Anabolic steroids were first isolated, identified, and synthesized in the 1930s, and are now used therapeutically in medicine to stimulate bone growth and appetite, induce male puberty, and treat chronic wasting conditions, such as cancer and AIDS. The American College of Sports Medicine acknowledges that AAS, in the presence of adequate diet, can contribute to increases in body weight, often as lean mass increases, and that the gains in muscular strength achieved through high-intensity exercise and proper diet can be additionally increased by the use of AAS in some individuals.[1]
Health risks can be produced by long-term use or excessive doses of anabolic steroids.[2][3] These effects include harmful changes in cholesterol levels (increased low-density lipoprotein and decreased high-density lipoprotein), acne, high blood pressure, liver damage (mainly with oral steroids), dangerous changes in the structure of the left ventricle of the heart.[4] Conditions pertaining to hormonal imbalances such as gynecomastia and testicular atrophy may also be caused by anabolic steroids.
Ergogenic uses for anabolic steroids in sports, racing, and bodybuilding are controversial because of their adverse effects and the potential to gain unfair advantage and considered cheating. Their use is referred to as doping and banned by all major sporting bodies. For many years, AAS have been by far the most detected doping substances in IOC-accredited laboratories.[5][6] In countries where AAS are controlled substances, there is often a black market in which smuggled, clandestinely manufactured, or even counterfeit drugs are sold to users.
History
Isolation of gonadal AAS
In the 1930s, it was already known that the testes contain a more powerful androgen than androstenone, and three groups of scientists, funded by competing pharmaceutical companies in the Netherlands, Germany, and Switzerland, raced to isolate it.[8][9] This hormone was first identified by Karoly Gyula David, E. Dingemanse, J. Freud and Ernst Laqueur in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)."[10] They named the hormone testosterone, from the stems of testicle and sterol, and the suffix of ketone. The chemical synthesis of testosterone was achieved in August that year, when Butenandt and G. Hanisch published a paper describing "A Method for Preparing Testosterone from Cholesterol."[11] Only a week later, the third group, Ruzicka and A. Wettstein, announced a patent application in a paper "On the Artificial Preparation of the Testicular Hormone Testosterone (Androsten-3-one-17-ol)."[12] Ruzicka and Butenandt were offered the 1939 Nobel Prize in Chemistry for their work, but the Nazi government forced Butenandt to decline the honor, although he accepted the prize after the end of World War II.[8][9]
Clinical trials on humans, involving either oral doses of methyltestosterone or injections of testosterone propionate, began as early as 1937.[8] Testosterone propionate is mentioned in a letter to the editor of Strength and Health magazine in 1938; this is the earliest known reference to an anabolic steroid in a U.S. weightlifting or bodybuilding magazine.[8] There are often reported rumors that German soldiers were administered anabolic steroids during the Second World War, the aim being to increase their aggression and stamina, but these are, as yet, unproven.[13] Adolf Hitler himself, according to his physician, was injected with testosterone derivatives to treat various ailments.[14] AAS were used in experiments conducted by the Nazis on concentration camp inmates,[14] and later by the allies attempting to treat the malnourished victims that survived Nazi camps.[13] President John F. Kennedy was administered steroids both before and during his presidency.[15]
Development of synthetic AAS
Three major ideas governed modifications of testosterone into a multitude of AAS: Alkylation at 17-alpha position with methyl or ethyl group created orally active compounds because it slows the degradation of the drug by the liver; esterification of testosterone and nortestosterone at the 17-beta position allows the substance to be administered parenterally and increases the duration of effectiveness because agents soluble in oily liquids may be present in the body for several months; and alterations of the ring structure were applied for both oral and parenteral agents to seeking to obtain different anabolic to androgenic effect ratios.[18]
Pharmacology
Routes of administrations
Testosterone can be administered parenterally, but it has more irregular prolonged absorption time and greater activity in propionate, enanthate, undecanoate, or cypionate ester form. These derivatives are hydrolyzed to release free testosterone at the site of injection; absorption rate (and thus injection schedule) varies among different esters, but medical injections are normally done anywhere between semi-weekly to once every 12 weeks. A more frequent schedule may be desirable in order to maintain a more constant level of hormone in the system.[19] Injectable steroids are typically administered into the muscle, not into the vein, to avoid sudden changes in the amount of the drug in the bloodstream. In addition, because estered testosterone is dissolved in oil, intravenous injection has the potential to cause a dangerous embolism (clot) in the bloodstream.
Transdermal patches (adhesive patches placed on the skin) may also be used to deliver a steady dose through the skin and into the bloodstream. Testosterone-containing creams and gels that are applied daily to the skin are also available, but absorption is inefficient (roughly 10%, varying between individuals) and these treatments tend to be more expensive. Individuals who are especially physically active and/or bathe often may not be good candidates, since the medication can be washed off and may take up to six hours to be fully absorbed. There is also the risk that an intimate partner or child may come in contact with the application site and inadvertently dose himself or herself; children and women are highly sensitive to testosterone and can suffer unintended masculinization and health effects, even from small doses. Injection is the most common method used by individuals administering anabolic steroids for non-medical purposes.[20]
The traditional routes of administration do not have differential effects on the efficacy of the drug. Studies indicate that the anabolic properties of anabolic steroids are relatively similar despite the differences in pharmacokinetic principles such as first-pass metabolism. However, the orally available forms of AAS may cause liver damage in high doses.[6][21]
Mechanism of action
See also: Steroid hormone
The effect of anabolic steroids on muscle mass is caused in at least two ways:[26] first, they increase the production of proteins; second, they reduce recovery time by blocking the effects of stress hormone cortisol on muscle tissue, so that catabolism of muscle is greatly reduced. It has been hypothesized that this reduction in muscle breakdown may occur through anabolic steroids inhibiting the action of other steroid hormones called glucocorticoids that promote the breakdown of muscles.[27] Anabolic steroids also affect the number of cells that develop into fat-storage cells, by favouring cellular differentiation into muscle cells instead.[28] Anabolic steroids can also decrease fat by increasing basal metabolic rate (BMR), since an increase in muscle mass increases BMR.
Anabolic and androgenic effects
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Some examples of the anabolic effects of these hormones are increased protein synthesis from amino acids, increased appetite, increased bone remodeling and growth, and stimulation of bone marrow, which increases the production of red blood cells. Through a number of mechanisms anabolic steroids stimulate the formation of muscle cells and hence cause an increase in the size of skeletal muscles, leading to increased strength.[29][30][31]
The androgenic effects of AAS are numerous. Depending on the length of use, the side effects of the steroid can be irreversible. Processes affected include pubertal growth, sebaceous gland oil production, and sexuality (especially in fetal development). Some examples of virilizing effects are growth of the clitoris in females and the penis in male children (the adult penis does not grow, and will eventually get smaller even when exposed to high doses of androgens), increased growth of androgen-sensitive hair (pubic, beard, chest, and limb hair), increased vocal cord size, deepening the voice, increased libido, suppression of natural sex hormones, and impaired production of sperm.[32]
The androgenic:anabolic ratio of an AAS is an important factor when determining the clinical application of these compounds. Compounds with a high ratio of androgenic to an anabolic effects are the drug of choice in androgen-replacement therapy (e.g., treating hypogonadism in males), whereas compounds with a reduced androgenic:anabolic ratio are preferred for anemia and osteoporosis, and to reverse protein loss following trauma, surgery, or prolonged immobilization. Determination of androgenic:anabolic ratio is typically performed in animal studies, which has led to the marketing of some compounds claimed to have anabolic activity with weak androgenic effects. This disassociation is less marked in humans, where all anabolic steroids have significant androgenic effects.[19]
A commonly used protocol for determining the androgenic:anabolic ratio, dating back to the 1950s, uses the relative weights of ventral prostate (VP) and levator ani muscle (LA) of male rats. The VP weight is an indicator of the androgenic effect, while the LA weight is an indicator of the anabolic effect. Two or more batches of rats are castrated and given no treatment and respectively some AAS of interest. The LA/VP ratio for an AAS is calculated as the ratio of LA/VP weight gains produced by the treatment with that compound using castrated but untreated rats as baseline: (LAc,t–LAc)/(VPc,t–VPc). The LA/VP weight gain ratio from rat experiments is not unitary for testosterone (typically 0.3–0.4), but it is normalized for presentation purposes, and used as basis of comparison for other AAS, which have their androgenic:anabolic ratios scaled accordingly (as shown in the table above).[25][33] In the early 2000s, this procedure was standardized and generalized throughout OECD in what is now known as the Hershberger assay.
Body composition and strength improvements
A review spanning more than three decades of experimental studies in men found that body weight may increase by 2–5 kg as a result of short-term (<10 weeks) AAS use, which may be attributed mainly to an increase of lean mass. Animal studies also found that fat mass was reduced, but most studies in humans failed to elucidate significant fat mass decrements. The effects on lean body mass have been shown to be dose-dependent. Both muscle hypertrophy and the formation of new muscle fibers have been observed. The hydration of lean mass remains unaffected by AAS use, although small increments of blood volume cannot be ruled out.[34]The upper region of the body (thorax, neck, shoulders, and upper arm) seems to be more susceptible for AAS than other body regions because of predominance of androgen receptors in the upper body. The largest difference in muscle fiber size between AAS users and non-users was observed in type I muscle fibers of the vastus lateralis and the trapezius muscle as a result of long-term AAS self-administration. After drug withdrawal, the effects fade away slowly, but may persist for more than 6–12 weeks after cessation of AAS use.[34]
The same review observed strength improvements in the range of 5–20% of baseline strength, depending largely on the drugs and dose used as well as the administration period. Overall, the exercise where the most significant improvements were observed is the bench press.[35] For almost two decades, it was assumed that AAS exerted significant effects only in experienced strength athletes, particularly based on the studies of Hervey and coworkers.[36][37] In 1996, a randomized controlled trial published in the New England Journal of Medicine demonstrated, however, that even in novice athletes a 10-week strength training program accompanied by testosterone enanthate at 600 mg/week may improve strength more than training alone does.[35][38] The same study found that dose to be sufficient to significantly improve lean muscle mass relative to placebo even in subjects that did not exercise at all.[38] A 2001 study by the same first author, showed that the anabolic effects of testosterone enanthate were highly dose dependent.[34][39]
Adverse effects
Anabolic steroids can cause many adverse effects. Depending on the length of drug abuse, there is a chance that the immune system can be damaged. Most of these side-effects are dose-dependent, the most common being elevated blood pressure, especially in those with pre-existing hypertension,[40] and harmful changes in cholesterol levels: Some steroids cause an increase in LDL "bad" cholesterol and a decrease in HDL "good" cholesterol.[41] Anabolic steroids have been shown to alter fasting blood sugar and glucose tolerance tests.[42] Anabolic steroids such as testosterone also increase the risk of cardiovascular disease[2] or coronary artery disease.[43][44] Acne is fairly common among anabolic steroid users, mostly due to stimulation of the sebaceous glands by increased testosterone levels.[45][46] Conversion of testosterone to dihydrotestosterone (DHT) can accelerate the rate of premature baldness for males genetically predisposed, but testosterone itself can produce baldness in females.[47]High doses of oral anabolic steroid compounds can cause liver damage, as the steroids are metabolized (17α-alkylated) in the digestive system to increase their bioavailability and stability.[3]
There are also sex-specific side-effects of anabolic steroids. Development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), may arise because of increased conversion of testosterone to estradiol by the enzyme aromatase.[48] Reduced sexual function and temporary infertility can also occur in males.[49][50][51] Another male-specific side-effect that can occur is testicular atrophy, caused by the suppression of natural testosterone levels, which inhibits production of sperm (most of the mass of the testes is developing sperm). This side-effect is temporary: The size of the testicles usually returns to normal within a few weeks of discontinuing anabolic steroid use as normal production of sperm resumes.[52] Female-specific side-effects include increases in body hair, permanent deepening of the voice, enlarged clitoris, and temporary decreases in menstrual cycles. When taken during pregnancy, anabolic steroids can affect fetal development by causing the development of male features in the female fetus and female features in the male fetus.[53]
A number of severe side-effects can occur if adolescents use anabolic steroids.
For example, the steroids may prematurely stop the lengthening of bones (premature epiphyseal fusion through increased levels of estrogen metabolites), resulting in stunted growth. Other effects include, but are not limited to, accelerated bone maturation, increased frequency and duration of erections, and premature sexual development. Anabolic steroid use in adolescence is also correlated with poorer attitudes related to health.[54]
Other side-effects can include alterations in the structure of the heart, such as enlargement and thickening of the left ventricle, which impairs its contraction and relaxation.[4] Possible effects of these alterations in the heart are hypertension, cardiac arrhythmias, congestive heart failure, heart attacks, and sudden cardiac death.[55] These changes are also seen in non-drug-using athletes, but steroid use may accelerate this process.[56][57] However, both the connection between changes in the structure of the left ventricle and decreased cardiac function, as well as the connection to steroid use have been disputed.[58][59]
Psychiatric effects
A 2005 review in CNS Drugs determined that "significant psychiatric symptoms including aggression and violence, mania, and less frequently psychosis and suicide have been associated with steroid abuse. Long-term steroid abusers may develop symptoms of dependence and withdrawal on discontinuation of AAS".[60] High concentrations of AAS, comparable to those likely sustained by many recreational AAS users, produce apoptotic effects on neurons, raising the specter of possibly irreversible neuropsychiatric toxicity. Recreational AAS use appears to be associated with a range of potentially prolonged psychiatric effects, including dependence syndromes, mood disorders, and progression to other forms of substance abuse, but the prevalence and severity of these various effects remains poorly understood.[61] There is no evidence that steroid dependence develops from therapeutic use of anabolic steroids to treat medical disorders, but instances of AAS dependence have been reported among weightlifters and bodybuilders who chronically administered supraphysiologic doses.[62] Mood disturbances (e.g. depression, [hypo-]mania, psychotic features) are likely to be dose- and drug-dependent, but AAS dependence or withdrawal effects seem to occur only in a small number of AAS users.[63]Large-scale long-term studies of psychiatric effects on AAS users are not currently available.[61] In 2003, the first naturalistic long-term study on ten users, seven of which having completed the study, found a high incidence of mood disorders and substance abuse, but few clinically relevant changes in physiological parameters or laboratory measures were noted throughout the study, and these changes were not clearly related to periods of reported AAS use.[64] A 13-month study, which was published in 2006 and which involved 320 body builders and athletes suggests that the wide range of psychiatric side-effects induced by the use of AAS is correlated to the severity of abuse.[65]
Aggression and hypomania
From the mid-1980s onward, the media reported "roid rage" as a side-effect of AAS.[66]A 2005 review determined that some, but not all, randomized controlled studies have found that anabolic steroid use correlates with hypomania and increased aggressiveness, but pointed out that attempts to determine whether AAS use triggers violent behavior have failed, primarily because of high rates of non-participation.[67] A 2008 study on a nationally representative sample of young adult males in the United States found an association between lifetime and past-year self-reported anabolic-androgenic steroid use and involvement in violent acts. Compared with individuals that did not use steroids, young adult males that used anabolic-androgenic steroids reported greater involvement in violent behaviors even after controlling for the effects of key demographic variables, previous violent behavior, and polydrug use.[68] A 1996 review examining the blind studies available at that time also found that these had demonstrated a link between aggression and steroid use, but pointed out that with estimates of over one million past or current steroid users in the United States at that time, an extremely small percentage of those using steroids appear to have experienced mental disturbance severe enough to result in clinical treatments or medical case reports.[69]
A 1996 randomized controlled trial, which involved 43 men, did not find an increase in the occurrence of angry behavior during 10 weeks of administration of testosterone enanthate at 600 mg/week, but this study screened out subjects that had previously abused steroids or had any psychiatric antecedents.[38][70] A trial conducted in 2000 using testosterone cypionate at 600 mg/week found that treatment significantly increased manic scores on the YMRS, and aggressive responses on several scales. The drug response was highly variable. However: 84% of subjects exhibited minimal psychiatric effects, 12% became mildly hypomanic, and 4% (2 subjects) became markedly hypomanic. The mechanism of these variable reactions could not be explained by demographic, psychological, laboratory, or physiological measures.[71]
A 2006 study of two pairs of identical twins, in which one twin used anabolic steroids and the other did not, found that in both cases the steroid-using twin exhibited high levels of aggressiveness, hostility, anxiety, and paranoid ideation not found in the "control" twin.[72] A small-scale study of 10 AAS users found that cluster B personality disorders were confounding factors for aggression.[73]
Depression and suicide
The relationship between AAS use and depression is inconclusive. There have been anecdotal reports of depression and suicide in teenage steroid users,[74] but little systematic evidence. A 1992 review found that anabolic-androgenic steroids may both relieve and cause depression, and that cessation or diminished use of anabolic-androgenic steroids may also result in depression, but called for additional studies due to disparate data.[75]Addiction potential
In an animal study, male rats developed a conditioned place preference to testosterone injections into the nucleus accumbens, an effect blocked by dopamine antagonists, which suggests that androgen reinforcement is mediated by the brain. Moreover, testosterone appears to act through the mesolimbic dopamine system, a common substrate for drugs of abuse. Nonetheless, androgen reinforcement is not comparable to that of cocaine, nicotine, or heroin. Instead, testosterone resembles other mild reinforcers, such as caffeine, or benzodiazepines. The potential for androgen addiction remains to be determined.[76]Medical and ergogenic uses
Medical uses
- Bone marrow stimulation: For decades, anabolic steroids were the mainstay of therapy for hypoplastic anemias due to leukemia or kidney failure, especially aplastic anemia.[77] Anabolic steroids have largely been replaced in this setting by synthetic protein hormones (such as epoetin alfa) that selectively stimulate growth of blood cell precursors.
- Growth stimulation: Anabolic steroids can be used by pediatric endocrinologists to treat children with growth failure.[78] However, the availability of synthetic growth hormone, which has fewer side effects, makes this a secondary treatment.
- Stimulation of appetite and preservation and increase of muscle mass: Anabolic steroids have been given to people with chronic wasting conditions such as cancer and AIDS.[79][80]
- Induction of male puberty: Androgens are given to many boys distressed about extreme delay of puberty. Testosterone is now nearly the only androgen used for this purpose and has been shown to increase height, weight, and fat-free mass in boys with delayed puberty.[81]
- Male contraception, in the form of testosterone enanthate; potential for use in the near-future as a safe, reliable, and reversible male contraceptive.[51][82]
- Stimulation of lean body mass and prevention of bone loss in elderly men, as some studies indicate.[83][84][85] However, a 2006 placebo-controlled trial of low-dose testosterone supplementation in elderly men with low levels of testosterone found no benefit on body composition, physical performance, insulin sensitivity, or quality of life.[86]
- Hormone replacement for men with low levels of testosterone; also effective in improving libido for elderly males.[87][88][89][90]
- Gender Identity Disorder, by producing secondary male characteristics, such as a deeper voice, increased bone and muscle mass, facial hair, increased levels of red blood cells, and clitoral enlargement in female-to-male patients.[91]
Ergogenic use and abuse
See also: Ergogenic use of anabolic steroids
Anabolic steroid users tend to be disillusioned by the portrayal of anabolic steroids as deadly in the media and in politics.[97] According to one study, AAS users also distrust their physicians and in the sample 56% had not disclosed their AAS use to their physicians.[98] Another 2007 study had similar findings, showing that, while 66% of individuals using anabolic steroids for non-medical purposes were willing to seek medical supervision for their steroid use, 58% lacked trust in their physicians, 92% felt that the medical community's knowledge of non-medical anabolic steroid use was lacking, and 99% felt that the public has an exaggerated view of the side-effects of anabolic steroid use.[20] A recent study has also shown that long term AAS users were more likely to have symptoms of muscle dysmorphia and also showed stronger endorsement of more conventional male roles.[99]
Anabolic steroids have been used by men and women in many different kinds of professional sports to attain a competitive edge or to assist in recovery from injury. These sports include bodybuilding, weightlifting, shot put and other track and field, cycling, baseball, wrestling, mixed martial arts, boxing, football, and cricket. Such use is prohibited by the rules of the governing bodies of most sports. Anabolic steroid use occurs among adolescents, especially by those participating in competitive sports. It has been suggested that the prevalence of use among high-school students in the U.S. may be as high as 2.7%.[100] Male students used anabolic steroids more frequently than female students and, on average, those that participated in sports used steroids more often than those that did not.
Legal and sport restrictions
Legal status
United States
The same act also introduced more stringent controls with higher criminal penalties for offenses involving the illegal distribution of anabolic steroids and human growth hormone. By the early 1990s, after anabolic steroids were scheduled in the U.S., several pharmaceutical companies stopped manufacturing or marketing the products in the U.S., including Ciba, Searle, Syntex, and others. In the Controlled Substances Act, anabolic steroids are defined to be any drug or hormonal substance chemically and pharmacologically related to testosterone (other than estrogens, progestins, and corticosteroids) that promote muscle growth. The act was amended by the Anabolic Steroid Control Act of 2004, which added prohormones to the list of controlled substances, with effect from January 20, 2005.[107]
United Kingdom
In the United Kingdom, anabolic steroids are classified as class C drugs for their illegal abuse potential, which puts them in the same class as benzodiazepines. Anabolic steroids are in Schedule 4, which is divided in 2 parts; Part 1 contains most of the benzodiazepines and Part 2 contains the anabolic and androgenic steroids. There are no special controls on Schedule 4 drugs. Many prohormones or designer steroids remain legal in the UK;[citation needed] however, they may be banned by anti-doping regulations in sports.Status in sports
Detection of use
The most commonly employed human physiological specimen for detecting anabolic steroid usage is urine, although both blood and hair have been investigated for this purpose. The anabolic steroids, whether of endogenous or exogenous origin, are subject to extensive hepatic biotransformation by a variety of enzymatic pathways. The primary urinary metabolites may be detectable for up to 30 days after the last use, depending on the specific agent, dose and route of administration. A number of the drugs have common metabolic pathways, and their excretion profiles may overlap those of the endogenous steroids, making interpretation of testing results a very significant challenge to the analytical chemist. Methods for detection of the substances or their excretion products in urine specimens usually involve gas chromatography–mass spectrometry or liquid chromatography-mass spectrometry.[121][122][123][124]Illegal trade
Main article: Illegal trade in anabolic steroids
In the late 2000s, the worldwide trade in illicit AAS increased significantly, and authorities announced record captures on three continents. In 2006, Finnish authorities announced a record seizure of 11.8 million AAS tablets. A year later, the DEA seized 11.4 million units of AAS in the largest U.S seizure ever. In the first three months of 2008, Australian customs reported a record 300 seizures of AAS shipments.[129]
In the U.S., Canada, and Europe, illegal steroids are sometimes purchased just as any other illegal drug, through dealers who are able to obtain the drugs from a number of sources. Illegal anabolic steroids are sometimes sold at gyms and competitions, and through the mail, but may also be obtained through pharmacists, veterinarians, and physicians.[130] In addition, a significant number of counterfeit products are sold as anabolic steroids, in particular via mail order from websites posing as overseas pharmacies. In the U.S., black-market importation continues from Mexico, Thailand, and other countries where steroids are more easily available, as they are legal.[131]
Ergogenic uses for anabolic steroids in sports, racing, and bodybuilding are controversial because of their adverse effects and the potential to gain unfair advantage and considered cheating.
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