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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Crystal structure of human sex hormone-binding globulin, transporting 5α-dihydrotestosterone.[1]

Anabolic steroids, also known as anabolic-androgenic steroids or AAS, are a class of steroid hormones related to the hormone testosterone. They increase protein synthesis within cells, which results in the buildup of cellular tissue (anabolism), especially in muscles. Anabolic steroids also have androgenic and virilizing properties, including the development and maintenance of masculine characteristics such as the growth of the vocal cords and body hair. The word anabolic comes from the Greek: anabole, "to build up", and the word androgenic comes from the Greek: andros, "man" + genein, "to produce".

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. Anabolic steroids also produce increases in muscle mass and physical strength, and are consequently used in sport and bodybuilding to enhance strength or physique. Serious health risks can be produced by long-term use or excessive doses of anabolic steroids. These effects include harmful changes in cholesterol levels (increased bad cholesterol and decreased good cholesterol), acne, high blood pressure, liver damage, and dangerous changes in the structure of the left ventricle of the heart. Some of these effects can be mitigated by exercise, or by taking supplemental drugs.


History

Performance enhancing substances have been used for thousands of years in traditional medicine by societies around the world, with the aim of promoting vitality and strength.[2] In particular, the use of steroid hormones pre-dates their identification and isolation: medical use of testicle extract began in the late 19th century, and its effects on strength were also studied then.[3] In 1889, the 72-year-old British neurologist Charles-Édouard Brown-Séquard injected himself with an extract of dog and guinea pig testicles, and reported at a scientific meeting that these injections had led to a variety of beneficial effects.[4]

The development of modern pharmaceutical anabolic steroids can be traced back to 1931 when Adolf Butenandt, a chemist in Marburg, obtained 15 milligrams of the male hormone androstenone from tens of thousands of liters of urine. This hormone was synthesized in 1934 by Leopold Ruzicka, a chemist in Zurich. It was already known that the testes contained 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.[5][6]

This testicular 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)."[7] 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."[8] 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)."[9] Ruzicka and Butenandt were offered the 1939 Nobel Prize for Chemistry for their work, but the Nazi government forced Butenandt to decline the honor.[5][6]

Clinical trials on humans, involving either oral doses of methyl testosterone or injections of testosterone propionate, began as early as 1937.[5] 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.

During the Second World War, German scientists synthesized other anabolic steroids, and experimented on concentration camp inmates and prisoners of war in an attempt to treat chronic wasting.[5] They also experimented on German soldiers, hoping to increase their aggression. Adolf Hitler himself, according to his physician, was injected with testosterone derivatives to treat various ailments.[10] 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 amateur weight lifters.[11] In response to the success of Russian weightlifters, the U.S. Olypmic Team physician worked with synthetic chemists to develop an anabolic steroid for American weightlifters, resulting in the production of methandrostenolone (Dianabol).[12] Dianabol was approved for use in the U.S. by the Food and Drug Administration in 1958.

From the 1950s until the 1980s, there were doubts that anabolic steroids produced anything more than a placebo effect. In a 1972 study,[13] participants were informed they would receive injections of anabolic steroids on a daily basis, but instead had actually been given a placebo. They reportedly could not tell the difference, and the perceived performance enhancement was similar to that of subjects taking the real anabolic compounds. According to Geraline Lin, a researcher for the National Institute on Drug Abuse, these results remained unchallenged for 18 years, even though the study used inconsistent controls and insignificant doses.[14] In a 2001 study, the effects of high doses of anabolic steroids were examined, by injecting variable doses (up to 600 mg/week) of testosterone enanthate into muscle tissue for 20 weeks. The results showed a clear increase in muscle mass and decrease in fat mass associated with the testosterone doses.[15]

Pharmacology

Further information: [[:Steroid hormone, Steroid hormone receptor]]

Anabolic and androgenic effects

Chemical structure of the natural anabolic hormone testosterone, 17β-hydroxy-4-androsten-3-one.

As the name suggests, anabolic-androgenic steroids have two different, but overlapping, types of effects. First, they are anabolic, meaning that they promote anabolism (cell growth). 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.

Second, these steroids are androgenic or virilizing, meaning in particular that they affect the development and maintenance of masculine characteristics. The biochemical functions of androgens such as testosterone are numerous. 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 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.[16]

Through a combination of these effects, anabolic steroids stimulate the formation of muscles and hence cause an increase in the size of muscle fibers, leading to increased muscle mass and strength.[17][18][19] This increase in muscle mass is mostly due to larger skeletal muscles, and is caused by both increased production of muscle proteins as well as a decline in the breakdown rate of these proteins. A high testosterone dose also decreases the amount of fat in muscle, while increasing protein content. Steroids also decrease overall fat.

Adverse effects

Anabolic steroids can cause many adverse effects. Most of these side effects are dose-dependent, the most common being elevated blood pressure, especially in those with pre-existing hypertension,[20] and harmful changes in cholesterol levels: some steroids cause an increase in bad cholesterol and a decrease in good cholesterol.[21] Anabolic steroids such as testosterone also increase the risk of cardiovascular disease[22] or coronary artery disease.[23][24] Acne is fairly common among anabolic steroid users, mostly due to stimulation of the sebaceous glands by increased testosterone levels.[25][26] Conversion of testosterone to dihydrotestosterone (DHT) can accelerate the rate of premature baldness for those who are genetically predisposed.

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.[27] Possible effects of these alterations in the heart are hypertension, cardiac arrhythmias, congestive heart failure, heart attacks, and sudden cardiac death.[28] These changes are also seen in non-drug using athletes, but steroid use may accelerate this process.[29][30] 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.[31][32]

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.[33] When high doses of such steroids are used for long periods, the liver damage may be severe and lead to liver cancer.[34][35]

There are also gender-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 estrogen), may arise because of increased conversion of testosterone to estrogen by the enzyme aromatase.[36] Reduced sexual function and temporary infertility can also occur in males.[37][38][39] Another male-specific side effect which 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.[40] Female-specific side effects include increases in body hair, 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.[41]

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.[42]

The human androgen receptor bound to testosterone.[43] The protein is shown as a ribbon diagram in red, green and blue, with the steroid shown in white.

Mechanism of action

The effect of anabolic steroids on muscle mass is caused in at least two ways:[44] 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.[45] Anabolic steroids also affect the number of cells that develop into fat-storage cells, by favouring cellular differentiation into muscle cells instead.[46]

The main way in which steroid hormones interact with cells is by binding to proteins called steroid receptors. When steroids bind to these receptors, the proteins move into the cell nucleus and either alter the expression of genes[47] or activate processes that send signals to other parts of the cell.[48]

In the case of anabolic steroids, the receptors involved are called the androgen receptors. The mechanisms of action differ depending on the specific anabolic steroid. Different types of anabolic steroids bind to the androgen receptor with different affinities, depending on their chemical structure.[25] Anabolic steroids such as methandrostenolone bind weakly to this receptor and instead directly affect protein synthesis or glycogenolysis.[49] On the other hand, steroids such as oxandrolone bind tightly to the receptor and act mostly on gene expression.

Medical and non-medical uses

Medical uses

Various anabolic steroids and related compounds.

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.

Non-medical use and abuse

Numerous vials of injectable Anabolic Steroids.

It is difficult to determine what percent of the population in general have actually used anabolic steroids, but the number seems to be fairly low. Studies in the United States have shown 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.[66] 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.[67] Another study found that non medical use of AAS among college students was at or less than 1%.[68] Most users do not compete in sports. Anabolic steroid users often are stereotyped as uneducated "muscle heads" by popular media and culture; however, a 1998 study on steroid users showed them to be the most educated drug users out of all users of controlled substances.[69] Anabolic steroid users also tend to research the drugs they are taking more than any other group of users of controlled substances. Moreover, anabolic steroid users tend to be disillusioned by the portrayal of anabolic steroids as deadly in the media and in politics.[70] According to one study, AAS users also distrust their physicians and in the sample 56% had not disclosed their AAS use to their physicians.[71] 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.[72]

Anabolic steroids have been used by men and women in many different kinds of professional sports (cricket, track and field, weightlifting, bodybuilding, shot put, cycling, baseball, wrestling, mixed martial arts, boxing, football, etc.) to attain a competitive edge or to assist in recovery from injury. Such use is prohibited by the rules of the governing bodies of many 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%.[73] Male students used anabolic steroids more frequently than female students and, on average, those who participated in sports used steroids more often than those who did not.

A vial of the injectable anabolic steroid, depo-testosterone cypionate

Administration

There are three common forms in which anabolic steroids are administered: oral pills, injectable steroids, and skin patches. Oral administration is most convenient, but the steroid must be chemically modified so that the liver cannot break it down before it reaches the systemic circulation; these formulations can cause liver damage in high doses.[74] 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. Transdermal patches (adhesive patches placed on the skin) may also be used to deliver a steady dose through the skin and into the bloodstream.

Minimization of side effects

Further information: [[:Steroid cycle, Post-cycle therapy]]

Various methods of minimizing the adverse effects of anabolic steroids have been implemented by those using them either for medical or other reasons. For example, users may increase their cardiovascular exercise level to help to counter the effects of changes in the left ventricle.[75] Some androgens are converted by the body into estrogen, a process, known as aromatisation, which has potential adverse effects described previously. Consequently, during a steroid cycle, users may also take drugs to prevent aromatisation (called aromatase inhibitors) or drugs which affect estrogen receptor binding (called selective estrogen receptor modulators or SERMs): for example, the SERM tamoxifen prevents binding to the estrogen receptor in the breast, and so it can be used to reduce the risk of gynecomastia.[76]

To combat the natural testosterone suppression and to restore proper function of numerous glands involved, what is known as "post-cycle therapy" or PCT is sometimes used. PCT takes place after each cycle of anabolic steroid use and typically consists of a combination of the following drugs, depending on which protocol is used:

The aim of PCT is to return the body's endogenous hormonal balance to its original state within the shortest period of time. People prone to the premature hair loss exacerbated by steroid use have been known to take the prescription drug finasteride for prolonged periods of time. Finasteride reduces the conversion of testosterone to DHT, the latter having much higher potency for alopecia. Finasteride is useless in the cases when steroid is not converted into a more androgenic derivative.[79] Since anabolic steroids can be toxic to the liver or can cause increases in blood pressure or cholesterol, many users consider it ideal to get frequent blood work tests and blood pressure tests to make sure their blood pressure or cholesterol are still within normal levels.

Misconceptions and controversies

Anabolic steroids, like many other drugs, have generated much controversy. There are also many popular misconceptions concerning their effects and side effects. One common misconception in popular culture and the media is that anabolic steroids are highly dangerous and users' mortality rates are high.[80] Anabolic steroids are used widely in medicine with an acceptable side-effect profile, so long as patients are monitored for possible complications.[81][82][83][84] Former assistant professor at the University of Toronto and World Wrestling Entertainment athletic physician Mauro Di Pasquale has stated, "As used by most people, including athletes, the adverse effects of anabolic steroids appear to be minimal."[85]

One of the earliest misconceptions concerning anabolic steroids revolve around claims that Lyle Alzado died from brain cancer caused by anabolic steroids. Indeed, Alzado himself claimed that anabolic steroids were the cause of his cancer.[86] However, although steroids can cause liver cancer,[87] there is no published evidence that anabolic steroids cause either brain cancer or the specific type of T-cell lymphoma that caused his death.[88][86] Alzado's doctors stated that anabolic steroids did not contribute to his death.[89]

Another example is the misconception that anabolic steroids can shrink the male penis. It is possible that this idea came from temporary side effect that anabolic steroids have on testicle size (testicular atrophy), discussed previously.

Other purported side effects include the idea that anabolic steroids have caused many teenagers to commit suicide.[90] While lower levels of testosterone have been known to cause depression, and ending a steroid cycle temporarily lowers testosterone levels, the hypothesis that anabolic steroids are responsible for suicides among teenagers remains unproven. Although teen bodybuilders have been using steroids since at least the early 1960s, only a few cases suggesting a link between steroids and suicide have been reported in the medical literature.[91]

Another condition that is frequently discussed as a possible side effect of anabolic steroids is known as "roid rage"; however there is no consensus in the medical literature as to whether such a condition actually exists. Testosterone levels are indeed associated with aggression and hypomania, but the link between other anabolic steroids and aggression remains unclear.[92] While some studies have shown a correlation between manic symptoms and anabolic steroid use,[93] later studies have questioned these conclusions.[94] Currently, three blind studies have demonstrated a link between aggression and steroid use, but with estimates of over one million past or current steroid users in the United states, 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.[95] [96] Individual studies vary in their findings, with some reporting no increase in aggression or hostility with anabolic steroid use, and others finding a correlation.[97][98] Including a 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.[99]

It has previously been theorized that some studies showing a correlation between angry behavior and steroid use are confounded by the fact that steroid users are likely to demonstrate cluster B personality disorders prior to administering steroids.[100] In addition, many case studies have concluded anabolic steroids have little or no real effect on increased aggressive behavior.[94][81][101][102]

Arnold Schwarzenegger is the subject of an urban legend regarding the side effects of anabolic steroids. Schwarzenegger has admitted to using anabolic steroids during his bodybuilding career for many years prior to them being made illegal,[103] and in 1997 he underwent surgery to correct a defect relating to his heart. Some have assumed this was due to anabolic steroids. Although anabolic steroid use can sometimes cause unfavorable enlargement and thickening of the left ventricle, Schwarzenegger was born with a congenital genetic defect in which his heart had a bicuspid aortic valve — in other words, whereas normal hearts have three cusps, his had only two, which can occasionally cause problems later in life.[104]




See also

References

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