Androgens are the major circulating sex hormone in men and regulate a wide range of physiologic processes through an intracellular androgen receptor (AR) [12,58,133]. In men, normal total plasma testosterone levels range from 300 ng/dL to 800 ng/dL, with most of the testosterone bound to sex hormone-binding protein and inactive. Free testosterone is the active form and comprises only 2% to 3% of circulating testosterone [110].

Testosterone is the primary anabolic steroid. Testosterone analogs are synthesized by modifying the testosterone molecule with the goal of enhancing bioavailability and activity, minimizing side effects, or avoiding detection in antidoping tests. Anabolic steroids in current use are active when taken orally, as an intramuscular (IM) depot injection, or via the transdermal route, depending on the position and type of the molecular alteration [71,110].

Delayed-release formulations and structural modifications to the primary testosterone molecule are designed to increase effectiveness through eliminating the extensive first-pass metabolism that oral testosterone undergoes. These alterations include esterification of the 17ß-hydroxyl group to allow for IM use (Class A analogs); alkylation at the 17αposition to allow for oral administration, inhibition of hepatic metabolism, and increased bioavailability (Class B analogs); and numerous other modifications of the A, B, or C rings intended to increase potency (Class C analogs) [30,53]. Alkylated analogs and analogs with a modified ring structure are metabolized at a slower rate in the liver than testosterone and its 17ß-esterified derivatives, making class B and C analogs available for oral use [7]. Commonly used anabolic androgenic steroids include [55]:

Testosterone is metabolized into dihydrotestosterone (DHT), which has 10 times the potency of testosterone, and estradiol, which has feminizing effects [55]. The primary metabolic substrate of testosterone is the hepatic isoenzyme family of cytochrome P450. Class A derivatives have long alkyl side-chains, slowing their hepatic metabolism and increasing their half-life in peripheral tissue. Modification in the class B and C derivatives alters their metabolic pathway to produce a longer half-life. They are excreted either unaltered or as metabolites and conjugates in the urine or feces [7,99].

Hypogonadism is the primary clinical indication for medical testosterone use [136]. The goal of ART is to provide physiologic-range serum testosterone levels (typically 280–800 ng/dL) and physiologic-range dihydrotestosterone and estradiol levels in order to facilitate optimal virilization and normal sexual function [1].

Anabolic steroids should be given to patients with hypogonadism and AIDS-associated wasting. A meta-analysis found that androgen supplementation for three to six months in persons with HIV-associated wasting produced significantly greater gains relative to placebo in fat-free mass, lean body mass, and overall body weight. Testosterone administration was associated with significantly greater improvements in muscle strength than placebo. Testosterone esters were found to produce greater increments in fat-free mass than transdermal preparations [11]. Nandrolone decanoate has been shown to increase overall weight and lean body mass and improve quality of life among patients with AIDS who had lost 5% to 15% of ideal body weight [83]. Oxandrolone increased average weight, appetite, and lean body mass when used alone in patients with HIV wasting, with gains in weight highest among patients combining oxandrolone with progressive resistance training [7,83]. Oral formulations are seldom used because of rapid metabolism and inactivation among class A analogs and liver toxicity among class B and C analogs. However, the orally active testosterone derivative oxandrolone may be suitable for treatment of HIV-associated wasting [83].

A 2011 survey of 506 AAS users found that the average user was 29.3 years of age and that most (70%) were in-fact "recreational exercisers" who used an average of 11 performance-enhancing substances in their routine [144]. The survey also revealed a higher prevalence of substance dependence disorders among AAS users (23.4%) than non-AAS users (11.2%). An estimated 30% of illicit AAS users go on to develop a dependence syndrome, characterized by chronic AAS use despite adverse effects on physical, psychosocial, or occupational functioning. The average age of onset for AAS dependence appears to be the late 20s, considerably older than the apparent typical age of onset of 19 years for initial AAS use [48].

Risk factors for AAS use are incompletely understood but include poor paternal relationships, history of conduct disorder, history of substance abuse, history of sexual abuse, and poor body image. Race, education level, and income do not appear to be significant factors. Among adolescents, boys are more likely to abuse steroids than girls, and participation in organized sports and knowing someone who uses anabolic steroids are predictors of future use [110,144].

Cultural factors may increase the likelihood of AAS abuse. These include increased competitiveness, body image concerns, and advances in biochemical technology. Younger people can be affected by these influences because of the highly competitive nature of high school and collegiate sports, especially considering that the performance enhancement provided by AAS may be the deciding factor in securing an athletic scholarship or acceptance into professional sports [110].

Evidence exists that body image disorders and associated non-medical AAS use are much more prevalent in Western societies than among other cultures. Several factors are believed to account for these cultural differences, including the emphasis on muscularity and fitness as a measure of masculinity in Western cultures, increasing exposure of men in Western cultures to muscular male bodies in media images, and greater decline in traditional male roles in the West resulting in greater emphasis on the body as a measure of masculinity [125].

Anabolic steroids are correctly regarded by regulatory bodies in professional sports as performance enhancers and as harmful to the health. The International Olympic Committee Medical Commission identified anabolic steroids as a banned class of drugs in 1974 [53]. The Drug Enforcement Administration categorizes AAS as a schedule III controlled substance, defined as substances with accepted medical uses that may cause moderate or low physical dependence or high psychologic dependence. The Anabolic Steroid Control Act of 2004 lists 59 different AAS formulations as controlled substances [75]. The Designer Anabolic Steroid Control Act of 2014 expanded this list by adding 25 new compounds [160,161].

Although AAS are controlled substances in Australia, Argentina, Brazil, Canada, the United Kingdom, and the United States, they are readily available in most other countries, where they can be sold legally without a prescription [27,42]. Foreign distributors do not violate the laws of their own country when they sell AAS overseas via the Internet or by e-mail order. Much of the AAS used in the United States originates from Mexico and other countries, such as Russia, Romania, and Greece [27,53]. Illicit AAS is also synthesized in clandestine laboratories or illegally diverted from pharmacies [75]. A large study of AAS users found that 52.7% of respondents purchased their AAS via the Internet; other sources included local dealers (16.7%), friends or training partners (15%), a physician's prescription (6.6%), and trafficking AAS from foreign countries (5.8%) [23]. Some participants obtained AAS through multiple methods.

Nandrolone, oxandrolone, testosterone, stanozolol, methandienone, and methenolol are the most frequently abused AAS agents. IM formulations of these drugs are preferred over oral formulations, and combinations of androgens are used more frequently than single agents [21]. In one survey, the average total AAS dose of testosterone was 500–1,000 mg per week. The highest dosage of testosterone used for four or more weeks was 797.5 mg per week, and 95% of users injected their steroids [23].

Another study found that 66% of male bodybuilding participants were willing to seek medical supervision, and that 61% obtained a blood work-up at least annually to assess the effects of AAS use on their health [23]. However, 58% lacked sufficient trust in their physician to report their AAS use, 92% felt the medical community's knowledge of AAS use was lacking, and 99% believed the public had an ill-informed view of AAS side effects [23].

AAS misuse has been linked to severe mental disorders, including mania, depression, suicidality, and psychoses [29]. AAS impact the central nervous system via multiple mechanisms and pathways, including the release of endogenous opiate peptides and the conversion of AAS into estrogen derivatives that activate secondary messenger systems. Electroencephalogram changes induced by AAS are similar to those observed with amphetamines and tricyclic antidepressants [110].

Excessive and inappropriate aggression is the behavioral response most often associated with AAS abuse [98]. It appears that chronic AAS use modifies homeostatic processes, affects neurotransmitters, and can cause changes in brain structures, leading to increased anxiety and tendency for aggressive behavior or poor impulse control [163]. The "roid rage" from high AAS doses may be the manifestation of an AAS-induced hypomanic syndrome that begins with feelings of invincibility and worsens as dosages increase [29]. These rages can result in property damage, self-injury (including reckless driving or crashing cars), assaults, marriage break-ups, domestic violence, child abuse, suicide, and attempted murder or murder [17,19,20,61,85,100,127]. The impulsive perpetration of homicide and attempted homicide has been documented as occurring in male AAS users with benign premorbid psychiatric histories, no evidence of antisocial personality disorder, and no history of violence, with steroid use playing a necessary, if not primary, role in the violent acts [85]. One group of men who may take high-dose AAS are those working as security officers or nightclub bouncers; under the influence of the drug, they may be provoked into a rage and engage in violent behavior resulting in injury or death [25,31].

Intimate relationships may represent the most likely setting where AAS-induced aggression and violence manifest. Choi and Pope found that AAS abusers reported significantly more verbal and physical aggression and violence toward their partners when using AAS than when not using AAS. When not on an AAS cycle, the AAS users off-drug did not significantly differ from nonusers [19]. These findings support anecdotal evidence that partners of AAS users may be at risk of serious injury from users while they are on-drug.

The prevalence of AAS-induced rages is unknown. Although prolonged high-dose use of AAS is the most common antecedent, not all people taking high doses develop steroid rages, and reports exist of rages occurring with low-dose AAS use [25]. Although serum testosterone level is correlated with aggressiveness, the relationship between supraphysiologic doses of AAS and aggressive and/or violent behavior is complex. Pope, Kouri, and Hudson observed that most normal males given 600 mg testosterone did not experience psychiatric symptoms [88]. The overall effect was of increased manic symptoms, which was also variable, with few participants reporting increased aggression levels.

Supraphysiologic doses of AAS can produce a range of adverse cardiovascular effects, including hypertension, cardiomyopathy, left ventricular hypertrophy, dyslipidemia, myocardial ischemia, adverse effects on coagulation and platelet aggregation, and arrhythmias. Some of these effects, such as hypertension, dyslipidemia, and coagulation abnormalities, remit after AAS use is discontinued, but effects such as atherosclerosis and cardiomyopathy are likely irreversible. These effects have been blamed for numerous premature deaths among athletes between 20 and 40 years of age known or believed to have used AAS, either from cardiac disease or cerebrovascular accidents. Older former AAS users now entering the age bracket of increased cardiovascular risk may display an increased rate of serious cardiovascular events [30,47].

Healthcare providers should screen for AAS use in muscular patients. The first step in this process involves looking for visual or behavioral "red flags" of AAS use. These include [29,90]:

Many non-medical AAS users consider themselves intelligent and informed users of AAS and possess an attitude of personal invulnerability [79]. Their information on AAS typically comes from popular literature written by steroid "gurus," word-of-mouth from other AAS users, and their own personal experiences from experimentation. They may perceive athletes who fail an AAS screening test as showing no obvious signs of ill health and conclude that information related to the health consequences of anabolic steroids is exaggerated [53]. Many athletes who use AAS possess a rudimentary understanding of pharmacology from personal experience and anecdotal information and will dismiss the warnings of the lack of efficacy and potential dangers of AAS misuse that are traditionally used with potential or current substance abusers to deter future use [57]. Attempts to devalue the achievements of sports figures accused of using AAS often backfire. Attempting to communicate a social and moral admonishment of "cheating" to curtail AAS use also serves to highlight what may be seen as otherwise unattainable achievements. AAS users likely view AAS as a form of enhancement with an acceptable cost/benefit ratio [23].

To achieve credibility with AAS-abusing patients, providers should instead acknowledge the muscle development ability of AAS while emphasizing the risks and must also convey an understanding of the body-building lifestyle, how AAS are used, and AAS slang [29]. Providing the patient with this balanced perspective is mirrored by prevention research showing that such an approach is more effective in convincing adolescents about steroids' negative effects because of the greater perceived credibility of the information and provider [29].

The first step in treating the psychiatric consequences of AAS use is to convince the patient to stop using [109,110]. Stopping AAS use reverses most, but not all, physical and psychologic consequences [29]. Depression is common during AAS withdrawal, typically easing without medication after several weeks. However, severe depression may lead to suicidal ideation, and patients with severe or persistent depression should be treated by a mental health professional. Severe or persistent depressive symptoms respond to selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, which is also effective for body dysmorphic disorder [29,63,85,110].