Anabolic steroids, also known more properly as anabolic-androgenic steroids (AAS), are steroidal androgens that are structurally related to and have similar effects as testosterone in the body. They are anabolic and increase protein within cells, especially in skeletal muscles. AAS also have androgenic and virilizing effects, including induction of the development and maintenance of masculine secondary sexual characteristics such as the growth of the vocal cords and body hair. The word anabolic, referring to anabolism, comes from the Greek ἀναβολή anabole, "that which is thrown up, mound."
AAS were synthesized in the 1930s, and are now used therapeutically in medicine to stimulate muscle 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.
Health risks can be produced by long-term use or excessive doses of AAS. 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 most oral AAS), and dangerous changes in the structure of the left ventricle of the heart. Conditions pertaining to hormonal imbalances such as gynecomastia and testicular size reduction may also be caused by AAS.
Ergogenic uses for AAS in sports, racing, and bodybuilding as performance-enhancing drugs are controversial because of their adverse effects and the potential to gain unfair advantage in competitive physical competitions. Their use is referred to as doping and banned by most major sporting bodies. For many years, AAS have been by far the most detected doping substances in IOC-accredited laboratories. 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.
Examples of AAS
The most commonly used AAS in medicine are testosterone and its various esters (but most commonly testosterone undecanoate, testosterone enanthate, testosterone cypionate, and testosterone propionate), nandrolone (as, most commonly, nandrolone decanoate or nandrolone phenylpropionate), stanozolol, and metandienone (methandrostenolone). Others also available and used commonly but to a lesser extent include methyltestosterone, oxandrolone, mesterolone, and oxymetholone, as well as drostanolone propionate (dromostanolone propionate), metenolone (methylandrostenolone), and fluoxymesterone. Boldenone undecylenate and trenbolone acetate are used in veterinary medicine.
Since the discovery and synthesis of testosterone in the 1930s, anabolic steroids have been used by physicians for many purposes, with varying degrees of success, for the treatment of:
- Bone marrow stimulation: For decades, anabolic steroids were the mainstay of therapy for hypoplastic anemias due to leukemia or kidney failure, especially aplastic anemia. 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. 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.
- 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.
- Male contraception, in the form of testosterone enanthate; potential for use in the near-future as a safe, reliable, and reversible male contraceptive.
- Stimulation of lean body mass and prevention of bone loss in elderly men, as some studies indicate. 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.
- Hormone replacement for men with low levels of testosterone; also effective in improving libido for elderly males.
- Gender dysphoria, 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 trans man patients, among females or those who develop female secondary sexual characteristics but desire to rather be read as male or look more ambiguous, such as a number of non-binary transgender people, both intersex and dyadic, and dysphoric non-transgender intersex men.
- Increased Maximum Inspiratory Pressure: A study in "Research in Sports Medicine" has found that the combination of resistance training and anabolic steroid administration produce a significant increase in MIP in a cohort of long-term AAS users.
Most steroid users are not athletes. Between 1 million and 3 million people (1% of the population) are thought to have misused AAS in the United States. Studies in the United States have shown that anabolic steroid users tend to be mostly middle-class heterosexual men with a median age of about 25 who are noncompetitive bodybuilders and non-athletes and use the drugs for cosmetic purposes. "Among 12- to 17-year-old boys, use of steroids and similar drugs jumped 25 percent from 1999 to 2000, with 20 percent saying they use them for looks rather than sports, a study by insurer Blue Cross Blue Shield found."(Eisenhauer) Another study found that non-medical use of AAS among college students was at or less than 1%. According to a recent survey, 78.4% of steroid users were noncompetitive bodybuilders and non-athletes, while about 13% reported unsafe injection practices such as reusing needles, sharing needles, and sharing multidose vials, though a 2007 study found that sharing of needles was extremely uncommon among individuals using anabolic steroids for non-medical purposes, less than 1%. Another 2007 study found that 74% of non-medical anabolic steroid users had post-secondary degrees and more had completed college and fewer had failed to complete high school than is expected from the general populace. The same study found that individuals using anabolic steroids for non-medical purposes had a higher employment rate and a higher household income than the general population. Anabolic steroid users tend to research the drugs they are taking more than other controlled-substance users; however, the major sources consulted by steroid users include friends, non-medical handbooks, internet-based forums, blogs, and fitness magazines, which can provide questionable or inaccurate information.
Anabolic steroid users tend to be disillusioned by the portrayal of anabolic steroids as deadly in the media and in politics. According to one study, AAS users also distrust their physicians and in the sample 56% had not disclosed their AAS use to their physicians. 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. 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. A recent study in the Journal of Health Psychology showed that many users believed that steroids used in moderation were safe.
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%. 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.
There are four common forms in which anabolic steroids are administered: oral pills; injectable steroids; creams/gels for topical application; and skin patches. Oral administration is the most convenient. Testosterone administered by mouth is rapidly absorbed, but it is largely converted to inactive metabolites, and only about 1/6 is available in active form. In order to be sufficiently active when given by mouth, testosterone derivatives are alkylated at the 17 position, e.g. methyltestosterone and fluoxymesterone. This modification reduces the liver's ability to break down these compounds before they reach the systemic circulation.
Testosterone can be administered parenterally, but it has more irregular prolonged absorption time and greater activity in muscle in 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. 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.
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.
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". 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 neurotoxicity. 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. 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. 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.
Large-scale long-term studies of psychiatric effects on AAS users are not currently available. 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. 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.
Diagnostic Statistical Manual assertion
DSM-IV lists General diagnostic criteria for a personality disorder guideline that "The pattern must not be better accounted for as a manifestation of another mental disorder, or to the direct physiological effects of a substance (e.g. drug or medication) or a general medical condition (e.g. head trauma).". As a result, anabolic steroid users may get misdiagnosed by a psychiatrist not told about their habit.
Cooper, Noakes, Dunne, Lambert, and Rochford identified that anabolic–androgenic steroid (AAS) using individuals are more likely to score higher on borderline (4.7 times), antisocial (3.8 times), paranoid (3.4 times), schizotypal (3.1 times), histrionic (2.9 times), passive-aggressive (2.4 times), and narcissistic (1.6 times) personality profiles than non-users. Other studies have suggested that antisocial personality disorder is slightly more likely among anabolic steroid users than among non-users (Pope & Katz, 1994). Bipolar dysfunction, substance dependency, and conduct disorder have also been associated with AAS use.
Mood and anxiety
Affective disorders have long been recognised as a complication of anabolic steroid use. Case reports describe both hypomania and mania, along with irritability, elation, recklessness, racing thoughts and feelings of power and invincibility that did not meet the criteria for mania/hypomania. Of 53 bodybuilders who used anabolic steroids, 27 (51%) reported unspecified mood disturbance.
Aggression and hypomania
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. 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. 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.
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. 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.
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. A small-scale study of 10 AAS users found that cluster B personality disorders were confounding factors for aggression.
Androgenic steroids are known to increase aggression with greater likelihood when compared to more anabolic steroids. Trenbolone is frequently noted for its increases in aggression. Equipoise is known to increase anxiety in some users.
The relationship between AAS use and depression is inconclusive. There have been anecdotal reports of depression and suicide in teenage steroid users, 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. In the case of suicide, 3.9% of a sample of 77 those classified as AAS users reported attempting suicide during withdrawal (Malone, Dimeff, Lombardo, & Sample, 1995).
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. In addition to morphological changes of the heart which may alter cardiovascular inefficiency irreversibly.
Anabolic steroids have been shown to alter fasting blood sugar and glucose tolerance tests. Anabolic steroids such as testosterone also increase the risk of cardiovascular disease or coronary artery disease. Acne is fairly common among anabolic steroid users, mostly due to stimulation of the sebaceous glands by increased testosterone levels. 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.
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.
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. Possible effects of these alterations in the heart are hypertension, cardiac arrhythmias, congestive heart failure, heart attacks, and sudden cardiac death. These changes are also seen in non-drug-using athletes, but steroid use may accelerate this process. 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.
AAS use can cause harmful changes in cholesterol levels: Some steroids cause an increase in LDL "bad" cholesterol and a decrease in HDL "good" cholesterol. In addition, steroids provoke a rapid increase in body weight and an accompanying rise in blood pressure, both of which leave users more vulnerable to a cardiovascular event.
AAS use in adolescents quickens bone maturation and may reduce adult height in high doses. Low doses of anabolic steroids such as oxandrolone are used in the treatment of idiopathic short stature, but this may only quicken maturation rather than increasing adult height.
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. Reduced sexual function and temporary infertility can also occur in males. 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.
Female-specific side effects include increases in body hair, permanent deepening of the voice, enlarged clitoris, and temporary decreases in menstrual cycles. Alteration of fertility and ovarian cysts can also occur in females. 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.
Kidney tests revealed that nine of the ten steroid users developed a condition called focal segmental glomerulosclerosis, a type of scarring within the kidneys. The kidney damage in the bodybuilders has similarities to that seen in morbidly obese patients, but appears to be even more severe.
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. Peliosis hepatis has been increasingly recognised with the use of anabolic steroids.
Mechanism of action
The pharmacodynamics of anabolic steroids are unlike peptide hormones. Water-soluble peptide hormones cannot penetrate the fatty cell membrane and only indirectly affect the nucleus of target cells through their interaction with the cell’s surface receptors. However, as fat-soluble hormones, anabolic steroids are membrane-permeable and influence the nucleus of cells by direct action. The pharmacodynamic action of anabolic steroids begin when the exogenous hormone penetrates the membrane of the target cell and binds to an androgen receptor located in the cytoplasm of that cell. From there, the compound hormone-receptor diffuses into the nucleus, where it either alters the expression of genes or activates processes that send signals to other parts of the cell. Different types of anabolic steroids bind to the androgen receptor with different affinities, depending on their chemical structure. Some anabolic steroids such as methandrostenolone bind weakly to this receptor in vitro, but still exhibit androgenic effects in vivo. The reason for this discrepancy is not known.
The effect of anabolic steroids on muscle mass is caused in at least two ways: 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. Anabolic steroids also affect the number of cells that develop into fat-storage cells, by favouring cellular differentiation into muscle cells instead. Anabolic steroids can also decrease fat by increasing basal metabolic rate (BMR), since an increase in muscle mass increases BMR.
Anabolic and androgenic effects
As the name suggests, anabolic-androgenic steroids have two different, but overlapping, types of effects: anabolic, meaning that they promote anabolism (cell growth), and androgenic (or virilising), meaning that they affect the development and maintenance of masculine characteristics.
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.
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 size does not change due to steroids ), increased vocal cord size, increased libido, suppression of natural sex hormones, and impaired production of sperm. Effects on women include deepening of the voice, facial hair growth, and possibly a decrease in breast size. Men may develop an enlargement of breast tissue, known as gynecomastia, testicular atrophy, and a reduced sperm count.
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.
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). 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
Body weight in men 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.
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.
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. For almost two decades, it was assumed that AAS exerted significant effects only in experienced strength athletes. A randomized controlled trial 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. This dose is sufficient to significantly improve lean muscle mass relative to placebo even in subjects that did not exercise at all. The anabolic effects of testosterone enanthate were highly dose dependent.
Dissociation of anabolic and androgenic effects
Endogenous androgens like testosterone and DHT and synthetic anabolic-androgenic steroids mediate their effects by binding to and activating the androgen receptor (AR). On the basis of animal bioassays, the effects of these agents have been divided into two partially dissociable types: anabolic (myotrophic) and androgenic. Dissociation between the ratios of these two types of effects is observed in rat bioassays with various anabolic-androgenic steroids relative to the ratio observed with testosterone. Explanations for the dissociation include differences in intracellular metabolism, functional selectivity (recruitment of coactivators), and non-genomic mechanisms (i.e., signaling through non-AR membrane androgen receptors). Support for the latter two explanations is limited and more hypothetical, but there is a good deal of support for the intracellular metabolism explanation.
The measurement of the dissociation between anabolic and androgenic effects among anabolic-androgenic steroids is based largely on a simple although arguably unsophisticated and outdated model involving rat tissue bioassays. It is referred to as the myotrophic-androgenic index. In this model, anabolic (myotrophic) activity is measured by change in the weight of the rat bulbocavernosus/levator ani muscle and androgenic activity is measured by change in the weight of the rat ventral prostate (or, alternatively, the rat seminal vesicles) in response to exposure of the anabolic-androgenic steroid, and the measurements are then compared and used to form a ratio.
Testosterone is metabolized in various tissues by 5α-reductase into DHT, which is 3- to 10-fold more potent as an AR agonist, and by aromatase into estradiol, which is an estrogen and lacks significant AR affinity. In addition, DHT is metabolized by 3α-hydroxysteroid dehydrogenase (3α-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) into metabolites with little or no AR affinity. 5α-Reductase is widely distributed throughout the body, and is concentrated to various extents in skin (particularly the scalp, beard-area of the face, pubic area, and genital area (penis and scrotum)), prostate, seminal vesicles, liver, and the brain. In contrast, expression of 5α-reductase in skeletal muscle is undetectable. Aromatase is highly expressed in adipose tissue and the brain, and is also expressed significantly in skeletal muscle.
Endogenous androgens like testosterone and DHT and synthetic anabolic-androgenic steroids are analogues and are very similar structurally, and due to this structural similarity, have the capacity to bind to and be metabolized by the same enzymes. According to the intracellular metabolism explanation, the androgenic-to-anabolic ratio of a given AR agonist is based on its capacity to be transformed by the aforementioned enzymes in conjunction with the AR activity of any resulting products. As an example, whereas the AR activity of testosterone is greatly potentiated by local conversion via 5α-reductase into DHT in tissues where 5α-reductase is expressed, an anabolic steroid that is not metabolized by 5α-reductase or has already been 5α-reduced, such as DHT itself or a derivative (like mesterolone or drostanolone), would not experience such potentiation in said tissues. Moreover, nandrolone is metabolized by 5α-reductase, but unlike the case of testosterone and DHT, the 5α-reduced metabolite of nandrolone has much lower affinity for the AR than does nandrolone itself, and this results in reduced AR activation in 5α-reductase-expressing tissues. As so-called "androgenic" tissues such as skin/hair follicles and reproductive tissues are very high in 5α-reductase expression, while skeletal muscle is virtually devoid of 5α-reductase, this may primarily explain the high myotrophic-androgenic ratio and dissociation seen with nandrolone, as well as with various other anabolic-androgenic steroids.
Aside from 5α-reductase, aromatase may inactivate testosterone signaling in skeletal muscle and adipose tissue, so anabolic-androgenic steroids that lack aromatase affinity, in addition to being free of the potential side effect of gynecomastia, might be expected to have a higher myotrophic-androgenic ratio in comparison. In addition, DHT is inactivated by high activity of 3α-HSD in skeletal muscle (and cardiac tissue), and anabolic-androgenic steroids that lack affinity for 3α-HSD could similarly be expected to have a higher myotrophic-androgenic ratio (although perhaps also increased long-term cardiovascular risks).
The intracellular metabolism theory explains how and why remarkable dissociation between anabolic and androgenic effects can occur, but why dissociation is invariably incomplete. In support of the model is the rare condition congenital 5α-reductase deficiency, in which the 5α-reductase enzyme is defective, production of DHT is impaired, and DHT levels are very low while testosterone levels are normal. Males with this condition are born with ambiguous genitalia and an underdeveloped prostate gland. In addition, saliently, such males develop normal musculature, voice changes/deepening, and libido at puberty, but have little to no acne or facial, pubic, or body hair, minimal enlargement of the prostate, and no incidence of male-pattern baldness or prostate cancer. They also notably do not develop gynecomastia as a consequence of their condition.
Changes in endogenous testosterone levels may also contribute to differences in myotrophic-androgenic ratio between testosterone and synthetic anabolic-androgenic steroids. Anabolic-androgenic steroids are antigonadotropic – that is, they dose-dependently suppress gonadal testosterone production and hence reduce systemic testosterone concentrations. By suppressing endogenous testosterone levels and effectively replacing AR signaling in the body with that of the exogenous anabolic-androgenic steroid, the myotrophic-androgenic ratio would be expected to be further increased, and this hence may be yet an additional mechanism contributing to the differences in myotrophic-androgenic ratio. In addition, some anabolic-androgenic steroids, such as nandrolone, are also potent progestogens, and activation of the progesterone receptor is antigonadotropic similarly to activation of the AR. As such, combined progestogenic activity might further increase the myotrophic-androgenic ratio for a given anabolic-androgenic steroid.
Interaction with the GABAA receptor
Some anabolic-androgenic steroids, such as testosterone, dihydrotestosterone, stanozolol, and methyltestosterone, have been found to modulate the GABAA receptor similarly to endogenous neurosteroids like allopregnanolone, 3α-androstanediol, dehydroepiandrosterone sulfate, and pregnenolone sulfate. It has been suggested that this may contribute as an alternative or additional mechanism to the neurological and behavioral effects of anabolic-androgenic steroids.
Comparison of AAS
5α-Reductase and androgenicity
Testosterone can be robustly converted by 5α-reductase into dihydrotestosterone (DHT) in so-called androgenic tissues such as skin, scalp, prostate, and seminal vesicles, but not in muscle or bone, where 5α-reductase either is not expressed or is only minimally expressed. As DHT is 3- to 10-fold more potent as an agonist of the androgen receptor (AR) than is testosterone, the AR agonist activity of testosterone is thus markedly and selectively potentiated in such tissues. In contrast to testosterone, DHT and other 4,5α-dihydrogenated AAS are already 5α-reduced, and for this reason, cannot be potentiated in androgenic tissues. 19-Nortestosterone derivatives like nandrolone can be metabolized by 5α-reductase similarly to testosterone, but 5α-reduced metabolites of 19-nortestosterone derivatives tend to have reduced activity as AR agonists, resulting in reduced androgenic activity in tissues that express 5α-reductase. In addition, some 19-nortestosterone derivatives, including trestolone (7α-methyl-19-nortestosterone (MENT)), 11β-methyl-19-nortestosterone (11β-MNT), and dimethandrolone (7α,11β-dimethyl-19-nortestosterone), cannot be 5α-reduced. Conversely, 17α-alkylated AAS can be 5α-reduced and are potentiated in androgenic tissues similarly to testosterone, with an exception being 17α-alkylated AAS that are already 4,5α-reduced.
The capacity to be metabolized by 5α-reductase and the AR activity of the resultant metabolites appears to be one of the major, if not the most important determinant of the androgenic-myotrophic ratio for a given AAS. AAS that are not potentiated by 5α-reductase or that are weakened by 5α-reductase in androgenic tissues have a reduced risk of androgenic side effects such as acne, androgenic alopecia (male-pattern baldness), hirsutism (excessive male-pattern hair growth), benign prostatic hyperplasia (prostate enlargement), and prostate cancer, while incidence and magnitude of other effects such as muscle hypertrophy, bone changes, voice deepening, and changes in sex drive show no difference.
Aromatase and estrogenicity
Testosterone can be metabolized by aromatase into estradiol, and many other AAS can be metabolized into their corresponding estrogenic metabolites as well. As an example, the 17α-alkylated AAS methyltestosterone and metandienone are converted by aromatase into methylestradiol. 4,5α-Dihydrogenated derivatives of testosterone such as DHT cannot be aromatized, whereas 19-nortestosterone derivatives like nandrolone can be but to a greatly reduced extent. Some 19-nortestosterone derivatives, such as dimethandrolone and 11β-MNT, cannot be aromatized due to steric hindrance provided by their 11β-methyl group, whereas the closely related AAS trestolone (7α-methyl-19-nortestosterone), in relation to its lack of an 11β-methyl group, can be aromatized. AAS that are 17α-alkylated (and not also 4,5α-reduced or 19-demethylated) are also aromatized but to a lesser extent than is testosterone. However, it is notable that estrogens that are 17α-substituted (e.g., ethinyl estradiol and methylestradiol) are of markedly increased estrogenic potency due to improved metabolic stability, and for this reason, 17α-alkylated AAS can actually have high estrogenicity and comparatively greater estrogenic effects than testosterone.
The major effect of estrogenicity is gynecomastia (woman-like breasts). AAS that have a high potential for aromatization like testosterone and particularly methyltestosterone show a high risk of gynecomastia, while AAS that have a reduced potential for aromatization like nandrolone show a much lower risk (though still significant at high dosages). In contrast, AAS that are 4,5α-reduced, and some other AAS (e.g., 11β-methylated 19-nortestosterone derivatives), have no risk of gynecomastia. In addition to gynecomastia, AAS with high estrogenicity have increased antigonadotropic activity, which results in increased potency in suppression of the hypothalamic-pituitary-gonadal axis and gonadal testosterone production.
Some 19-nortestosterone derivatives, including nandrolone, ethylestrenol (ethylnandrol), metribolone (R-1881), trestolone, 11β-MNT, dimethandrolone, and others, are potent agonists of the progesterone receptor (AR) and hence are progestogens in addition to AAS. Similarly to the case of estrogenic activity, the progestogenic activity of these drugs serves to augment their antigonadotropic activity. This results in increased potency and effectiveness of these AAS as antispermatogenic agents and male contraceptives (or, put in another way, increased potency and effectiveness in producing azoospermia and male infertility).
Oral activity and hepatotoxicity
Non-17α-alkylated testosterone derivatives such as testosterone itself, DHT, and nandrolone all have poor oral bioavailability due to extensive first-pass hepatic metabolism and hence are not orally active. A notable exception to this are AAS that are androgen precursors or prohormones, including dehydroepiandrosterone (DHEA), androstenediol, androstenedione, boldione (androstadienedione), bolandiol (norandrostenediol), bolandione (norandrostenedione), dienedione, mentabolan (MENT dione, trestione), and methoxydienone (methoxygonadiene) (although these are relatively weak AAS). AAS that are not orally active are used almost exclusively in the form of esters administered by intramuscular injection, which act as depots and function as long-acting prodrugs. Examples include testosterone, as testosterone cypionate, testosterone enanthate, and testosterone propionate, and nandrolone, as nandrolone phenylpropionate and nandrolone decanoate, among many others (see here for a full list of testosterone and nandrolone esters). An exception is the very long-chain ester testosterone undecanoate, which is orally active, albeit with only very low oral bioavailability (approximately 3%). In contrast to most other AAS, 17α-alkylated testosterone derivatives show resistance to metabolism due to steric hindrance and are orally active, though they may be esterified and administered via intramuscular injection as well.
In addition to oral activity, 17α-alkylation also confers a high potential for hepatotoxicity, and all 17α-alkylated AAS have been associated, albeit uncommonly and only after prolonged use (different estimates between 1 and 17%), with hepatotoxicity. In contrast, testosterone esters have only extremely rarely or never been associated with hepatotoxicity, and other non-17α-alkylated AAS only rarely, although long-term use may reportedly still increase the risk of hepatic changes (but at a much lower rate than 17α-alkylated AAS, and reportedly not at replacement dosages). In accordance, D-ring glucuronides of testosterone and DHT have been found to be cholestatic.
Aside from prohormones and testosterone undecanoate, almost all orally active AAS are 17α-alkylated. A few AAS that are not 17α-alkylated are orally active. Some examples include the testosterone 17-ethers cloxotestosterone, quinbolone, and silandrone, which are prodrugs (to testosterone, boldenone (Δ1-testosterone), and testosterone, respectively), the DHT 17-ethers mepitiostane, mesabolone, and prostanozol (which are also prodrugs), the 1-methylated DHT derivatives mesterolone and metenolone (although these are relatively weak AAS), and the 19-nortestosterone derivatives dimethandrolone and 11β-MNT, which have improved resistance to first-pass hepatic metabolism due to their 11β-methyl groups (in contrast to them, the related AAS trestolone (7α-methyl-19-nortestosterone) is not orally active). As these AAS are not 17α-alkylated, they show minimal potential for hepatotoxicity.
DHT, via its metabolite 3α-androstanediol (produced by 3α-hydroxysteroid dehydrogenase (3α-HSD)), is a neurosteroid that acts via positive allosteric modulation of the GABAA receptor. Testosterone, via conversion into DHT, also produces 3α-androstanediol as a metabolite and hence has similar activity. Some AAS that are or can be 5α-reduced, including testosterone, DHT, stanozolol, and methyltestosterone, among many others, can or may modulate the GABAA receptor, and this may contribute as an alternative or additional mechanism to their central nervous system effects in terms of mood, anxiety, aggression, and sex drive.
Detection in body fluids
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.
Isolation of gonadal anabolic-androgenic steroids
The use of gonadal steroids pre-dates their identification and isolation. Medical use of testicle extract began in the late 19th century while its effects on strength were still being studied. The isolation of gonadal steroids can be traced back to 1931, when Adolf Butenandt, a chemist in Marburg, purified 15 milligrams of the male hormone androstenone from tens of thousands of litres of urine. This steroid was subsequently synthesized in 1934 by Leopold Ruzicka, a chemist in Zurich.
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. 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)." 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." 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)." 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.
Clinical trials on humans, involving either oral doses of methyltestosterone or injections of testosterone propionate, began as early as 1937. 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. 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.:6 Adolf Hitler himself, according to his physician, was injected with testosterone derivatives to treat various ailments. AAS were used in experiments conducted by the Nazis on concentration camp inmates, and later by the allies attempting to treat the malnourished victims that survived Nazi camps.:6 President John F. Kennedy was administered steroids both before and during his presidency.
Development of synthetic AAS
The development of muscle-building properties of testosterone was pursued in the 1940s, in the Soviet Union and in Eastern Bloc countries such as East Germany, where steroid programs were used to enhance the performance of Olympic and other amateur weight lifters. In response to the success of Russian weightlifters, the U.S. Olympic Team physician John Ziegler worked with synthetic chemists to develop an anabolic steroid with reduced androgenic effects. Ziegler's work resulted in the production of methandrostenolone, which Ciba Pharmaceuticals marketed as Dianabol. The new steroid was approved for use in the U.S. by the Food and Drug Administration (FDA) in 1958. It was most commonly administered to burn victims and the elderly. The drug's off-label users were mostly bodybuilders and weight lifters. Although Ziegler prescribed only small doses to athletes, he soon discovered that those having abused Dianabol suffered from enlarged prostates and atrophied testes. AAS were placed on the list of banned substances of the IOC in 1976, and a decade later the committee introduced 'out-of-competition' doping tests because many athletes used AAS in their training period rather than during competition.
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.
Society and culture
The legal status of anabolic steroids varies from country to country: some have stricter controls on their use or prescription than others though in many countries they are not illegal. In the U.S., anabolic steroids are currently listed as Schedule III controlled substances under the Controlled Substances Act, which makes simple possession of such substances without a prescription a federal crime punishable by up to one year in prison for the first offense. Unlawful distribution or possession with intent to distribute anabolic steroids as a first offense is punished by up to ten years in prison. In Canada, anabolic steroids and their derivatives are part of the Controlled drugs and substances act and are Schedule IV substances, meaning that it is illegal to obtain or sell them without a prescription; however, possession is not punishable, a consequence reserved for schedule I, II, or III substances. Those guilty of buying or selling anabolic steroids in Canada can be imprisoned for up to 18 months. Import and export also carry similar penalties. In Canada, researchers have concluded that steroid use among student athletes is extremely widespread. A study conducted in 1993 by the Canadian Centre for Drug-Free Sport found that nearly 83,000 Canadians between the ages of 11 and 18 use steroids. Anabolic steroids are also illegal without prescription in Australia, Argentina, Brazil and Portugal, and are listed as Class C Controlled Drugs in the United Kingdom. Anabolic steroids are readily available without a prescription in some countries such as Mexico and Thailand.
The history of the U.S. legislation on anabolic steroids goes back to the late 1980s, when the U.S. Congress considered placing anabolic steroids under the Controlled Substances Act following the controversy over Ben Johnson's victory at the 1988 Summer Olympics in Seoul. Anabolic steroids were added to Schedule III of the Controlled Substances Act in the Anabolic Steroids Control Act of 1990.
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.
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.
Part 1 drugs are subject to full import and export controls with possession being an offence without an appropriate prescription. There is no restriction on the possession when it is part of a medicinal product. Part 2 drugs require a Home Office licence for importation and export unless the substance is in the form of a medicinal product and is for self-administration by a person.
Status in sports
Anabolic steroids are banned by all major sports bodies including Association of Tennis Professionals, Major League Baseball, Fédération Internationale de Football Association the Olympics, the National Basketball Association, the National Hockey League, World Wrestling Entertainment and the National Football League. The World Anti-Doping Agency (WADA) maintains the list of performance-enhancing substances used by many major sports bodies and includes all anabolic agents, which includes all anabolic steroids and precursors as well as all hormones and related substances. Spain has passed an anti-doping law creating a national anti-doping agency. Italy passed a law in 2000 where penalties range up to three years in prison if an athlete has tested positive for banned substances. In 2006, Russian President Vladimir Putin signed into law ratification of the International Convention Against Doping in Sport which would encourage cooperation with WADA. Many other countries have similar legislation prohibiting anabolic steroids in sports including Denmark, France, the Netherlands and Sweden.
United States federal law enforcement officials have expressed concern about AAS use by police officers. "It's a big problem, and from the number of cases, it's something we shouldn't ignore. It's not that we set out to target cops, but when we're in the middle of an active investigation into steroids, there have been quite a few cases that have led back to police officers," says Lawrence Payne, a spokesman for the United States Drug Enforcement Administration. The FBI Law Enforcement Bulletin stated that “Anabolic steroid abuse by police officers is a serious problem that merits greater awareness by departments across the country". It is also believed that police officers across the United Kingdom "are using criminals to buy steroids" which he claims to be a top risk factor for police corruption.
Following the murder-suicide of Chris Benoit in 2007, the Oversight and Government Reform Committee investigated steroid usage in the wrestling industry. The Committee investigated WWE and Total Nonstop Action Wrestling (TNA), asking for documentation of their companies' drug policies. WWE CEO and Chairman, Linda and Vince McMahon respectively, both testified. The documents stated that 75 wrestlers—roughly 40 percent—had tested positive for drug use since 2006, most commonly for steroids.
Anabolic steroids are frequently produced in pharmaceutical laboratories, but, in nations where stricter laws are present, they are also produced in small home-made underground laboratories, usually from raw substances imported from abroad. In these countries, the majority of steroids are obtained illegally through black market trade. These steroids are usually manufactured in other countries, and therefore must be smuggled across international borders. As with most significant smuggling operations, organized crime is involved.
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.
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. 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.
- List of androgens/anabolic steroids
- Selective androgen receptor modulator
- Androgen insensitivity syndrome
- Steroid rosacea
- Steroid use in Bollywood
- Bigger, Stronger, Faster
- Juiced: Wild Times, Rampant 'Roids, Smash Hits & How Baseball Got Big
- List of androgens/anabolic steroids available in the United States
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