athlete who is adding AAS to a rigorous exercise regimen. Clearly, exercise increases muscle mass on its own. The prospective, placebo-controlled testosterone trial in eugonadal men by Bhasin and colleagues (1996) that compared placebo, testosterone, exercise, or exercise plus testosterone showed clearly that effects of testosterone and resistance exercise were additive. Another recent study suggests a possible mechanism by which AAS use and exercise might complement each other. Resistance exercise itself increases androgen receptor mRNA and/or binding in both rodent and human muscle (Deschenes et al., 1994; Bamman et al., 2001). If androgen receptor number is induced in muscle by exercise, then more binding sites become available.
F. ROLE OF THE CENTRAL NERVOUS SYSTEM IN AAS EFFECTS ON STRENGTH
An increased sense of energy and wellbeing is one of the earliest and most frequently documented effects in hypogonadal men. It has been suggested that effects within the central nervous system (CNS) contribute to AAS effects on strength because AAS users feel more energetic and therefore train harder. Case reports, cross-sectional studies, and prospective, longitudinal studies show that AAS use by athletes can be accompanied by increased feelings of energy, aggressiveness, and elevated mood (Bahrke and Yesalis, 1996; Rubinow and Schmidt, 1996; Pope et al., 2000). Effects of AAS typically focus on negative reports of psychotic symptoms and criminal aggressive behavior (Pope et al., 1988,2000; Uzych, 1992; Porcerelli and Sandler, 1998). However, two studies of high-dose androgen administration to normal volunteers reported increases in euphoria, energy, and sexual arousal, as well as several negative mood characteristics, including irritability, mood swings, violent feelings, and hostility (Hannan et al., 1991; Su et al., 1993). However, administration of supraphysiologic levels of testosterone did not change aggression as assessed with the Multi-Dimensional Anger Inventory in normal, eugonadal men (Tricker et al., 1996). These few laboratory studies do not provide definitive answers to this question because they utilize controlled dosing of testosterone (although in the supraphysiologic range), employ a variety of methods for measuring aggression/hostility, and use as subjects eugonadal men in laboratory settings rather than athletes in highly competitive settings who are self-administering even-higher doses of steroids. However, the frequency of case reports of extreme behaviors and positive findings in controlled studies suggest that AAS might influence strength through effects on behavior.
The mechanism by which the psychological effects of androgens occur is unknown. A study of cerebrospinal fluid (CSF) monoamine levels in a controlled study of high-dose methyltestosterone administration reported that levels of the serotonin metabolite 5HIAA were higher and levels of the norepinephrine metabolite MHPG were lower after methyltestosterone treatment. 5HIAA levels correlated negatively in subjects who experienced more negative mood symptoms (e.g., irritability, hostility) and higher 5HIAA in subjects who experienced increased mood symptoms such as euphoria (Daly et al., 2001). The latter findings are consistent with a broad literature supporting an association between low serotonin and aggression/irritability/hostility (Lucki, 1998; Oquendo and Mann, 2000). Another study showed increases in aggression that correlated with changes in CSF dopamine metabolites (Hannan et al., 1991).
Testosterone influences brain function by three mechanisms. It contributes to the differentiation of brain areas that regulate regulation of reproductive hormone secretion, sexual behavior, as well nonreproductive behaviors, including aggression (reviewed by Rubinow and Schmidt, 1996). While these organizational effects establish the anatomical basis for sex-specific behavior patterns, they do not contribute to the acute effects of AAS. Androgens also influence many neural functions through both classical genomic effects and rapid membrane effects. Androgen receptors are distributed (Simerly et al., 1990; Pelletier, 2000) and likely have similar distributions in humans. AAS administration - at least in animal models - can increase androgen receptor number in some brain areas, just as it does in muscle (Lynch and Story, 2000). Effects on many neurotransmitter-specific proteins, including serotonin receptors, choline acetyltransferase, the rate-limiting synthetic enzyme for acetylcholine, and monoamine oxidase have been described (see review in Rubinow and Schmidt, 1996). These likely reflect changes in transcriptional activity but effects of suprapharmacologic doses are virtually unexplored.
Rapid membrane effects also may contribute to behavioral effects of AAS. Suprapharmacologic doses of AAS influence GABA receptor function acutely, over a timeframe that likely reflects rapid membrane rather than genomic effects. In some brain areas and model systems, AAS decrease GABA receptor function, while in others it increases it (Masonis and McCarthy, 1996; Jorge-Rivera et al., 2000). Rapid changes in GABA function theoretically could contribute to disinhibition of behavior and changes in arousal like those reported in AAS users. A single recent report (Schlussman et al., 2000) showed nandrolone caused increases in corticotropin (ACTH) and corticosterone secretion acutely as well as protracted effects that were the reverse 24 hours later. This finding indicates that AAS influences at least one neuronal system related to stress and arousal exhibits through what may be both rapid and genomic effects.
Unfortunately, the question remains: do the behavioral effects of AAS influence training intensity and, therefore, muscle strength? Furthermore, although speculations abound that AAS improve neuromuscular function, this hypothesis has not been tested either.
The issue of AAS "dependence" reflects another widely publicized notion based on a small amount of data. Although not directly related to anabolic effects of AAS, a brief discussion is provided because this issue features prominently in discussion of AAS effects on behavior. Several studies report incidence of steroid "dependence" as reflected by psychological symptoms, including depressed mood, fatigue, anorexia, insomnia, restlessness, muscle and joint pain, depression, and desire to take more AAS when athletes stop using (Uzych, 1992; Bahrke and Yesalis, 1996). These reports - and the public perception that AAS use represented a public health crisis - led to the labeling of AAS as "addictive" drugs that were then scheduled by the Drug Enforcement Agency.
There are no clear data supporting the "addictiveness" of AAS use. This may reflect a lack of information or the fact that these drugs are not "addictive" in a neurobiologic sense. "Addictive drugs" must 1) be self-administered by humans and animals, 2) produce positive subjective effects, and 3) produce tolerance and dependence, manifested as a withdrawal syndrome when use stops. Other addictive drugs elicit positive subjective effects by activating the "reward" system in the brain, adaptation of which is thought to produce the gradual dysregulation of drug use (Wise, 1998). In a classical sense, anabolic steroids do not activate the reward system. They are not self-administered by animals and people cannot discriminate an injection of testosterone from placebo (see review in Lukas, 1996). It is impossible to conduct double-blind, placebo-controlled studies of long-term testosterone treatment on mood because users can usually recognize the active drug from the side effects. However, few AAS users fulfill psychiatric criteria for drug dependence (Lukas, 1996).
Nevertheless, some AAS users report positive feelings when they are taking drug and changes in mood when they stop (Su et al., 1993; Lukas 1996). How does one reconcile the clinical reports with the laboratory studies? Genomic effects of AAS are delayed rather than immediate, so they would not be detected in any of the standard models of drug taking. It is possible that AAS do affect reward systems in the brain but in a delayed manner, as would be expected from a gonadal steroid, and so these effects have not been detected. Occasional reports of AAS effects on aspects of dopaminergic transmission, including upregulation of D1 receptors and increases in dopamine turnover, suggest that further exploration of this possibility is warranted (Thiblin et al., 1999; Kindlundh et al., 2001).
VI. Other Consequences of Suprapharmacologic AAS Regimens
Androgen receptors are distributed throughout the body. Androgens affect behavior, cardiovascular function, reproduction, and other endocrine functions. Since anabolic actions are not easily dissociated pharmacologically from the other actions of testosterone derivatives, anabolic steroid use by athletes and patients inevitably is accompanied by unwanted side effects that result from the many actions of androgens in the body. During a typical high-dose paradigm, additional AAS effects occur, including 1) feedback inhibition of reproductive function, including decreased production of testosterone and sperm; 2) acne, due to stimulation of sebaceous glands in the skin; and 3) male-pattern hair distribution (Wilson, 1988). In addition, multiple effects on the cardiovascular system occur, including increased blood pressure, change in the ratio of blood lipids (decrease in HDL:LDL ratio), increased blood clotting, increased production of red blood cells, and left ventricular hypertrophy and subsequent decreased left ventricular function (Sullivan et al., 1998). Extended discussion of potential mechanisms for these effects is beyond the scope of this review. However, the regular occurrence of these additional effects contradicts the common argument that AAS cannot be anabolic because androgen receptors are completely saturated at physiologic levels of androgen. The impact of these other systemic effects on the anabolic effects of AAS is unknown. Although increased production of red blood cells should theoretically improve oxygen-carrying capacity of the blood, and so the ability to do sustained work, these effects have not been documented in eugonadal men. One final note about the use of AAS for their anabolic properties: when used in women, they produce a consistent pattern of virilizing side effects that are predictable, severe, and, in some cases, irreversible. The first published study (Strauss et al., 1985) reported physical changes in the majority of a small group of AAS-using female athletes, including deepening of the voice, clitoral hypertrophy, menstrual irregularities, decreased body fat, and increased facial hair. Behavioral changes included increased libido, aggressiveness, and appetite. About half reported additional changes, including acne, breast size, and body hair distribution. A more recent study (Malarkey et al., 1991) reported a 39% fall in HDL lipoprotein. All of these effects were reported more recently (Gruber and Pope, 2000) in a study involving a larger group. Some of these effects (e.g., deepening of the voice, clitoral hypertrophy) represent irreversible virilization, while others (e.g., reproductive effects, acne, blood lipids) are reversible. The consistency of these findings argues strongly that clinical trials for AAS use for anabolic purposes, as in burn patients, be conducted with great caution because there is no clinically available AAS that lacks androgenizing effects in women.
Studies in AAS-using human subjects as well as experimental model systems have refuted the decades-old assertion that suprapharmacologic dose regimens of AAS are not anabolic in normal men or are only anabolic due to the impact of their CNS effects on motivation to train. The physiopathology of suprapharmacologic doses of AAS is clearly demonstrated and predicted by the beneficial effects on the same systems when AAS are used in hypogonadal men. However, there has been surprisingly little work on the mechanism by which these suprapharmacologic doses exert their actions or on pharmacologic strategies to distinguish beneficial (anabolic) effects from pathologic side effects on brain and heart. The recent demonstration of clinical benefits of suprapharmacologic regimens (Bhasin et al., 1996,1997,1999,2001) suggests that such developments could be clinically beneficial. A recent review proposed the potential value of exploring the possible tissue specificity of protein regulators of androgen receptor function, comparable to those which have been exploited so successfully in the development of selective estrogen receptor modulators (Negro-Vilar, 1999).
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