Anabolic Androgenic Steroid Use Pharmacology, Prevalence, and Psychiatric Aspects Check Points

Public concern about the use of anabolic androgenic steroids by athletes and others has led to enhanced testing for these drugs as well as an improved understanding of their medical and psychiatric effects. This article reviews the pharmacology of these compounds, the prevalence and effects of their use among athletes, and the basics of steroid testing, and it concludes with treatment recommendations. Even though athletes may use other illicit substances, such as stimulants, human growth hormone, and erythropoietin, this article focuses only on anabolic androgenic steroids. Review articles on the psychiatric effects of the other performance-enhancing substances are available elsewhere.^1,2

¸*****Psychiatric symptoms of anabolic androgenic steroid use may include depression, hypomania, frank mania, and suicidal ideation.

¸*****Both physiological dependence and withdrawal may occur in heavy users of anabolic androgenic steroids.

¸*****Primary prevention focuses on effective testing and meaningful sanctions.

¸*****Treatment may include palliative measures for physiological withdrawal, psychiatric interventions, and the development of alternative strategies for athletic success.

Although anabolic androgenic steroids have some well-defined medical uses, including the treatment of AIDS wasting syndrome, hereditary angioedema, and metastatic breast cancer, active athletes are unlikely to suffer from any of these conditions. Testosterone deficiency in males can be treated with exogenous testosterone and would require an exemption from a sports organization to allow the therapeutic use of a banned substance. Although anabolic androgenic steroids are used illicitly by athletes for enhancing their performance, the "illicitness" of the drug is a social construct rather than an edict from the heavens: if we just wanted to keep athletes safe, we would not let them play potentially dangerous sports. But the construct that makes anabolic androgenic steroids illegal without a valid prescription and banned in both amateur and professional athletics is based on a coherent risk-benefit analysis for individual users as well as for the sport itself.

Pharmacology

Anabolic androgenic steroids are distinct from corticosteroids and female gonadotrophic hormones: all are steroids, but only anabolic androgenic steroids build muscle mass, thereby potentially enhancing athletic performance. Anabolic androgenic steroids are thought to enhance muscle growth by increasing RNA transcription, which causes the growth of new myofilaments in skeletal muscle. Another proposed mechanism of action is an observed cross-reaction of high-dose anabolic androgenic steroids with the glucocorticoid receptors that control protein catabolic processes.³

Figure 1 shows that cholesterol metabolizes to dehydroepiandrosterone (DHEA), which is the precursor for androstenedione and testosterone.Although both cholesterol and DHEA are produced endogenously, DHEA can also be ingested and may increase testosterone levels. Androstenedione was once legal and widely available as a dietary supplement, but it has now been reclassified as a schedule III anabolic androgenic steroid and banned by most sports organizations. DHEA is still available as a dietary supplement, however. The testicular atrophy and gynecomastia associated with anabolic androgenic steroid use are caused by down-regulation of testicular production of testosterone and aromatization to estrogen, respectively.

Testosterone extracts were developed in the 1880s and synthetic testosterone was synthesized in 1935, although its use did not become prominent among athletes until the mid-1950s. Anabolic androgenic steroids were allegedly used by Soviet athletic teams, causing obvious masculinizing changes in female athletes who received large amounts of the steroids, and many suffered devastating long-term consequences, including heart disease and stroke.⁴ Although the International Olympic Committee banned the use of anabolic androgenic steroids in 1967, the substances remained widely available in the United States despite the Anabolic Steroid Control Act of 1990 and the subsequent stricter Anabolic Steroid Control Act of 2004. The dietary oral supplements, such as androstenedione, many of which are prohormone precursors, were correctly reclassified by the 2004 act as anabolic steroids.

Another problem with dietary supplements is that their manufacturing standards and oversight by the FDA are much less stringent than are those for traditional pharmaceuticals. This has led to many instances of contamination and unreliable labeling. One study that sampled 12 over-the-counter steroid supplements found that one contained prescription-only testosterone, another contained 77% more steroid than the label indicated, and 11 contained less steroid than the label reported.⁵ Despite the present regulations on anabolic steroid supplements and tighter controls overall, anabolic androgenic steroids are widely available, in both injectable and oral preparations. The Table lists some of the illicitly used but commonly available anabolic androgenic steroids in the United States. Although avoiding first-pass metabolism (and potential hepatotoxicity) by using intramuscular preparations might seem like a viable way to increase the effectiveness of the anabolic androgenic steroids, in fact there is no evidence that when injected, these intramuscular steroids are any more effective than those that are taken orally. The potential risk of multiple self-injections must also be taken into account.

Prevalence

Professional and Olympic athletes have been much in the press lately for their admitted use of anabolic androgenic steroids. Marion Jones's acknowledgement of her use of steroids during the 2000 Olympics arose directly from the federal government's BALCO investigation.⁶ Barry Bonds's breaking of the all-time home-run record and subsequent departure from the San Francisco Giants was shadowed by accusations of steroid use.⁷ In 2003, the first year of reported testing in major league baseball, 5.77% of 1438 anonymous urine samples tested were positive for anabolic androgenic steroids.⁸ In one celebrated case, 5 members of the National Football League's Carolina Panthers were linked to steroids distributed by a physician in Charlotte, NC.⁹ Despite these and many other high-profile cases, the number of elite athletes who use anabolic androgenic steroids remains unknown.

However, data provided by student athletes suggest that the use of anabolic androgenic steroids is more common than suspected and that the numbers are essentially unchanged over the past several years (Figure 2). The United States Census Bureau estimates that there are roughly 4 million 12th graders in the United States, and if 1.8% of them used anabolic androgenic steroids in 2006, there would have been no fewer than 72,000 acknowledged 12th graders using steroids.

In addition, some users of anabolic androgenic steroids may be using them for aesthetic purposes as opposed to enhancement of athletic performance, although demographic data are unavailable for this group of users.

Practical aspects

The typical user of illicit anabolic androgenic steroids finds information on how to use the various preparations from the Internet or gets the information from other users, and, occasionally, from knowledgeable physicians. One Web site provides information about the potential hepatotoxic effects of oral steroids, how to "front-load" by doubling the usual daily dose, and how to "cycle" steroids up and down before competition to obtain the best results, as well as how to avoid the feminizing adverse effects by using antiestrogen agents such as anastrazole.¹⁰ "Stacking," another term often used by anabolic androgenic steroid users, is the practice of using various steroids at the same time, thus purportedly achieving a synergistic effect.³

Detection

Since elite athletes who use anabolic androgenic steroids have huge financial and emotional investments in avoiding detection, the testing methods must be sophisticated, admissible in legal settings, and dynamic enough to find new substances or evasive maneuvers. The testing must be reasonable in terms of convenience and risk and must be as respectful as possible of the athlete's privacy. Generally, sports drug testing exclusively involves the use of urine collection for analysis.

Gas chromatography-mass spectroscopy, which separates substances based on their chromatographic retention time and then breaks down each substance to its identifying ions, has been used in drug testing since the 1980s.¹¹ This method readily identifies anabolic androgenic steroid metabolites and can quantify the amount of testosterone in a sample.

The most common test for the presence of exogenous testosterone or testosterone precursors is the testosterone-to-epitestosterone (T:E) ratio, which in the nonuser hovers around 1:1. If an individual ingests exogenous testosterone, the ratio increases because epitestosterone is biologically inactive and is suppressed by testosterone use. Since some individuals can have a naturally elevated T:E ratio, most testing organizations set a T:E ratio limit of 6 or above to avoid punishing those individuals with physiologically high ratios. (Since T:E ratios are stable over time in the same individual, sequential ratios can also differentiate naturally occurring high T:E ratios from those caused by the introduction of exogenous testosterone.)

An even more sophisticated test, isotope ratio mass spectroscopy, can identify exogenous testosterone or epitestosterone by measuring the relative percentage of ¹³C and ¹²C atoms in the substance being tested. This is advantageous because pharma- ceutical testosterone has fewer ¹³C atoms than does naturally produced testosterone.¹²

The methodologies for ensuring that the test is accurate and that the specimen comes from the athlete in question are as important as the reliability of the testing methods. For urine samples, testing for specific gravity, temperature, and the presence of adulterants is standard procedure. The urine collector directly observes the athlete voiding and thereby starts the written "chain of custody" document that goes from urine collector, to the transporter, and finally to the laboratory technician who tests the sample. For the athlete who tests positive, an appeals process should be in place to evaluate the result for any laboratory or handling error, or the possibility that the athlete has a legitimate medical need for the banned substance.

Psychiatric effects

In addition to adverse physical effects, such as tendon rupture,¹³ reductions in high-density lipoprotein cholesterol levels, shrunken testes, and liver cysts,³ anabolic androgenic steroid use has been associated with significant psychiatric pathology. Of the multiple behavioral and psychiatric phenomena reported, the most distinctive is "roid rage." As in the case of World Wrestling Entertainment wrestler Chris Benoit, the popular media may exaggerate the effects of steroids on complex human behaviors.¹⁴ However, the peer-reviewed literature contains case series and literature reviews documenting anabolic androgenic steroid-related hostility, aggression, hallucinations, and delusions.^15,16

Steroid-related affective symptoms are much more common than psychosis. The affective symptoms are generally experienced by unsophisticated anabolic androgenic steroid users who are taking doses at the high end of the spectrum, far beyond the doses that are required for performance enhancement. Mood symptoms can include depression, hypomania, and frank mania.¹⁷ One manifestation of withdrawal from anabolic androgenic steroids can be a profound depression,¹⁸ which has been implicated in the completed suicide of some users.¹⁹

Although the very existence of true physiological dependence and withdrawal from anabolic androgenic steroids has been questioned, careful analysis shows that both phenomena occur, especially in the heavy user of anabolic androgenic steroids. An early case study of an anabolic androgenic steroid user who stopped abruptly revealed typical correlates of withdrawal, including the sudden onset of dysphoria, fatigue, psychomotor re- tardation, and impaired concentration, along with suicidal ideation.²⁰ This symptom picture disappeared after 4 days. The same authors later reported a case series of 49 competitive weight lifters who used anabolic androgenic steroids and found that 94% endorsed at least one symptom of DSM-III-R dependence, 84% experienced physiological withdrawal, 51% used more anabolic androgenic steroids than intended, and 49% spent more time than intended on substance-related activities.²¹

Prevention

Although true addictive behaviors do follow some anabolic androgenic steroid use, most users experience little in the way of immediate dependence or withdrawal. Despite the lack of immediate addictive consequences, users face the same long-term risk of medical and psychiatric sequelae as those who experience short-term negative effects. In addition, the legal consequences of illicit use and the negative effects on an institution condoning or even promoting anabolic androgenic steroids can be catastrophic.

A structured 7-session educational program was offered to more than 700 high school athletes: the program provided substantial information on anabolic androgenic steroids, substitute training methods, and personal vulnerability to negative effects. When compared with a control group at the 12-month follow-up, the participants showed sustained improved knowledge regarding the use of anabolic androgenic steroids and decreased intent to use them.²²

Since much anabolic androgenic steroid use is nonaddictive and simply a matter of cheating, primary prevention focuses on effective testing and meaningful sanctions. The athlete who assesses the risk-to-benefit ratio of using steroids as stacked the wrong way will decide against using them. Providing a level playing field for all competitors will discourage anabolic androgenic steroid use for those who might otherwise have been swayed. Of course, given the wide penetration of anabolic androgenic steroids and other illicit substances in both amateur and professional sports, efforts to fortify banned substance restrictions will have to be serious and long-lasting.

Treatment

Of course, users in whom addictive symptoms to anabolic androgenic steroids develop deserve treatment. That treatment can consist of palliative measures for physiological withdrawal, psychiatric treatment, and the development of alternative strategies for athletic success or enhancing self-worth in other ways. The psychotherapeutic support should be delivered by a clinician who understands the athlete's core emotional needs to succeed in his or her sport, needs that often transcend the more obvious rewards of money or public adulation.

There is increasing empirical support for psychotherapy's efficacy for the treatment of substance abuse,²³ and the nonaddicted steroid-using athlete will likely respond well to supportive psychotherapy. Rather than simple "hand-holding," supportive psychotherapy in this context consists of supporting constructive defenses such as sublimation or intellectualization. For instance, the athlete who faces severe sanctions can be helped to define his behavior on an intellectualized risk-benefit analysis that will rule out the use of anabolic androgenic steroids because of likely catastrophic punishment. Anger over being forced to stop using steroids can, under the best circumstances, be worked out in the weight room or on the training field.

For the athlete who uses anabolic androgenic steroids and manifests addictive behaviors, such as compulsive use or withdrawal symptoms, standard relapse prevention techniques can be used.²⁴ For example, identifying cues to use, alternative strategies, and adaptive responses to slips can help the addicted user slow down and then stop the substance use.

Acute withdrawal symptoms should be treated symptomatically, and only in extreme cases is there a need for endocrinologist-managed manipulation of the hypothalamic-pituitary-gonadal axis.^25,26 For the steroid user who finds that he has permanently depressed gonadal function, testosterone replacement is an option.²⁷

Psychopharmacological intervention for longer-term withdrawal depression or anxiety may also be necessary. Symptoms arising in the context of steroid withdrawal may be simply a substance-induced depressive disorder or a psychotic disorder, but neither should be underestimated. For the athlete manifesting steroid-related affective or psychotic symptoms, the clinician's initial goals should be to:

• Keep the user (and others) safe.

• Ameliorate the uncomfortable immediate symptoms.

Pharmacological approaches to these early goals include the use of anxiolytics such as benzodiazepines and, in rare cases, antipsychotic agents.

Conclusion

Although anabolic androgenic steroid use has been widespread in athletic venues over the past 20 years, better public understanding of these drugs' pernicious effects on individual athletes and sport itself has led to increased vigilance for illicit use and severe sanctions for the users. Although primary prevention is best, sanctions for those who can be deterred by them and treatment for those who become addicted can have significant positive effects. However, only continued efforts on the part of athletes, coaches, sporting organizations, and clinicians can prevent the next generation of illicit substances from harming athletes--and athletics.

References:

Anastrazole (Arimidex)Boldenone (Equipoise)Methandrostenelone (Dianabol)Nandralone decanoate (Deca-Duroblin)Oxandrolone (Oxandrin)Stanazalol (Winstrol)Testosterone cypionate (Depo-Testosterone)

1.

McDuff DR, Baron D. Substance use in athletics: a sports psychiatry perspective.

Clin Sports Med.

2005; 24:885-897.

2.

Tokish JM, Kocher MS, Hawkins RJ. Ergogenic aids: a review of basic science, performance, side effects, and status in sports.

Am J Sports Med.

2004;32:1543-1553.

3.

Lukas SE. The pharmacology of steroids. In:

Principles of Addiction Medicine

. 2nd ed.Chevy Chase, Md: American Society of Addiction Medicine; 1998:173-182.

4.

Yesalis CE, ed.

Anabolic Steroids in Sport and Exercise.

2nd ed. Champaign, Ill: Human Kinetics; 2000.

5.

Green GA, Catlin DH, Starcevic B. Analysis of over-the-counter supplements.

Clin J Sport Med.

2001;11: 254-259.

6.

Wilson D, Schmidt MS. Olympic champion acknowledges use of steroids.

The New York Times

. October 5, 2007. Available at: http://www.nytimes.com/2007/ 10/05/sports/othersports/05balco.html?_r=1&oref= slogin. Accessed November 20, 2007.

7.

McKinley J. A subdued farewell for a city's baseball hero.

The New York Times

. September 27, 2007. Available at: http://www.nytimes.com/2007/09/28/ us/ 28frisco.html. Accessed November 20, 2007.

8.

Crasnick J. Steroid policy elicits harsh reactions.

BaseballAmerica

. December 8, 2003.

9.

Waxman wants NFL probe of Panthers' steroid use reopened.

USA Today

. August 30, 2006. Available at: http://www.usatoday.com/sports/football/nfl/2006-08-30-steroids-panthers-waxman_x.htm? POE=SPOISVA&loc=interstitialskip. Accessed December 7, 2007.

10.

Beginner's Steroids FAQs. Available at: http://www.muscletalk.co.uk/article-beginners-steroids-faq.aspx. Accessed November 20, 2007.

11.

Green GA. Doping control for the team physician; a review of drug testing procedures in sport.

Am J Sports Med.

2006;34:1690-1698.

12.

Aguilera R, Becchi M, Casabianca H, et al. Improved method of detection of testosterone abuse by gas chromatography/combustion/isotope ratio mass spectroscopy analysis of urinary steroids.

J Mass Spectrom.

1996;31:169-176.

13.

Laseter JT, Russell JA. Anabolic steroid-induced tendon pathology: a review of the literature.

Med Sci Sports Exerc.

1991;23:1-3.

14.

Goodman B. Wrestler kills wife, son, and himself.

The New York Times

. June 26, 2007. Available at: http://www.nytimes.com/2007/06/27/us/27wrestler.html?_r=1&oref=slogin. Accessed December 7, 2007.

15.

Perry PJ, Andersen KH, Yates WR. Illicit anabolic steroid use in athletes. A case series analysis.

Am J Sports Med.

1990;18:422-428.

16.

Pope HG Jr, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use.

Am J Psychiatry.

1988;145:487-490.

17.

Trenton AJ, Currier GW. Behavioural manifestations of anabolic steroid use.

CNS Drugs.

2005;19:571-595.

18.

Brower KJ, Eliopulos GA, Blow FC, et al. Evidence of physical and psychological dependence on anabolic androgenic steroids in eight weight lifters.

Am J Psychiatry.

1990;147:510-512.

19.

The Taylor Hooton Foundation. Fighting Steroid Abuse. Available at: http://www.taylorhooton.org/. Accessed November 20, 2007.

20.

Brower KJ, Blow FC, Beresford TP, Fuelling C. Anabolic-androgenic steroid dependence.

J Clin Psychiatry.

1989;50:31-32.

21.

Brower KJ, Blow FC, Young JP, Hill EM. Symptoms and correlates of anabolic-androgenic steroid dependence.

Br J Addict.

1991;86:759-768.

22.

Goldberg L, Elliot D, Clarke GN, et al. Effects of a multidimensional anabolic steroid prevention intervention. The Adolescents Training and Learning to Avoid Steroids (ATLAS) Program.

JAMA.

1996;276:1555-1562.

23.

Washton AM, ed.

Psychotherapy and Substance Abuse: A Practitioner's Handbook.

New York: Guilford Press; 1995: 60.

24.

Marlatt GA, Gordon JR, eds. Relapse Prevention: Maintenance strategies in the treatment of addictive behaviors. New York: Guilford Press; 1985.

25.

Medras M, Tworowska U. Treatment strategies of withdrawal from long-term use of anabolic-androgenic steroids [in Polish].

Pol Merkur Lekarski.

2001;11:535-538.

26.

Bahrke MS, Yesalis CE, Brower KJ. Anabolic-androgenic steroid abuse and performance-enhancing drugs among adolescents.

Child Adolesc Psychiatr Clin N Am.

1998;7:821-838.

27.

Miner MM, Sadiovsky R. Evolving issues in male hyopogonadism: evaluation, management, and related comorbidities.

Cleve Clin J Med.

2007;74(suppl 3): S38-46.