Anabolic steroid

Anabolic

• Bone marrow stimulation: For decades, AAS were the mainstay of therapy for hypoplastic anemias due to leukemia, kidney failure or aplastic anemia.^[10]
• Growth stimulation: AAS can be used by pediatric endocrinologists to treat children with growth failure.^[11] However, the availability of synthetic growth hormone, which has fewer side effects, makes this a secondary treatment.
• Stimulation of appetite and preservation and increase of muscle mass: AAS have been given to people with chronic wasting conditions such as cancer and AIDS.^[12][13]
• Stimulation of lean body mass and prevention of bone loss in elderly men, as some studies indicate.^[14][15][16] However, a 2006 placebo-controlled trial of low-dose testosterone supplementation in elderly men with low levels of testosterone found no benefit on body composition, physical performance, insulin sensitivity, or quality of life.^[17]
• Prevention or treatment of osteoporosis in postmenopausal women.^[18][19] Nandrolone decanoate is approved for this use.^[20] Although they have been indicated for this indication, AAS saw very little use for this purpose due to their virilizing side effects.^[18][21]
• Aiding weight gain following surgery or physical trauma, during chronic infection, or in the context of unexplained weight loss.^[22][23]
• Counteracting the catabolic effect of long-term corticosteroid therapy.^[22][23]
• Oxandrolone improves both short-term and long-term outcomes in people recovering from severe burns and is well-established as a safe treatment for this indication.^[24][25]
• Treatment of idiopathic short stature, hereditary angioedema, alcoholic hepatitis, and hypogonadism.^[26][27]
• Methyltestosterone is used in the treatment of delayed puberty, hypogonadism, cryptorchidism, and erectile dysfunction in males, and in low doses to treat menopausal symptoms (specifically for osteoporosis, hot flashes, and to increase libido and energy), postpartum breast pain and engorgement, and breast cancer in women.^[28][29][30]

Androgenic

• Androgen replacement therapy for men with low levels of testosterone; also effective in improving libido for elderly males.^{[31][32][33][34]}
• Induction of male puberty: Androgens are given to many boys distressed about extreme delay of puberty. Testosterone is now nearly the only androgen used for this purpose and has been shown to increase height, weight, and fat-free mass in boys with delayed puberty.^[35]
• Masculinizing hormone therapy for transgender men, other transmasculine people, and intersex people, by producing masculine secondary sexual characteristics such as a voice deepening, increased bone and muscle mass, masculine fat distribution, facial and body hair, and clitoral enlargement, as well as mental changes such as alleviation of gender dysphoria and increased sex drive.^{[36][37][38][39][40]}

Other

• Treatment of breast cancer in women, although they are now very rarely used for this purpose due to their marked virilizing side effects.^[41][18][42]
• In low doses as a component of hormone therapy for postmenopausal and transgender women, for instance to increase energy, well-being, libido, and quality of life, as well as to reduce hot flashes.^{[43][44][45][46]} Testosterone is usually used for this purpose, although methyltestosterone is also used.^[46][47]
• Male hormonal contraception; currently experimental, but potential for use as effective, safe, reliable, and reversible male contraceptives.^[48]

Routes of administration

A vial of injectable testosterone cypionate

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 17α 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.^[72] 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.^[54]

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.^[9][73]

Cancer

WHO organization International Agency for Research on Cancer (IARC) list AAS under Group 2A: Probably carcinogenic to humans.^[91]

Cardiovascular

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.^[5] Possible effects of these alterations in the heart are hypertension, cardiac arrhythmias, congestive heart failure, heart attacks, and sudden cardiac death.^[92] These changes are also seen in non-drug-using athletes, but steroid use may accelerate this process.^[93][94] 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.^[95][96]

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.^[97]

Growth defects

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.^[98]

Feminization

22-year-old man with gynecomastia not due to AAS use. Before and after gynecomastia surgery.

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.^[99] Reduced sexual function and temporary infertility can also occur in males.^{[100][101][102]} 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.^[103]

Masculinization

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.^[104] 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.^[105]

Kidney problems

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.^[106]

Liver problems

High doses of oral AAS compounds can cause liver damage.^[4] Peliosis hepatis has been increasingly recognised with the use of AAS.

Diagnostic Statistical Manual assertion

DSM-IV lists General diagnostic criteria for a personality disorder guideline that "The pattern must not be better accounted for as a manifestation of another mental disorder, or to the direct physiological effects of a substance (e.g. drug or medication) or a general medical condition (e.g. head trauma).". As a result, AAS users may get misdiagnosed by a psychiatrist not told about their habit.^[112]

Personality profiles

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.^[113] Other studies have suggested that antisocial personality disorder is slightly more likely among AAS users than among non-users (Pope & Katz, 1994).^[112] Bipolar dysfunction,^[114] substance dependency, and conduct disorder have also been associated with AAS use.^[115]

Mood and anxiety

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.^[116] Of 53 bodybuilders who used AAS, 27 (51%) reported unspecified mood disturbance.^[117]

Aggression and hypomania

From the mid-1980s onward, the media reported "roid rage" as a side effect of AAS.^[118]: 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.^[119] 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.^[120] 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.^[121]

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.^[122][123] 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.^[124]

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.^[125] A small-scale study of 10 AAS users found that cluster B personality disorders were confounding factors for aggression.^[126]

The relationship between AAS use and depression is inconclusive. There have been anecdotal reports of depression and suicide in teenage steroid users,^[127] 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.^[128] 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).^[129]

Body composition and strength improvements

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.^[8]

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.^[8]

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.^[8] For almost two decades, it was assumed that AAS exerted significant effects only in experienced strength athletes.^[147][148] 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.^[8][122] This dose is sufficient to significantly improve lean muscle mass relative to placebo even in subjects that did not exercise at all.^[122] The anabolic effects of testosterone enanthate were highly dose dependent.^[8][149]

Intracellular metabolism

Testosterone is metabolized in various tissues by 5α-reductase into DHT, which is 3- to 10-fold more potent as an AR agonist, and by aromatase into estradiol, which is an estrogen and lacks significant AR affinity.^[1] In addition, DHT is metabolized by 3α-hydroxysteroid dehydrogenase (3α-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) into 3α-androstanediol and 3β-androstanediol, respectively, which are metabolites with little or no AR affinity.^[1] 5α-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.^[1] In contrast, expression of 5α-reductase in skeletal muscle is undetectable.^[1] Aromatase is highly expressed in adipose tissue and the brain, and is also expressed significantly in skeletal muscle.^[1] 3α-HSD is highly expressed in skeletal muscle as well.^[66]

Natural AAS like testosterone and DHT and synthetic AAS are analogues and are very similar structurally.^[1] For this reason, they have the capacity to bind to and be metabolized by the same steroid-metabolizing enzymes.^[1] 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.^[1] For instance, whereas the AR activity of testosterone is greatly potentiated by local conversion via 5α-reductase into DHT in tissues where 5α-reductase is expressed, an AAS that is not metabolized by 5α-reductase or is already 5α-reduced, such as DHT itself or a derivative (like mesterolone or drostanolone), would not undergo such potentiation in said tissues.^[1] Moreover, nandrolone is metabolized by 5α-reductase, but unlike the case of testosterone and DHT, the 5α-reduced metabolite of nandrolone has much lower affinity for the AR than does nandrolone itself, and this results in reduced AR activation in 5α-reductase-expressing tissues.^[1] As so-called "androgenic" tissues such as skin/hair follicles and male reproductive tissues are very high in 5α-reductase expression, while skeletal muscle is virtually devoid of 5α-reductase, this may primarily explain the high myotrophic–androgenic ratio and dissociation seen with nandrolone, as well as with various other AAS.^[1]

Aside from 5α-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.^[1] In addition, DHT is inactivated by high activity of 3α-HSD in skeletal muscle (and cardiac tissue), and AAS that lack affinity for 3α-HSD could similarly be expected to have a higher myotrophic–androgenic ratio (although perhaps also increased long-term cardiovascular risks).^[1] In accordance, DHT, mestanolone (17α-methyl-DHT), and mesterolone (1α-methyl-DHT) are all described as very poorly anabolic due to inactivation by 3α-HSD in skeletal muscle, whereas other DHT derivatives with other structural features like metenolone, oxandrolone, oxymetholone, drostanolone, and stanozolol are all poor substrates for 3α-HSD and are described as potent anabolics.^[66]

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.^[1] In support of the model is the rare condition congenital 5α-reductase type 2 deficiency, in which the 5α-reductase type 2 enzyme is defective, production of DHT is impaired, and DHT levels are low while testosterone levels are normal.^[150][151] Males with this condition are born with ambiguous genitalia and a severely underdeveloped or even absent prostate gland.^[150][151] 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.^{[151][152][153][154][155]} They also notably do not develop gynecomastia as a consequence of their condition.^[153]

Functional selectivity

An animal study found that two different kinds of androgen response elements could differentially respond to testosterone and DHT upon activation of the AR.^[156][157] Whether this is involved in the differences in the ratios of anabolic-to-myotrophic effect of different AAS is unknown however.^{[156][157][1]}

Non-genomic mechanisms

Testosterone signals not only through the nuclear AR, but also through mARs, including ZIP9 and GPRC6A.^[158][159] It has been proposed that differential signaling through mARs may be involved in the dissociation of the anabolic and androgenic effects of AAS.^[1] 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.^[159] This indicates that AAS do show differential interactions with the AR and mARs.^[159] 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.^[160] 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.^[160] These women have little or no sebum production, incidence of acne, or body hair growth (including in the pubic and axillary areas).^[160] Moreover, CAIS women have lean body mass that is normal for females but is of course greatly reduced relative to males.^[161] These observations suggest that the AR is mainly or exclusively responsible for masculinization and myotrophy caused by androgens.^{[160][161][162]} 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.^[159][163]

Antigonadotropic effects

Changes in endogenous testosterone levels may also contribute to differences in myotrophic–androgenic ratio between testosterone and synthetic AAS.^[66] AR agonists are antigonadotropic – that is, they dose-dependently suppress gonadal testosterone production and hence reduce systemic testosterone concentrations.^[66] 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.^[66] 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.^[66] 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%).^[48][164] As such, combined progestogenic activity may serve to further increase the myotrophic–androgenic ratio for a given AAS.^[66]

5α-Reductase and androgenicity

Testosterone can be robustly converted by 5α-reductase into DHT in so-called androgenic tissues such as skin, scalp, prostate, and seminal vesicles, but not in muscle or bone, where 5α-reductase either is not expressed or is only minimally expressed.^[1] 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.^[1] In contrast to testosterone, DHT and other 4,5α-dihydrogenated AAS are already 5α-reduced, and for this reason, cannot be potentiated in androgenic tissues.^[1] 19-Nortestosterone derivatives like nandrolone can be metabolized by 5α-reductase similarly to testosterone, but 5α-reduced metabolites of 19-nortestosterone derivatives (e.g., 5α-dihydronandrolone) tend to have reduced activity as AR agonists, resulting in reduced androgenic activity in tissues that express 5α-reductase.^[1] In addition, some 19-nortestosterone derivatives, including trestolone (7α-methyl-19-nortestosterone (MENT)), 11β-methyl-19-nortestosterone (11β-MNT), and dimethandrolone (7α,11β-dimethyl-19-nortestosterone), cannot be 5α-reduced.^[172] Conversely, certain 17α-alkylated AAS like methyltestosterone are 5α-reduced and potentiated in androgenic tissues similarly to testosterone.^[1][66] 17α-Alkylated DHT derivatives cannot be potentiated via 5α-reductase however, as they are already 4,5α-reduced.^[1][66]

The capacity to be metabolized by 5α-reductase and the AR activity of the resultant metabolites appears to be one of the major, if not the most important determinant of the androgenic–myotrophic ratio for a given AAS.^[1] AAS that are not potentiated by 5α-reductase or that are weakened by 5α-reductase in androgenic tissues have a reduced risk of androgenic side effects such as acne, androgenic alopecia (male-pattern baldness), hirsutism (excessive male-pattern hair growth), benign prostatic hyperplasia (prostate enlargement), and prostate cancer, while incidence and magnitude of other effects such as muscle hypertrophy, bone changes,^[173] voice deepening, and changes in sex drive show no difference.^[1][174]

Aromatase and estrogenicity

Testosterone can be metabolized by aromatase into estradiol, and many other AAS can be metabolized into their corresponding estrogenic metabolites as well.^[1] As an example, the 17α-alkylated AAS methyltestosterone and metandienone are converted by aromatase into methylestradiol.^[175] 4,5α-Dihydrogenated derivatives of testosterone such as DHT cannot be aromatized, whereas 19-nortestosterone derivatives like nandrolone can be but to a greatly reduced extent.^[1][176] Some 19-nortestosterone derivatives, such as dimethandrolone and 11β-MNT, cannot be aromatized due to steric hindrance provided by their 11β-methyl group, whereas the closely related AAS trestolone (7α-methyl-19-nortestosterone), in relation to its lack of an 11β-methyl group, can be aromatized.^[176] AAS that are 17α-alkylated (and not also 4,5α-reduced or 19-demethylated) are also aromatized but to a lesser extent than is testosterone.^[1][177] However, it is notable that estrogens that are 17α-substituted (e.g., ethinylestradiol and methylestradiol) are of markedly increased estrogenic potency due to improved metabolic stability,^[175] and for this reason, 17α-alkylated AAS can actually have high estrogenicity and comparatively greater estrogenic effects than testosterone.^[175][66]

The major effect of estrogenicity is gynecomastia (woman-like breasts).^[1] 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).^[1] In contrast, AAS that are 4,5α-reduced, and some other AAS (e.g., 11β-methylated 19-nortestosterone derivatives), have no risk of gynecomastia.^[1] 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.^[178]

Progestogenic activity

Many 19-nortestosterone derivatives, including nandrolone, trenbolone, ethylestrenol (ethylnandrol), metribolone (R-1881), trestolone, 11β-MNT, dimethandrolone, and others, are potent agonists of the progesterone receptor (AR) and hence are progestogens in addition to AAS.^[1][179] Similarly to the case of estrogenic activity, the progestogenic activity of these drugs serves to augment their antigonadotropic activity.^[179] 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).^[179]

Oral activity and hepatotoxicity

Non-17α-alkylated testosterone derivatives such as testosterone itself, DHT, and nandrolone all have poor oral bioavailability due to extensive first-pass hepatic metabolism and hence are not orally active.^[1] 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).^[180][181] 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.^[1] 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).^[1] An exception is the very long-chain ester testosterone undecanoate, which is orally active, albeit with only very low oral bioavailability (approximately 3%).^[182] In contrast to most other AAS, 17α-alkylated testosterone derivatives show resistance to metabolism due to steric hindrance and are orally active, though they may be esterified and administered via intramuscular injection as well.^[1]

In addition to oral activity, 17α-alkylation also confers a high potential for hepatotoxicity, and all 17α-alkylated AAS have been associated, albeit uncommonly and only after prolonged use (different estimates between 1 and 17%),^[183][184] with hepatotoxicity.^{[1][185][186]} In contrast, testosterone esters have only extremely rarely or never been associated with hepatotoxicity,^[184] and other non-17α-alkylated AAS only rarely, although long-term use may reportedly still increase the risk of hepatic changes (but at a much lower rate than 17α-alkylated AAS and reportedly not at replacement dosages).^{[183][187][70]} In accordance, D-ring glucuronides of testosterone and DHT have been found to be cholestatic.^[188]

Aside from prohormones and testosterone undecanoate, almost all orally active AAS are 17α-alkylated.^[189] A few AAS that are not 17α-alkylated are orally active.^[1] Some examples include the testosterone 17-ethers cloxotestosterone, quinbolone, and silandrone, which are prodrugs (to testosterone, boldenone (Δ¹-testosterone), and testosterone, respectively), the DHT 17-ethers mepitiostane, mesabolone, and prostanozol (which are also prodrugs), the 1-methylated DHT derivatives mesterolone and metenolone (although these are relatively weak AAS),^[1][70] and the 19-nortestosterone derivatives dimethandrolone and 11β-MNT, which have improved resistance to first-pass hepatic metabolism due to their 11β-methyl groups (in contrast to them, the related AAS trestolone (7α-methyl-19-nortestosterone) is not orally active).^[1][179] As these AAS are not 17α-alkylated, they show minimal potential for hepatotoxicity.^[1]

Neurosteroid activity

DHT, via its metabolite 3α-androstanediol (produced by 3α-hydroxysteroid dehydrogenase (3α-HSD)), is a neurosteroid that acts via positive allosteric modulation of the GABA_A receptor.^[1] Testosterone, via conversion into DHT, also produces 3α-androstanediol as a metabolite and hence has similar activity.^[1] Some AAS that are or can be 5α-reduced, including testosterone, DHT, stanozolol, and methyltestosterone, among many others, can or may modulate the GABA_A 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.^{[1][165][166][167][168][169][170]}

United States

Steroid pills intercepted by the US Drug Enforcement Administration during the Operation Raw Deal bust in September 2007.

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.^[215]

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.^[216]

Even though they can still be prescribed by a medical doctor in the U.S, the use of anabolic steroids for injury recovery purposes has been a taboo subject, even amongst the majority of sports medicine doctors and endocrinologists.

United Kingdom

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.^[217]

Law enforcement

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.^[231] 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".^[232] 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.

Professional wrestling

Following the murder-suicide of Chris Benoit in 2007, the Oversight and Government Reform Committee investigated steroid usage in the wrestling industry.^[233] The Committee investigated WWE and Total Nonstop Action Wrestling (now known as Impact Wrestling), 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.^[234][235]