Anabolic Androgenic Steroids
Anabolic-androgenic steroids (AASs) increase muscle mass and lean body weight, and cause nitrogen retention.145 The androgenic effects of steroids are responsible for male appearance and secondary sexual characteristics such as increased growth of body hair and deepening of the voice. Testosterone is the prototypical androgen, and most AASs are synthetic testosterone derivatives. The WADA categorizes AASs into two groups: exogenous, referring to substances that are not ordinarily capable of being produced by the body naturally, and endogenous, referring to those capable of being produced by the body naturally. As such, there is sometimes discordance in categorization schemes with other governing entities. In this document, the term anabolic steroid means any xenobiotic, chemically and pharmacologically related to testosterone, other than estrogens, progestins, corticosteroids, and DHEA.
In the 1970s and 1980s, federal regulation of anabolic steroids was under the direction of the Food and Drug Administration (FDA). Because of increasing media reports on the use of AASs in sports, particularly by high school students and amateur athletes, Congress enacted the Anabolic Steroid Control Act of 1990, which amended the Controlled Substances Act and placed anabolic steroids in schedule III. Schedule III implies that a xenobiotic has a currently accepted medical use in the United States and has less potential for abuse than the drugs categorized as schedule I or II. The Anabolic Steroid Control Act of 2004 adds certain steroid precursors, such as androstenedione and dihydrotestosterone, to the list of controlled substances that are considered illegal without a prescription. However, DHEA is exempted. Possession of androstenedione or other metabolic precursors called prohormone drugs is considered a federal crime. Nevertheless, AASs are still available illicitly over the Internet from international marketers, veterinary pharmaceutical companies, and some legitimate US manufacturers (Table 40–2).
TABLE 40–2.Synthetic Testosterone Derivatives/Anabolic Androgenic Steroids: Generic Nomenclature
Antiestrogens and Antiandrogens
In male athletes using androgens, avoiding the unwanted side effects of feminization, such as gynecomastia, or in female athletes, avoiding masculinization and features such as facial hair and deepening voice, requires manipulation of the metabolic pathways of androgen metabolism. Creating a xenobiotic that completely dissociates the desired from the unwanted effects has not been possible. However, xenobiotics with properties capable of manipulating metabolic pathways associated with undesirable side effects are divided into four main groups, all on the Prohibited List.
Aromatase inhibitors such as anastrozole and aminoglutethimide prevent the conversion of androstenedione and testosterone into estrogen.
The antiestrogen clomiphene blocks estrogen receptors in the hypothalamus, opposing the negative feedback of estrogen, causing an increase in gonadotropin-releasing hormone, thereby increasing testosterone release.
Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene bind to estrogen receptors and exhibit agonist or antagonist effects at the estrogen receptors. By indirectly increasing gonadotropin release, SERMs restore endogenous testosterone production upon discontinuation of AASs.178
Selective androgen receptor modulators (SARMs) are nonsteroidal tissue selective anabolic xenobiotics. SARMS are neither not aromatized and are not substrates for 5α-reductase, nor do they undergo the same metabolic pathways as testosterone. Therefore, they have fewer unwanted androgenic side effects.73,209
Approximately 50% of AASs are taken orally. The remainder are administered by intramuscular injection, with one-fourth of intramuscular users sharing needles.53,152 One third of the needles and syringes exchanged in a needle-exchange program in Wales were used for AAS injections.159 Unlike therapeutically indicated regimens, which consist of fixed doses at regular intervals, athletes typically use AASs in cycles of 6 to 8 weeks.12 For example, the athlete may use steroids for 2 months and then abstain for 2 months. Cycling is based on the athlete’s individual preferences and not on any validated protocol. Stacking implies combining the use of several AASs at one time, often with both oral and intramuscular administration. To prevent plateauing, or developing tolerance, to any one xenobiotic, some athletes use an average of five different AASs simultaneously. The doses used are frequently hundreds of times in excess of scientifically based therapeutic recommendations.3,227Pyramiding implies starting the AASs at a low dose, increasing the dose many times, and then tapering once again. Fat soluble steroids may require several months to be totally eliminated, whereas water soluble steroids may require only days to weeks to be cleared by the kidney. Water soluble testosterone esters are used for “bridging therapy.” Bridging refers to the practice of halting the administration of long lasting alkylated testosterone formulations so that urine analyses at a specific time offer no evidence of use, whereas injections of shorter acting testosterone esters are used to replace the orally administered alkylated formulations. This strategy, which was used extensively in the German Democratic Republic, is documented in a review of the subject based on extensive research of previously classified records.65 Clearance profiles for testosterone congeners were determined for each athlete. In general, the daily injection of testosterone esters was used when termination of the more readily detectable synthetic alkylated testosterone derivatives was necessary to avoid a positive doping test. These daily injections of testosterone propionate were halted 4 to 5 days before competition. Corrupt officials involved in doping were sure that the values would decrease to acceptable concentrations in time for the event, based on the science of athletes’ clearance of testosterone esters.65
Clinical Manifestations of Anabolic-Androgenic Steroid Use
An association between AAS use and the development of cancer is observed in experimental animals.180 Testicular and prostatic carcinomas are reported in more frequent users of anabolic-androgenic steroids.61,71,179 Hepatocellular carcinoma,100,153 cholangiocarcinoma,12,80 Wilms tumor, and renal cell carcinoma are also reported in young AAS users.30,169 The relationship between the dose of AASs and cancer is unknown.
Cardiac complications include acute myocardial infarction, venous thromboembolism, and sudden cardiac arrest.7,64,87,96,127,129,131,141 Autopsy examination of the heart may reveal biventricular hypertrophy, extensive myocardial fibrosis, and contraction-band necrosis. Myofibrillar disorganization as well as hypertrophy of the interventricular septum and left ventricle are present.129 Intense training and use of AASs impair diastolic function by increasing left ventricular wall thickness. Animal models and in vitro myocardial cell studies show similar pathologic changes.45,113,142,208,216,217 Doppler echocardiography shows that several years after strength athletes discontinue using AASs, excessive concentric left ventricular hypertrophy remains. Growth hormone may potentiate the effects of AASs and further increase concentric remodeling of the left ventricle.105 In addition to direct myocardial injury, vasospasm or thrombosis may occur.142 Alkylated androgens lower the concentration of high-density lipoprotein (HDL) cholesterol and may increase platelet aggregation.3,64 Thromboembolic complications include pulmonaryembolus,50,72 stroke,109,110,196 carotid arterial occlusion,120 cerebral sinus thrombosis,117 poststeroid balance disorder,26 and popliteal artery entrapment.125
Cutaneous side effects are common and include keloid formation, sebaceous cysts, comedones, seborrheic furunculosis, folliculitis, and striae.192 Acne is associated with steroid use and sometimes is referred to as “gymnasium acne.”39,162 A common triad of acne, striae, and gynecomastia occurs. The production of sebum is an androgen-dependent process, and dihydrotestosterone is active in sebaceous glands.12 Gingival hyperplasia is reported.154
Conversion of AASs to estradiol in peripheral tissues results in feminization of male athletes. Gynecomastia may be irreversible. AAS use causes negative feedback inhibition of gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone from the hypothalamus. This process results in testicular atrophy and decreased spermatogenesis, which may be reversible. In women, menstrual irregularities and breast atrophy may occur.206
Hepatic subcapsular hematoma with hemorrhage is reported.191 Peliosis hepatis, a condition of blood-filled sinuses in the liver that may result in fatal hepatic rupture, occurs most commonly with alkylated androgens and may not improve when androgen use is stopped.13,91,198,225 This condition is not associated with the dose or duration of treatment.12,99,201 Cyproterone acetate is a chlorinated progesterone derivative that inhibits 5α-reductase and reportedly causes hepatotoxicity.12,70,75
Local complications from injection include infected joints,60 cutaneous abscess,137,173 and Candida albicans endophthalmitis.226 Injection of AASs using contaminated needles has led to transmission of infectious diseases such as human immunodeficiency virus and hepatitis B and C.152,155,172,175,193,197 Severe varicella is reported in long-term AAS users.101
Supraphysiologic doses of testosterone, when combined with strength training, increase muscle strength and size.22 The most common musculoskeletal complications of steroid use are tendon and ligament rupture.67,89,121,126
Distractibility, depression or mania, delirium, irritability, insomnia, hostility, anxiety, mood lability, and aggressiveness (“roid rage”) may occur.17,68,166,167,207 These neuropsychiatric effects do not appear to correlate with serum AAS concentrations.196,207 Withdrawal symptoms from AAS include decreased libido, fatigue, and myalgias.108,232
Specific Anabolic Xenobiotics
DHEA is a precursor to testosterone (Fig. 40–1). Because it is produced endogenously, DHEA most commonly is not categorized as an AAS. However, DHEA is weakly anabolic and weakly androgenic. Although banned by the FDA in 1996, this xenobiotic subsequently was marketed as a nutritional supplement and is available for purchase without a prescription.206 DHEA is converted to androstenedione and then to testosterone by the enzyme 17β-hydroxysteroid dehydrogenase.94,128,132 Administration of androstenedione in dosages of 300 mg/d increases testosterone and estradiol concentrations in some men and women.124 Women with adrenal insufficiency given DHEA replacement at a dose of 50 mg/d orally for 4 months demonstrated increased serum concentrations of DHEA, androstenedione, testosterone, and dihydrotestosterone. Serum total and HDL cholesterol concentrations simultaneously decreased. Some women experienced androgenic side effects, including greasy skin, acne, and hirsutism.10 Sense of well-being and sexuality increased in men and women after 4 months of treatment.10,146,147 The neuropsychiatric effects of DHEA have been demonstrated in animals. Increased hypothalamic serotonin, anxiolytic effects, antagonism at the γ-aminobutyric acid type A (GABAA) receptor, and agonism at the N-methyl-d-aspartate receptor (NMDA) are demonstrated.10,133,143
Metabolic pathway of dehydroepiandrosterone (DHEA).
Clenbuterol is a β2-adrenergic agonist that decreases fat deposition and prevents protein breakdown in animal models.6,38,90 Clenbuterol is also a potent nutrient partitioning agent, a term implying it can increase the amount of muscle and decrease the amount of fat produced per pound of feed given to cattle and other animals.68,177 Use of clenbuterol in cattle farming is illegal in many countries. Nevertheless, the consumption of veal liver contaminated with clenbuterol has resulted in sympathomimetic symptoms and positive urine tests in affected individuals.183 Clenbuterol is composed of a racemic mixture of (+) and (–) stereoisomers, eliminated in urine in approximately equal amounts. As clenbuterol accumulates in animal meat, stereoisomer ratios change over time and (–) clenbuterol is depleted. By analyzing urinary ratios of clenbuterol stereoisomers, it is possible to differentiate administration of therapeutic clenbuterol preparations from inadvertent ingestion of clenbuterol in meat products.211 Clenbuterol increases the glycolytic capacity of muscle and causes hypertrophy, enhancing the growth of fast-twitch fibers134,234 (Chap. 66).