Pharmacology of Anabolic Steroids
The mechanism of action of anabolic steroids is not fully understood
Determining the mechanisms underlying the strength-enhancing effects of anabolic steroids has proven to be a challenge. We will consider this issue specifically with respect to testosterone, as all anabolic steroid preparations either contain testosterone itself or are testosterone derivatives. Testosterone and other androgens are agonists at the androgen receptor. These receptors are present in many different tissues, including skeletal muscle. In the inactive state, androgen receptors are located in the cytoplasm of the cell.
Androgen molecules diffuse across the cell membrane and bind to the receptor, thereby activating it. The activated hormone-receptor complex then translocates into the cell nucleus, where it regulates the transcription of specific genes, depending on the cell type. Researchers haven’t yet identified the specific muscle cell genes that are “turned on” by androgens, but the overall effect is to increase protein synthesis and growth of the muscle.
The actions of testosterone are complicated by the fact that this substance is converted enzymatically to two other bioactive hormones within the body. In some tissues, an enzyme called 5a-reductase converts testosterone to dihydrotestosterone (DHT), which also has potent androgenic effects. This conversion does not occur in skeletal muscle, which has little or no 5a-reductase activity. In fact, some synthetic anabolic steroids were designed to avoid this metabolic reaction because it decreases the ratio of anabolic to androgenic activity. A second enzyme, aromatase, converts testosterone to the female sex hormone estradiol in a chemical reaction called aromatization. Aromatization is a normal process, even in males, and it plays a vital role in some of testosterone’s actions within the CNS. In the present circumstance, however, aromatization is extremely undesirable because it leads to the feminizing side effects of steroid use. Again, some of the synthetic anabolic steroids were created to resist aromatization and thus minimize these particular side effects.
As suggested in the preceding discussion, the muscle-building effects of anabolic steroids are believed to be mediated at least partly by activation of androgen receptors. However, at least for men, this hypothesis has been questioned based on the idea that these receptors may be saturated (that is, completely filled) at normal physiological levels of testosterone. If this is true and the androgen receptors are already maximally activated, then how can raising the amount of circulating steroids produce a change in the muscle? We don’t yet know the answer to this question, but there is recent evidence that anabolic steroid treatment can induce androgen receptor expression in muscle (Sheffield-Moore et al, 1999).
Increasing the number of androgen receptors in the tissue would allow steroids to produce greater anabolic effects than they would in the presence of normal receptor expression. Another possibility stems from the fact that at high levels, androgens act as antagonists to glucocorticoid hormones. In muscle, glucocorticoids are catabolic, which means that they tend to produce an overall decrease in protein synthesis and an increase in protein breakdown. Hence, a second mechanism of action for anabolic steroids could be their anticatabolic effects via glucocorticoid antagonism. Further studies are needed to investigate these and other hypotheses of anabolic steroid action.
Many adverse side effects are associated with anabolic steroid use
Table 15.3 presents some of the potential adverse side effects of anabolic steroid use. Some of these effects are relatively common (for example, acne), whereas others are rare (peliosis hepatis). Many side effects, such as those involving the cardiovascular system, are reversible if the person stops using steroids. Others, however, can be irreversible, like the masculinizing effects that occur in women. Which side effects occur depends on a number of factors, including the age and sex of the user, the type of steroid used (especially oral vs. injectable), the dose, and the pattern and duration of use. As mentioned in the table, liver toxicity is mainly associated with oral steroids, but other side effects can occur with either oral or injectable forms. The documented decrease in high-density lipoprotein (HDL) cholesterol is noteworthy because it puts the user at increased risk for heart disease. Young people who are still growing also need to be concerned about the possible stunting effects of anabolic steroids produced by premature closure of the epiphyses.
The behavioral effects of anabolic steroids have been a matter of considerable debate over the years. This debate has focused mainly on two issues: (1) whether anabolic steroids cause increased irritability and aggressive behavior; and (2) whether users develop dependence on these compounds. We will focus on the first question here and take up the issue of dependence in the next section.
A variety of different approaches have been used to investigate the effects of anabolic steroids on mood and aggressiveness (Bahrke et al., 1996). Many surveys and retrospective studies seem to indicate an association between anabolic steroid use and increased irritability and aggressive behavior. Numerous case studies have also been reported in which men who were not previously aggressive or violent began to show such characteristics while on steroids. This phenomenon, which is called “’roid rage” on the street.
Controlled studies of anger or aggressive behavior in response to anabolic steroids have yielded less consistent results, with some studies finding that steroids have significant effects on mood or aggressive behavior but other studies reporting no such effects (Bahrke et al., 1996). Some of this inconsistency may be due to differing treatment regimens or methods for assessing aggressiveness. However, another important factor emerged from the recent double-blind, placebo-controlled study of Pope et al. (2000). Despite the fact that testosterone administration led to significant overall increases in manic symptoms and aggressive behavior, these effects were highly variable across subjects. Thus, 84% of the subjects exhibited little mood change in response to the treatment, 12% developed mild symptoms of mania, and just 4% showed strong manic symptoms. These findings suggest that some people are more susceptible than others to developing mood shifts and behavioral changes in response to anabolic steroid use. Such differential susceptibility could also explain why ’roid rage only occurs in a small subset of steroid users.
TABLE 1 Possible Health Consequences of Anabolic Steroid Use
|Cardiovascular effects||Hypertension (high blood pressure)Increased blood clotting
Increased red blood cells
Decreased HDL cholesterol (the “good” kind of cholesterol)
|Effects on the liver (particularly||Jaundice|
|from oral steroid use)||Peliosis hepatis (blood-filled cysts in the liver) Tumors|
|Effects on the skin and hair||Oily skin and scalpSevere acne
Male pattern baldness
|Growth effects||Growth stunting in adolescents due to premature epiphyseal closure|
|Behavioral effects||Increased libido (sex drive)Increased irritability and aggressiveness Dependence|
|Specific effects on men||Testicular shrinkageReduced sperm counts and possible infertility Prostate enlargement Gynecomastia (breast development)|
|Specific effects on women||Menstrual abnormalitiesDeepening of the voice
Excessive hair growth, especially on the face
Enlargement of the clitoris
Decreased breast size
Do anabolic steroids cause dependence?
By the late 1980s and early 1990s, reports began to appear suggesting that some anabolic steroid users meet DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for dependence on these substances. A recent review of this literature, which includes individual case reports, case series, and surveys, found a total of 165 published instances of presumed steroid dependence (Brower, 2002). According to survey studies (Brower et al, 1991; Midgley et al., 1999), some of the commonly reported signs of dependence using the standard DSM criteria are:
1. Withdrawal symptoms when use of the substance (steroid) is stopped
2. Taking more of the substance than originally intended
3. Inability to cut down or control usage despite a desire to do so
4. Spending a large amount of time on activities related to obtaining and using the substance
5. Continued substance use despite problems caused by such use
6. Replacement of other activities with substance use
Withdrawal symptoms can include fatigue, depressed mood, insomnia, restlessness, anorexia, decreased libido, dissatisfaction with body image, and a desire for more steroids (Brower et al., 1990, 1991). Evaluation of anabolic steroid dependence is hampered by an absence of large-scale controlled studies that would enable us to gauge the prevalence of the problem. There is no indication in the literature that a lot of steroid users are presenting themselves for psychiatric treatment. This could mean that severe dependence on anabolic steroids is a relatively rare phenomenon, but it is also possible that dependent steroid users are reluctant to seek treatment for various reasons.
Information on the potential abuse liability of testosterone has also been obtained from studies in laboratory animals. To our knowledge, there are no published reports of self-administration by animals of testosterone or any other anabolic steroid. On the other hand, systemic injections of testosterone or one of its biologically active metabolites have been shown to produce a conditioned place preference in male rats (Alexander et al., 1994; Frye et al., 2001). Because the cellular events triggered by steroid hormone receptors occur much more slowly than the rapid events triggered by neurotransmitter receptors (that is, altered gene transcription vs. ion channel opening or second-messenger synthesis), it is possible that place-conditioning procedures are better suited than self-administration methods for demonstrating the rewarding effects of anabolic steroids.
Further investigation demonstrated that place conditioning could be established with injections of testosterone or its metabolites directly into the nucleus accumbens, a brain area strongly associated with drug (particularly psychostimulant) reward (Packard et al., 1997; Frye et al., 2002). Moreover, the conditioned place preference produced by peripheral testosterone injections was completely blocked by either peripheral or intra-accumbens administration of the mixed DJ/D2 dopamine receptor antagonist a-flupenthixol (Packard et al., 1998). Taken together, the place-conditioning studies argue that testosterone can be rewarding under the appropriate conditions, and they additionally provide a neu- roanatomical and neurochemical link with other abused substances that have been shown to activate the accumbens dopamine system.
Even though anabolic steroids can apparently produce rewarding effects, dependence on these substances does not seem to have the same features as dependence on more typical drugs of abuse such as alcohol, nicotine, cocaine, and heroin. Under controlled laboratory conditions, administration of varying doses of testosterone to subjects who were not steroid users failed to produce any feelings of euphoria (Fingerhood et al., 1997). Indeed, the hormone wasn’t even reliably detected compared to placebo treatment in a drug discrimination paradigm. Moreover, users don’t typically report strong cravings when withdrawing from steroids, which differs from the intense cravings usually experienced by cocaine-, heroin-, alcohol-, or nicotine-dependent individuals undergoing forced abstinence.
In humans at least, it seems likely that the reinforcement obtained from taking anabolic steroids stems principally from their performance- boosting and body image-enhancing effects. As Brower (2002) points out, anabolic steroid dependence occurs in weightlifters who are highly motivated to increase their strength and who participate in a culture that places a premium on physical attractiveness, fitness, and competitiveness. He proposes that the development of steroid dependence is due to the “muscle-active” effects of these compounds rather than any specific psychoactive effects. However, based in part on the animal literature summarized in the preceding paragraphs, Brower goes on to speculate that with repeated high-dose usage, a second stage of steroid dependence may develop that is mediated by brain reward mechanisms. This interesting theory remains to be tested experimentally.
Anabolic-androgenic steroids are hormones that increase muscle mass and strength and also produce masculinizing effects in the user. These substances either contain the naturally occurring male sex hormone testosterone or are similar to testosterone in their chemical structure. Some anabolic steroids are taken orally, others by intramuscular injection.
Anabolic steroids were developed for their muscle-building and performance-enhancing effects. The Soviet Union was the first country in which steroids were administered to athletic competitors; however, the practice quickly spread to other countries. When the use and abuse of these substances became more widespread and numerous adverse side effects began to emerge, steroids were classified as Schedule III controlled substances in the United States. They were also banned by a variety of national and international athletic organizations.
Despite anecdotal reports and case studies of performance enhancement by anabolic steroids, researchers were skeptical about these claims for many years due to an absence of appropriate double-blind, placebo-controlled studies. However, controlled experimental studies published over the past 10 years have demonstrated the dose-dependent effects of testosterone on muscle fiber size, muscle mass, and strength. Thus at the present time there is no longer any doubt about the effectiveness of anabolic steroids.
Anabolic steroids are usually taken in specific patterns and combinations. In the case of cycling, the steroid is taken in alternating on and off periods. Cycling can be combined with pyramiding, in which the dose is increased during the early part of the cycle and then gradually decreased after the peak dose is reached at the midpoint of the cycle. Some users also combine two or more steroids, often one that is injected and another that is taken orally. This practice is known as stacking.
Testosterone and other androgens are agonists at androgen receptors. When activated by binding an androgen, these receptors translocate to the cell nucleus, where they modulate gene transcription. Muscle cells possess androgen receptors, but it is thought that these receptors may already be maximally occupied by normal circulating levels of testosterone. This would make it difficult to explain how supra-physiological androgen levels could produce their anabolic effects. One possibility is that high androgen concentrations increase receptor expression by the muscles, thereby permitting enhanced hormone action. It is also possible that high doses of anabolic steroids exert an anticatabolic effect through an antagonistic action against glucocorticoids.
There are a number of adverse side effects of anabolic steroids that affect the cardiovascular and reproductive systems. These substances can produce masculinizing effects in female users and growth stunting in adolescents. Oral steroids pose the additional risk of causing liver damage. Behavioral side effects include heightened irritability and aggressiveness that reaches extreme proportions in a small number of cases.
Anabolic steroid dependence and withdrawal have been reported in some users. Although androgen self-administration has not been demonstrated in experimental animals, there are several studies showing rewarding effects through place conditioning. There is also evidence that the nucleus accumbens dopamine system may be involved in androgen reward. Nevertheless, anabolic steroid dependence does not show the same intensity as dependence on many other drugs of abuse. Brower has proposed a two-stage hypothesis of anabolic steroid dependence in which these substances are initially taken for their muscle-active effects but may eventually engender direct reinforcing effects with prolonged high-dose use.