Chemical structure of the natural AAS testosterone (androst-4-en-17?-ol-3-one).
|Synonyms||Anabolic steroids; Androgens|
|Biological target||Androgen receptor|
|Chemical class||Steroids; Androstanes; Estranes|
Anabolic steroids, also known more properly as anabolic-androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects to testosterone. They are anabolic and increase protein within cells, especially in skeletal muscles, and also have varying degrees of androgenic and virilizing effects, including induction of the development and maintenance of masculine secondary sexual characteristics such as the growth of facial and body hair. The word anabolic, referring to anabolism, comes from the Greek ? anabole, "that which is thrown up, mound". Androgens or AAS are one of three types of sex hormone agonists, the others being estrogens like estradiol and progestogens like progesterone.
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. These risks are further increased when, as they often do, athletes take steroids alongside other drugs, causing significantly more damage to their bodies. The effect of anabolic steroids on the heart can cause myocardial infarction and strokes. Conditions pertaining to hormonal imbalances such as gynecomastia and testicular size reduction may also be caused by AAS. In women and children, AAS can cause irreversible masculinization.
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 physical competitions. Their use is referred to as doping and banned by most major sporting bodies. Athletes have been looking for drugs to enhance their athletic abilities since the Olympics started in Ancient Greece. 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.
Since the discovery and synthesis of testosterone in the 1930s, AAS have been used by physicians for many purposes, with varying degrees of success. These can broadly be grouped into anabolic, androgenic, and other uses.
Most steroid users are not athletes. In the United States, between 1 million and 3 million people (1% of the population) are thought to have used AAS. Studies in the United States have shown that AAS 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 AAS for non-medical purposes, less than 1%. Another 2007 study found that 74% of non-medical AAS 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 AAS for non-medical purposes had a higher employment rate and a higher household income than the general population. AAS 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.
AAS users tend to be unhappy with the portrayal of AAS 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 AAS 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 AAS use was lacking, and 99% felt that the public has an exaggerated view of the side-effects of AAS 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.
AAS 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. AAS 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 AAS more frequently than female students and, on average, those that participated in sports used steroids more often than those that did not.
|Route||Medication||Major brand names||Dosage range|
|Ethylestrenol||Maxibolin, Orabolin||2-8 mg/day|
|Fluoxymesterone||Halotestin, Ora-Testryl, Ultandren||2-40 mg/day|
|Metenolone acetate||Primobolan||10-150 mg/day|
|Methyltestosterone||Android, Metandren, Testred||1.5-200 mg/day|
|Norethandrolone||Nilevar, Pronabol||20-30 mg/day|
|Oxandrolone||Anavar, Oxandrin||2.5-20 mg/day|
|Oxymetholone||Anadrol, Anapolon||1-5 mg/kg/day (50-150 mg/day)|
|Testosteronea||-||400-800 mg/day (in divided doses)|
|Testosterone undecanoate||Andriol, Jatenzo||40-80 mg/2-4x day (with food)|
|Injection||Drostanolone propionate||Drolban, Masteril, Masteron||100 mg 3x/week|
|Metenolone enanthate||Primobolan Depot||25-100 mg/week|
|Nandrolone decanoate||Deca-Durabolin||12.5-200 mg/week (total)|
|Nandrolone phenylpropionate||Durabolin||6.25-200 mg/week (total)|
|Stanozolol||Winstrol Depot||50 mg 1x/2-3 weeks|
|Testosterone||Andronaq, Sterotate, Virosterone||25-100 mg 2-3x/week|
|Testosterone cypionate||Depo-Testosterone||50-400 mg 1x/1-4 weeks|
|Testosterone enanthate||Delatestryl||50-400 mg 1x/1-4 weeks|
|Testosterone propionate||Testoviron||25-50 mg 2-3x/week|
|Testosterone undecanoate||Aveed, Nebido||750-1,000 mg 1x/10-14 weeks|
|Trenbolone hexahydrobenzylcarbonate||Hexabolan, Parabolan||75 mg/1.5 weeks|
|Note: Dosage ranges are for varying indications and are not necessarily equivalent. Footnotes: a = Studied for male hypogonadism but never marketed. For comparison purposes. Sources: See template.|
|Route||Medication||Major brand names||Form||Dosage|
|Oral||Testosteronea||-||Tablet||400-800 mg/day (in divided doses)|
|Testosterone undecanoate||Andriol, Jatenzo||Capsule||40-80 mg/2-4x day (with meals)|
|Methyltestosteroneb||Android, Metandren, Testred||Tablet||10-50 mg/day|
|Fluoxymesteroneb||Halotestin, Ora-Testryl, Ultandren||Tablet||5-20 mg/day|
|Buccal||Testosterone||Striant||Tablet||30 mg 2x/day|
|Methyltestosteroneb||Metandren, Oreton Methyl||Tablet||5-25 mg/day|
|Sublingual||Testosteronea||-||Tablet||5 mg 3x/day|
|Methyltestosteroneb||Metandren, Oreton Methyl||Tablet||10-30 mg/day|
|Intranasal||Testosterone||Natesto||Nasal spray||11 mg 3x/day|
|Transdermal||Testosterone||AndroGel, Testim, TestoGel||Gel||25-125 mg/day|
|Androderm, AndroPatch, TestoPatch||Non-scrotal patch||2.5-15 mg/day|
|Testoderm||Scrotal patch||4-6 mg/day|
|Axiron||Axillary solution||30-120 mg/day|
|Androstanolone (DHT)||Andractim||Gel||100-250 mg/day|
|Rectal||Testosterone||Rektandron, Testosteronb||Suppository||40 mg 2-3x/day|
|Injection (IM or SC)||Testosterone||Andronaq, Sterotate, Virosterone||Aqueous suspension||10-50 mg 2-3x/week|
|Testosterone propionateb||Testoviron||Oil solution||10-50 mg 2-3x/week|
|Testosterone enanthate||Delatestryl||Oil solution||50-250 mg 1x/1-4 weeks|
|Xyosted||Auto-injector||50-100 mg 1x/week|
|Testosterone cypionate||Depo-Testosterone||Oil solution||50-250 mg 1x/1-4 weeks|
|Testosterone isobutyrate||Agovirin Depot||Aqueous suspension||50-100 mg 1x/1-2 weeks|
|Mixed testosterone esters||Sustanon 100, Sustanon 250||Oil solution||50-250 mg 1x/2-4 weeks|
|Testosterone undecanoate||Aveed, Nebido||Oil solution||750-1,000 mg 1x/10-14 weeks|
|Testosterone buciclatea||-||Aqueous suspension||600-1,000 mg 1x/12-20 weeks|
|Implant||Testosterone||Testopel||Pellet||150-1,200 mg/3-6 months|
|Notes: The testes produce 3 to 11 mg testosterone per day (mean 7 mg/day in young men). Footnotes: a = Never marketed. b = No longer used and/or no longer marketed. Sources: See template.|
|Route||Medication||Major brand names||Form||Dosage|
|Oral||Testosterone undecanoate||Andriol, Jatenzo||Capsule||40-80 mg 1x/1-2 days|
|Methyltestosterone||Metandren, Estratest||Tablet||0.5-10 mg/day|
|Fluoxymesterone||Halotestin||Tablet||1-2.5 mg 1x/1-2 days|
|Prasterone (DHEA)b||-||Tablet||25-100 mg/day|
|AndroGel||Gel, cream||1-10 mg/day|
|Vaginal||Prasterone (DHEA)||Intrarosa||Insert||6.5 mg/day|
|Injection||Testosterone propionatea||Testoviron||Oil solution||25 mg 1x/1-2 weeks|
|Testosterone enanthate||Delatestryl, Primodian Depot||Oil solution||25-100 mg 1x/4-6 weeks|
|Testosterone cypionate||Depo-Testosterone, Depo-Testadiol||Oil solution||25-100 mg 1x/4-6 weeks|
|Testosterone isobutyratea||Femandren M, Folivirin||Aqueous suspension||25-50 mg 1x/4-6 weeks|
|Mixed testosterone esters||Climacterona||Oil solution||150 mg 1x/4-8 weeks|
|Omnadren, Sustanon||Oil solution||50-100 mg 1x/4-6 weeks|
|Nandrolone decanoate||Deca-Durabolin||Oil solution||25-50 mg 1x/6-12 weeks|
|Prasterone enanthatea||Gynodian Depot||Oil solution||200 mg 1x/4-6 weeks|
|Implant||Testosterone||Testopel||Pellet||50-100 mg 1x/3-6 months|
|Footnotes: a = Mostly discontinued or unavailable. b = Over-the-counter. c = Compounded. Sources: See template.|
|Fluoxymesterone||Tablet||10-40 mg 3x/day|
|Calusterone||Tablet||40 mg 4x/day|
|Injection (IM or SC)||Testosterone propionate||Oil solution||50-100 mg 3x/week|
|Testosterone enanthate||Oil solution||200-400 mg 1x/2-4 weeks|
|Testosterone cypionate||Oil solution||200-400 mg 1x/2-4 weeks|
|Mixed testosterone esters||Oil solution||250 mg 1x/week|
|Methandriol||Aqueous suspension||100 mg 3x/week|
|Androstanolone (DHT)||Aqueous suspension||300 mg 3x/week|
|Drostanolone propionate||Oil solution||100 mg 3x/week|
|Nandrolone decanoate||Oil solution||50-100 mg 1x/1-3 weeks|
|Nandrolone phenylpropionate||Oil solution||50-100 mg/week|
|Note: Dosages are not necessarily equivalent. Sources: See template.|
The AAS that have been used most commonly in medicine are testosterone and its many esters (but most typically testosterone undecanoate, testosterone enanthate, testosterone cypionate, and testosterone propionate),nandrolone esters (typically nandrolone decanoate and nandrolone phenylpropionate), stanozolol, and metandienone (methandrostenolone). Others that have also been available and used commonly but to a lesser extent include methyltestosterone, oxandrolone, mesterolone, and oxymetholone, as well as drostanolone propionate (dromostanolone propionate), metenolone (methylandrostenolone) esters (specifically metenolone acetate and metenolone enanthate), and fluoxymesterone.Dihydrotestosterone (DHT), known as androstanolone or stanolone when used medically, and its esters are also notable, although they are not widely used in medicine.Boldenone undecylenate and trenbolone acetate are used in veterinary medicine.
Designer steroids are AAS that have not been approved and marketed for medical use but have been distributed through the black market. Examples of notable designer steroids include 1-testosterone (dihydroboldenone), methasterone, trenbolone enanthate, desoxymethyltestosterone, tetrahydrogestrinone, and methylstenbolone.
|Generic name||Class||Brand name(s)||Route(s)||Launch||Status||Hitsa|
|Androstanolone (DHT)||DHT||Andractim, others||Many||1953||Availableb||125,000|
|Boldenone undecylenate||T; Ester||Equipoise, Parenabol||IM||1960s||Veterinaryb||544,000|
|Drostanolone propionate||DHT; Ester||Masteron||IM||1961||Discontinued||574,000|
|Ethylestrenol||19-NT; Alkyl||Maxibolin, Orabolin||Oral||1961||Availableb||117,000|
|Fluoxymesterone||T; Alkyl||Halotestin, Ultandren||Oral||1957||Availableb||478,000|
|Mestanolone||DHT; Alkyl||Androstalone, Ermalone||Oral||1950s||Discontinued||278,000|
|Metandienone||T; Alkyl||Dianabol||Oral, IM||1958||Availableb||996,000|
|Metenolone acetate||DHT; Ester||Primobolan||Oral||1961||Availableb||224,000|
|Metenolone enanthate||DHT; Ester||Primobolan Depot||IM||1962||Availableb||371,000|
|Nandrolone decanoate||19-NT; Ester||Deca-Durabolin||IM||1962||Available||926,000|
|Nandrolone phenylpropionate||19-NT; Ester||Durabolin||IM||1959||Availableb||395,000|
|Norethandrolone||19-NT; Alkyl||Nilevar, Pronabol||Oral||1956||Availableb||124,000|
|Oxandrolone||DHT; Alkyl||Oxandrin, Anavar||Oral||1964||Availableb||1,280,000|
|Oxymetholone||DHT; Alkyl||Anadrol, Anapolon||Oral||1961||Availableb||902,000|
|Prasterone (DHEA)||T; Prohormone||Numerous||Many||1970s||Available||11,600,000|
|Stanozolol||DHT; Alkyl||Winstrol, Stromba||Oral, IM||1962||Discontinued||1,790,000|
|Testosterone cypionate||T; Ester||Depo-Testosterone||IM||1951||Available||1,290,000|
|Testosterone enanthate||T; Ester||Delatestryl||IM||1954||Available||1,210,000|
|Testosterone propionate||T; Ester||Testoviron||IM||1937||Available||1,010,000|
|Testosterone undecanoate||T; Ester||Aveed, Andriol, Nebido||Oral, IM||1970s||Available||385,000|
|Trenbolone acetate||19-NT; Ester||Finajet, Finaject||IM||1970s||Veterinary||651,000|
|Footnotes: a = Hits = Google Search hits (as of December 2017). b = Availability limited / mostly discontinued. Class: T = Testosterone. DHT = Dihydrotestosterone. 19-NT = 19-Nortestosterone (nandrolone). Alkyl = 17?-Alkylated. Sources: See individual articles.|
There are four common forms in which AAS 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 one-sixth 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 AAS 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 AAS 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.
Depending on the length of drug use, 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 have a permanent adverse effect on cardiovascular efficiency.
AAS have been shown to alter fasting blood sugar and glucose tolerance tests. AAS such as testosterone also increase the risk of cardiovascular disease or coronary artery disease.Acne is fairly common among AAS users, mostly due to stimulation of the sebaceous glands by increased testosterone levels. Conversion of testosterone to 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 AAS. For example, AAS 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. AAS 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, and therefore reducing ejected blood volume. 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 AAS 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 AAS. 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 AAS 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, AAS 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.
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 AAS 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.
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, AAS users may get misdiagnosed by a psychiatrist not told about their habit.
Cooper, Noakes, Dunne, Lambert, and Rochford identified that 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 AAS users than among non-users (Pope & Katz, 1994).Bipolar dysfunction,substance dependency, and conduct disorder have also been associated with AAS use.
Affective disorders have long been recognised as a complication of AAS 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 AAS, 27 (51%) reported unspecified mood disturbance.
From the mid-1980s onward, the media reported "roid rage" as a side effect of AAS.:23
A 2005 review determined that some, but not all, randomized controlled studies have found that AAS 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 AAS use and involvement in violent acts. Compared with individuals that did not use steroids, young adult males that used AAS 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 AAS 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.
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 AAS may both relieve and cause depression, and that cessation or diminished use of AAS 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).
Androgens such as testosterone, androstenedione and dihydrotestosterone are required for the development of organs in the male reproductive system, including the seminal vesicles, epididymis, vas deferens, penis and prostate. AAS are testosterone derivatives designed to maximize the anabolic effects of testosterone. AAS are consumed by elite athletes competing in sports like weightlifting, bodybuilding, and track and field. Male recreational athletes take AAS to achieve an "enhanced" physical appearance.
AAS consumption disrupts the hypothalamic-pituitary-gonadal axis (HPG axis) in males. In the HPG axis, gonadotropin-releasing hormone (GnRH) is secreted from the arcuate nucleus of the hypothalamus and stimulates the anterior pituitary to secrete the two gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). In adult males, LH stimulates the Leydig cells in the testes to produce testosterone which is required to form new sperm through spermatogenesis. AAS consumption leads to dose-dependent suppression of gonadotropin release through suppression of GnRH from the hypothalamus (long-loop mechanism) or from direct negative feedback on the anterior pituitary to inhibit gonadotropin release (short-loop mechanism), leading to AAS-induced hypogonadism.
The pharmacodynamics of AAS 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, AAS are membrane-permeable and influence the nucleus of cells by direct action. The pharmacodynamic action of AAS begin when the exogenous hormone penetrates the membrane of the target cell and binds to an androgen receptor (AR) 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 AAS bind to the AAR with different affinities, depending on their chemical structure. Some AAS such as metandienone bind weakly to this receptor in vitro, but still exhibit AR-mediated effects in vivo. The reason for this discrepancy is not known.
The effect of AAS 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 AAS inhibiting the action of other steroid hormones called glucocorticoids that promote the breakdown of muscles. AAS also affect the number of cells that develop into fat-storage cells, by favouring cellular differentiation into muscle cells instead. AAS can also decrease fat by increasing basal metabolic rate (BMR), since an increase in muscle mass increases BMR.
|Notes: In rodents. Footnotes: a = Ratio of androgenic to anabolic activity. Sources: See template.|
As their name suggests, AAS have two different, but overlapping, types of effects: anabolic, meaning that they promote anabolism (cell growth), and androgenic (or virilizing), 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 AAS 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[medical ] ), 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 AAS 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 weight in men may increase by 2 to 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 ARs 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 to 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.
Endogenous/natural AAS like testosterone and DHT and synthetic AAS mediate their effects by binding to and activating the 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 relative to the ratio observed with testosterone is observed in rat bioassays with various AAS. Theories for the dissociation include differences between AAS in terms of their intracellular metabolism, functional selectivity (differential recruitment of coactivators), and non-genomic mechanisms (i.e., signaling through non-AR membrane androgen receptors, or mARs). Support for the latter two theories is limited and more hypothetical, but there is a good deal of support for the intracellular metabolism theory.
The measurement of the dissociation between anabolic and androgenic effects among AAS is based largely on a simple but outdated and unsophisticated model using rat tissue bioassays. It has been referred to as the "myotrophic-androgenic index". In this model, myotrophic or anabolic 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 to the AAS. The measurements are then compared to form a ratio.
Testosterone is metabolized in various tissues by 5?-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 3?-hydroxysteroid dehydrogenase (3?-HSD) and 3?-hydroxysteroid dehydrogenase (3?-HSD) into 3?-androstanediol and 3?-androstanediol, respectively, which are metabolites with little or no AR affinity. 5?-reductase is widely distributed throughout the body, and is concentrated to various extents in skin (particularly the scalp, face, and genital areas), prostate, seminal vesicles, liver, and the brain. In contrast, expression of 5?-reductase in skeletal muscle is undetectable. Aromatase is highly expressed in adipose tissue and the brain, and is also expressed significantly in skeletal muscle. 3?-HSD is highly expressed in skeletal muscle as well.
Natural AAS like testosterone and DHT and synthetic AAS are analogues and are very similar structurally. For this reason, they have the capacity to bind to and be metabolized by the same steroid-metabolizing enzymes. According to the intracellular metabolism explanation, the androgenic-to-anabolic ratio of a given AR agonist is related to its capacity to be transformed by the aforementioned enzymes in conjunction with the AR activity of any resulting products. For instance, whereas the AR activity of testosterone is greatly potentiated by local conversion via 5?-reductase into DHT in tissues where 5?-reductase is expressed, an AAS that is not metabolized by 5?-reductase or is already 5?-reduced, such as DHT itself or a derivative (like mesterolone or drostanolone), would not undergo such potentiation in said tissues. Moreover, nandrolone is metabolized by 5?-reductase, but unlike the case of testosterone and DHT, the 5?-reduced metabolite of nandrolone has much lower affinity for the AR than does nandrolone itself, and this results in reduced AR activation in 5?-reductase-expressing tissues. As so-called "androgenic" tissues such as skin/hair follicles and male reproductive tissues are very high in 5?-reductase expression, while skeletal muscle is virtually devoid of 5?-reductase, this may primarily explain the high myotrophic-androgenic ratio and dissociation seen with nandrolone, as well as with various other AAS.
Aside from 5?-reductase, aromatase may inactivate testosterone signaling in skeletal muscle and adipose tissue, so AAS 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 3?-HSD in skeletal muscle (and cardiac tissue), and AAS that lack affinity for 3?-HSD could similarly be expected to have a higher myotrophic-androgenic ratio (although perhaps also increased long-term cardiovascular risks). In accordance, DHT, mestanolone (17?-methyl-DHT), and mesterolone (1?-methyl-DHT) are all described as very poorly anabolic due to inactivation by 3?-HSD in skeletal muscle, whereas other DHT derivatives with other structural features like metenolone, oxandrolone, oxymetholone, drostanolone, and stanozolol are all poor substrates for 3?-HSD and are described as potent anabolics.
The intracellular metabolism theory explains how and why remarkable dissociation between anabolic and androgenic effects might occur despite the fact that these effects are mediated through the same signaling receptor, and why this dissociation is invariably incomplete. In support of the model is the rare condition congenital 5?-reductase type 2 deficiency, in which the 5?-reductase type 2 enzyme is defective, production of DHT is impaired, and DHT levels are low while testosterone levels are normal. Males with this condition are born with ambiguous genitalia and a severely underdeveloped or even absent prostate gland. In addition, at the time of puberty, such males develop normal musculature, voice deepening, and libido, but have reduced facial hair, a female pattern of body hair (i.e., largely restricted to the pubic triangle and underarms), no incidence of male pattern hair loss, and no prostate enlargement or incidence of prostate cancer. They also notably do not develop gynecomastia as a consequence of their condition.
An animal study found that two different kinds of androgen response elements could differentially respond to testosterone and DHT upon activation of the AR. Whether this is involved in the differences in the ratios of anabolic-to-myotrophic effect of different AAS is unknown however.
Testosterone signals not only through the nuclear AR, but also through mARs, including ZIP9 and GPRC6A. It has been proposed that differential signaling through mARs may be involved in the dissociation of the anabolic and androgenic effects of AAS. Indeed, DHT has less than 1% of the affinity of testosterone for ZIP9, and the synthetic AAS metribolone and mibolerone are ineffective competitors for the receptor similarly. This indicates that AAS do show differential interactions with the AR and mARs. However, women with complete androgen insensitivity syndrome (CAIS), who have a 46,XY ("male") genotype and testes but a defect in the AR such that it is non-functional, are a challenge to this notion. They are completely insensitive to the AR-mediated effects of androgens like testosterone, and show a perfectly female phenotype despite having testosterone levels in the high end of the normal male range. These women have little or no sebum production, incidence of acne, or body hair growth (including in the pubic and axillary areas). Moreover, CAIS women have lean body mass that is normal for females but is of course greatly reduced relative to males. These observations suggest that the AR is mainly or exclusively responsible for masculinization and myotrophy caused by androgens. The mARs have however been found to be involved in some of the health-related effects of testosterone, like modulation of prostate cancer risk and progression.
Changes in endogenous testosterone levels may also contribute to differences in myotrophic-androgenic ratio between testosterone and synthetic AAS. AR agonists 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 AAS, the myotrophic-androgenic ratio of a given AAS may be further, dose-dependently increased, and this hence may be an additional factor contributing to the differences in myotrophic-androgenic ratio among different AAS. In addition, some AAS, such as 19-nortestosterone derivatives like nandrolone, are also potent progestogens, and activation of the progesterone receptor (PR) is antigonadotropic similarly to activation of the AR. The combination of sufficient AR and PR activation can suppress circulating testosterone levels into the castrate range in men (i.e., complete suppression of gonadal testosterone production and circulating testosterone levels decreased by about 95%). As such, combined progestogenic activity may serve to further increase the myotrophic-androgenic ratio for a given AAS.
Some AAS, such as testosterone, DHT, stanozolol, and methyltestosterone, have been found to modulate the GABAA receptor similarly to endogenous neurosteroids like allopregnanolone, 3?-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 AAS.
AAS differ in a variety of ways including in their capacities to be metabolized by steroidogenic enzymes such as 5?-reductase, 3-hydroxysteroid dehydrogenases, and aromatase, in whether their potency as AR agonists is potentiated or diminished by 5?-reduction, in their ratios of anabolic/myotrophic to androgenic effect, in their estrogenic, progestogenic, and neurosteroid activities, in their oral activity, and in their capacity to produce hepatotoxicity.
|Ethylestrenol||19-NT; 17?-A||+ (?)||±||-||***||+||+||+||+|
|Fluoxymesterone||T; 17?-A||+ (?)||-||-||*||-||-||+||+|
|Methyltestosterone||T; 17?-A||+ (?)||+||-||*||+||-||+||+|
|Norethandrolone||19-NT; 17?-A||+ (?)||±||-||***||+||+||+||+|
|Key: + = Yes. ± = Low. - = No. ? = Potentiated. ? = Inactivated. *** = High. ** = Moderate. * = Low. Abbreviations: 5?-R = Metabolized by 5?-reductase. AROM = Metabolized by aromatase. 3-HSD = Metabolized by 3?- and/or 3?-HSD. AAR = Anabolic-to-androgenic ratio (amount of anabolic (myotrophic) effect relative to androgenic effect). Estr = Estrogenic. Prog = Progestogenic. Oral = Oral activity. Hepat = Hepatotoxicity. Footnotes: a = As testosterone undecanoate. Sources: See template.|
|Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the PR, testosterone for the AR, estradiol for the ER, dexamethasone for the GR, aldosterone for the MR, dihydrotestosterone for SHBG, and cortisol for CBG. Footnotes: a = 1-hour incubation time (4 hours is standard for this assay; may affect affinity value). Sources: See template.|
|Route||Anabolic activity by||Androgenic
|Dissociation index by|
|Nitr. ratio||Myotrophy||Nitr. ratio||Myotrophy|
|Notes: All assays done with rodents, unless noted otherwise. Footnotes: a = Monkeys. Sources: See template.|
|Medication||Form||Major brand names||Duration|
|Testosterone||Aqueous suspension||Andronaq, Sterotate, Virosterone||2-3 days|
|Testosterone propionate||Oil solution||Androteston, Perandren, Testoviron||3-4 days|
|Testosterone phenylpropionate||Oil solution||Testolent||8 days|
|Testosterone isobutyrate||Aqueous suspension||Agovirin Depot, Perandren M||14 days|
|Mixed testosterone estersa||Oil solution||Triolandren||10-20 days|
|Mixed testosterone estersb||Oil solution||Testosid Depot||14-20 days|
|Testosterone enanthate||Oil solution||Delatestryl||14-20 days|
|Testosterone cypionate||Oil solution||Depovirin||14-20 days|
|Mixed testosterone estersc||Oil solution||Sustanon 250||28 days|
|Testosterone undecanoate||Oil solution||Aveed, Nebido||100 days|
|Testosterone buciclated||Aqueous suspension||20 Aet-1, CDB-1781e||90-120 days|
|Nandrolone phenylpropionate||Oil solution||Durabolin||10 days|
|Nandrolone decanoate||Oil solution||Deca Durabolin||21 days|
|Methandriol||Aqueous suspension||Notandron, Protandren||8 days|
|Methandriol bisenanthoyl acetate||Oil solution||Notandron Depot||16 days|
|Metenolone acetate||Oil solution||Primobolan||3 days|
|Metenolone enanthate||Oil solution||Primobolan Depot||14 days|
|Note: All are via i.m. injection. Footnotes: a = TP, TV, and TUe. b = TP and TKL. c = TP, TPP, TiCa, and TD. d = Studied but never marketed. e = Developmental code names. Sources: See template.|
|Testosterone ester||Form||Route of administration||Elimination half-life||Mean residence time|
|Testosterone undecanoate||Oil-filled capsules||Oral||1.6 hours||3.7 hours|
|Testosterone propionate||Oil solution||Intramuscular injection||0.8 days||1.5 days|
|Testosterone enanthate||Castor oil solution||Intramuscular injection||4.5 days||8.5 days|
|Testosterone undecanoate||Tea seed oil solution||Intramuscular injection||20.9 days||34.9 days|
|Testosterone undecanoate||Castor oil solution||Intramuscular injection||33.9 days||36.0 days|
|Testosterone buciclatea||Aqueous suspension||Intramuscular injection||29.5 days||60.0 days|
|Notes: Testosterone cypionate has very similar pharmacokinetics to TE. Footnotes: a = Never marketed. Sources: See template.|
Testosterone can be robustly converted by 5?-reductase into DHT in so-called androgenic tissues such as skin, scalp, prostate, and seminal vesicles, but not in muscle or bone, where 5?-reductase either is not expressed or is only minimally expressed. As DHT is 3- to 10-fold more potent as an agonist of the 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 4,5?-dihydrogenated AAS are already 5?-reduced, and for this reason, cannot be potentiated in androgenic tissues. 19-Nortestosterone derivatives like nandrolone can be metabolized by 5?-reductase similarly to testosterone, but 5?-reduced metabolites of 19-nortestosterone derivatives (e.g., 5?-dihydronandrolone) tend to have reduced activity as AR agonists, resulting in reduced androgenic activity in tissues that express 5?-reductase. In addition, some 19-nortestosterone derivatives, including trestolone (7?-methyl-19-nortestosterone (MENT)), 11?-methyl-19-nortestosterone (11?-MNT), and dimethandrolone (7?,11?-dimethyl-19-nortestosterone), cannot be 5?-reduced. Conversely, certain 17?-alkylated AAS like methyltestosterone are 5?-reduced and potentiated in androgenic tissues similarly to testosterone. 17?-Alkylated DHT derivatives cannot be potentiated via 5?-reductase however, as they are already 4,5?-reduced.
The capacity to be metabolized by 5?-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 5?-reductase or that are weakened by 5?-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.
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 17?-alkylated AAS methyltestosterone and metandienone are converted by aromatase into methylestradiol. 4,5?-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 11?-MNT, cannot be aromatized due to steric hindrance provided by their 11?-methyl group, whereas the closely related AAS trestolone (7?-methyl-19-nortestosterone), in relation to its lack of an 11?-methyl group, can be aromatized. AAS that are 17?-alkylated (and not also 4,5?-reduced or 19-demethylated) are also aromatized but to a lesser extent than is testosterone. However, it is notable that estrogens that are 17?-substituted (e.g., ethinylestradiol and methylestradiol) are of markedly increased estrogenic potency due to improved metabolic stability, and for this reason, 17?-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 at sufficiently high dosages, while AAS that have a reduced potential for aromatization like nandrolone show a much lower risk (though still potentially significant at high dosages). In contrast, AAS that are 4,5?-reduced, and some other AAS (e.g., 11?-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.
Many 19-nortestosterone derivatives, including nandrolone, trenbolone, ethylestrenol (ethylnandrol), metribolone (R-1881), trestolone, 11?-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 reversible male infertility).
Non-17?-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, 17?-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, 17?-alkylation also confers a high potential for hepatotoxicity, and all 17?-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-17?-alkylated AAS only rarely, although long-term use may reportedly still increase the risk of hepatic changes (but at a much lower rate than 17?-alkylated AAS and reportedly not at replacement dosages).[additional citation(s) needed] 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 17?-alkylated. A few AAS that are not 17?-alkylated are orally active. Some examples include the testosterone 17-ethers cloxotestosterone, quinbolone, and silandrone, which are prodrugs (to testosterone, boldenone (?1-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 11?-MNT, which have improved resistance to first-pass hepatic metabolism due to their 11?-methyl groups (in contrast to them, the related AAS trestolone (7?-methyl-19-nortestosterone) is not orally active). As these AAS are not 17?-alkylated, they show minimal potential for hepatotoxicity.
DHT, via its metabolite 3?-androstanediol (produced by 3?-hydroxysteroid dehydrogenase (3?-HSD)), is a neurosteroid that acts via positive allosteric modulation of the GABAA receptor. Testosterone, via conversion into DHT, also produces 3?-androstanediol as a metabolite and hence has similar activity. Some AAS that are or can be 5?-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.
As well as others such as 1-dehydrogenation (e.g., metandienone, boldenone), 1-substitution (e.g., mesterolone, metenolone), 2-substitution (e.g., drostanolone, oxymetholone, stanozolol), 4-substitution (e.g., clostebol, oxabolone), and various other modifications.
|Testosterone propionate||C17?||Propanoic acid||Straight-chain fatty acid||3||1.19||0.84||10||Short|
|Testosterone isobutyrate||C17?||Isobutyric acid||Aromatic fatty acid||- (~3)||1.24||0.80||9||Moderate|
|Testosterone cypionate||C17?||Cyclopentylpropanoic acid||Aromatic fatty acid||- (~6)||1.43||0.70||8||Moderate|
|Testosterone phenylpropionate||C17?||Phenylpropanoic acid||Aromatic fatty acid||- (~6)||1.46||0.69||7||Moderate|
|Testosterone isocaproate||C17?||Isohexanoic acid||Branched-chain fatty acid||- (~5)||1.34||0.75||6||Moderate|
|Testosterone caproate||C17?||Hexanoic acid||Straight-chain fatty acid||6||1.35||0.75||5||Moderate|
|Testosterone enanthate||C17?||Heptanoic acid||Straight-chain fatty acid||7||1.39||0.72||4||Moderate|
|Testosterone decanoate||C17?||Decanoic acid||Straight-chain fatty acid||10||1.53||0.65||3||Long|
|Testosterone undecanoate||C17?||Undecanoic acid||Straight-chain fatty acid||11||1.58||0.63||2||Long|
|Testosterone buciclated||C17?||Bucyclic acide||Aromatic carboxylic acid||- (~9)||1.58||0.63||1||Long|
|Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative testosterone content by weight (i.e., relative androgenic/anabolic potency). c = Duration by intramuscular or subcutaneous injection in oil solution (except TiB and TB, which are in aqueous suspension). d = Never marketed. e = Bucyclic acid = trans-4-Butylcyclohexane-1-carboxylic acid. Sources: See individual articles.|
|Boldenone undecylenate||C17?||Undecylenic acid||Straight-chain fatty acid||11||1.58||0.63||Long|
|Drostanolone propionate||C17?||Propanoic acid||Straight-chain fatty acid||3||1.18||0.84||Short|
|Metenolone acetate||C17?||Ethanoic acid||Straight-chain fatty acid||2||1.14||0.88||Short|
|Metenolone enanthate||C17?||Heptanoic acid||Straight-chain fatty acid||7||1.37||0.73||Long|
|Nandrolone decanoate||C17?||Decanoic acid||Straight-chain fatty acid||10||1.56||0.64||Long|
|Nandrolone phenylpropionate||C17?||Phenylpropanoic acid||Aromatic fatty acid||- (~6-7)||1.48||0.67||Long|
|Trenbolone acetate||C17?||Ethanoic acid||Straight-chain fatty acid||2||1.16||0.87||Short|
|Trenbolone enanthated||C17?||Heptanoic acid||Straight-chain fatty acid||7||1.41||0.71||Long|
|Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative androgen/anabolic steroid content by weight (i.e., relative androgenic/anabolic potency). c = Duration by intramuscular or subcutaneous injection in oil solution. d = Never marketed. Sources: See individual articles.|
The most commonly employed human physiological specimen for detecting AAS usage is urine, although both blood and hair have been investigated for this purpose. The AAS, 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.
The use of gonadal steroids pre-dates their identification and isolation. Extraction of hormones from urines began in China c. 100 BCE. 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 Ru?i?ka, 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 AAS in a U.S. weightlifting or bodybuilding magazine. There are often reported rumors that German soldiers were administered AAS during the Second World War, the aim being to increase their aggression and stamina, but these are, as yet, unproven.:6Adolf 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.
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 AAS 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 International Olympic Committee (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 C17? 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 C17? 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.
Androgens were discovered in the 1930s and were characterized as having effects described as androgenic (i.e., virilizing) and anabolic (e.g., myotrophic, renotrophic). The term anabolic steroid can be dated as far back as at least the mid-1940s, when it was used to describe the at-the-time hypothetical concept of a testosterone-derived steroid with anabolic effects but with minimal or no androgenic effects. This concept was formulated based on the observation that steroids had ratios of renotrophic to androgenic potency that differed significantly, which suggested that anabolic and androgenic effects might be dissociable.
In 1953, a testosterone-derived steroid known as norethandrolone (17?-ethyl-19-nortestosterone) was synthesized at G. D. Searle & Company and was studied as a progestin, but was not marketed. Subsequently, in 1955, it was re-examined for testosterone-like activity in animals and was found to have similar anabolic activity to testosterone, but only one-sixteenth of its androgenic potency. It was the first steroid with a marked and favorable separation of anabolic and androgenic effect to be discovered, and has accordingly been described as the "first anabolic steroid". Norethandrolone was introduced for medical use in 1956, and was quickly followed by numerous similar steroids, for instance nandrolone phenylpropionate in 1959 and stanozolol in 1962. With these developments, anabolic steroid became the preferred term to refer to such steroids (over "androgen"), and entered widespread use.
Although anabolic steroid was originally intended to specifically describe testosterone-derived steroids with a marked dissociation of anabolic and androgenic effect, it is applied today indiscriminately to all steroids with AR agonism-based anabolic effects regardless of their androgenic potency, including even non-synthetic steroids like testosterone. While many anabolic steroids have diminished androgenic potency in comparison to anabolic potency, there is no anabolic steroid that is exclusively anabolic, and hence all anabolic steroids retain at least some degree of androgenicity. (Likewise, all "androgens" are inherently anabolic.) Indeed, it is probably not possible to fully dissociate anabolic effects from androgenic effects, as both types of effects are mediated by the same signaling receptor, the AR. As such, the distinction between the terms anabolic steroid and androgen is questionable, and this is the basis for the revised and more recent term anabolic-androgenic steroid (AAS).
The legal status of AAS 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., AAS 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 AAS as a first offense is punished by up to ten years in prison. In Canada, AAS 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 AAS 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. AAS are also illegal without prescription in Australia, Argentina, Brazil, and Portugal, and are listed as Class C Controlled Drugs in the United Kingdom. AAS are readily available without a prescription in some countries such as Mexico and Thailand.
The history of the U.S. legislation on AAS goes back to the late 1980s, when the U.S. Congress considered placing AAS under the Controlled Substances Act following the controversy over Ben Johnson's victory at the 1988 Summer Olympics in Seoul. AAS 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 AAS and human growth hormone. By the early 1990s, after AAS 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, AAS 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, AAS are classified as class C drugs for their illegal abuse potential, which puts them in the same class as benzodiazepines. AAS are in Schedule 4, which is divided in 2 parts; Part 1 contains most of the benzodiazepines and Part 2 contains the AAS.
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.
AAS 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 AAS 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 AAS 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.
AAS 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 AAS 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 AAS, 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.
AAS, alone and in combination with progestogens, have been studied as potential male hormonal contraceptives. Dual AAS and progestins such as trestolone and dimethandrolone undecanoate have also been studied as male contraceptives, with the latter under active investigation as of 2018.
Topical androgens have been used and studied in the treatment of cellulite in women. Topical androstanolone on the abdomen has been found to significantly decrease subcutaneous abdominal fat in women, and hence may be useful for improving body silhouette. However, men and hyperandrogenic women have higher amounts of abdominal fat than healthy women, and androgens have been found to increase abdominal fat in postmenopausal women and transgender men as well.
[...] in a recent animal study, Hsiao et al. (10) found two different kinds of androgen response elements that could respond differentially to T and DHT. Therefore, it is possible that a selective androgen response element sequence may play a role in differential T vs. DHT AR trans-activation.
Although both testosterone and dihydrotestosterone activate the same androgen receptor, differences in the sequence of androgen response elements are responsible for differential regulation of these hormones (21).
Androgens, estrogens and progestins exert a negative feedback effect on the secretion of GnRH and LH by their actions on the pituitary and the hypothalamus. Most of the negative feedback effect of androgens is caused by their estrogenic metabolites produced by aromatization. 5?-Reduction does not seem to be necessary for the negative feedback effect of testosterone. (Rittmaster et al, 1992; Kumar et al, 1995a; Hayes et al, 2000).
In recent years several laboratories (Kochakian, Albright, Wilkins) have entertained the hope of finding a protein anabolic steroid without any, or with only minor, sexual effects. These studies have received special impetus and encouragement from the observation of Kochakian that certain steroids have greater renotrophic (anabolic?) than androgenic effects.