The impact of male gonadectomy has been common knowledge since ancient times, and treatment of impotence has been sought through the ingestion of testicles.1,2 But in 1849 Arnold Adolph Berthold from Göttingen demonstrated that it was possible to transplant testicles to castrated cockerels, and that this procedure ensured their normal development; and thus he concluded that testicles secreted a blood-bound substance with masculinizing properties.3 Berthold's experiments probably inspired the famous physician and scientist Charles-Edouard Brown-Sequard to inject himself with extracts from animal testicles, and in 1889 he reported of the rejuvenating effects he had experienced.4,5 Brown-Sequard's observations received widespread attention and an elixir bearing his name quickly reached the market.6 The same year the baseball player Pud Galvin experimented with this elixir as a performance-enhancing agent, and according to his contemporaries with convincing effect.7 Although the testosterone content in the testicles is significantly higher than in the serum, this naturally occurring testosterone is rapidly metabolized in the liver and is not expected to exert any biological effects.8–10 Under any circumstances, the enthusiasm about Brown-Sequard's elixir quickly vanished.6
In 1935, testosterone was finally isolated and synthesized, and testosterone-analogs soon entered the world of sports.5,11 Because of the low bioavailability of testosterone, certain molecular changes were required. The changes have consisted of alkylation of 17-alpha position and changes to the ring structure or esterification of the 17-beta hydroxyl-group. All these different synthetic derivates of testosterone will from now on be termed androgenic anabolic steroids and abbreviated AAS, and a detailed description of their chemical structure can be found elsewhere.12
Today, the use of these performance-enhancing agents is no longer confined to the elite sports milieu, and the lifetime prevalence of AAS use among men is estimated to be around 6%.13 Therefore, the adverse health effects related to AAS use are a matter of public health concern and the topic of this review.
The pharmacology of testosterone and Androgenic anabolic steroids
Testosterone is primarily synthesized in the Leydig cells of the testicles in response to luteinizing hormone secreted from the pituitary gland.14 The average daily production is estimated to be around 5–7 mg. In the bloodstream testosterone is primarily bound to sex hormone binding globulin, albumin, and corticosteroid binding globulin and only 1–2% is free. Testosterone is primarily metabolized to inactive substances in the liver; however, about 5% is converted to the more potent dihydrotestosterone (DHT) by the enzyme 5-alpha reductase, an enzyme which is found in various organs but in particular high concentrations in the prostate gland. Furthermore, a small fraction of the testosterone is converted to estradiol by the enzyme aromatase. Testosterone and DHT binds to the intracellular androgen receptor, which in turn leads to the transcription of target genes, and ultimately results in the characteristics of the male gender
Mortality related to anabolic steroids
Power sports, such as weightlifting, used to be associated with an increased longevity.15 Parssinen et al.16 conducted a follow-up study on 62 male powerlifters who came from first to fifth in the Finnish Championships between 1977 and 1982, and concluded that this cohort of athletes strongly suspected of being AAS users had a 4.6-fold greater mortality than Finnish men in general.
In a Swedish register-based study, Thiblin and co-workers followed 409 men who had tested positive for AAS and reported that the mortality was 18 times higher than anticipated.17 Doping tests were generally requested by the police, prisons and healthcare authorities, and this may bias the findings. However, in comparison with those who tested negative, the AAS-user still had a two-fold higher mortality rate. In the Swedish study excess mortality was primarily attributed to unnatural causes of death.17
Our own recently published study of 545 AAS users with a mean age of 26 years and a mean follow-up of 7.4 years, revealed that the mortality was three times higher than expected. Similar findings were made in the replication cohort consisting of males who received doping sanction because they refused to deliver a urine sample.18 Although the relative risks of death were high, the absolute risks were low, and the Danish data law prohibited a more detailed analysis on the causes of death.
Altogether there is strong evidence to support that AAS users have a shorter life expectancy, but whether this is caused by side effects to AAS, or is related to a hazardous lifestyle in general, still remains to be elucidated.
Morbidity related to anabolic steroids
AAS-users appear to have twice as many hospital contacts compared to their nondoping peers.18 We have previously investigated the incidence of somatic co-morbidity related to AAS use in a hypothesis-free approach. We simply compared the number of in- and outpatient contacts on ICD (International Classification of Diseases) -10 level 3 between the 545 AAS users and 5450 age and gender matched controls. We excluded diagnoses related to psychiatric disorders, violence, injuries and unspecific health examinations (ICD-10 groups F, S, T, U, V, X, Y and Z). All P values were adjusted for multiple testing, and this analysis revealed that 13 disorders were strongly associated with the use of AAS. Of these side effects the following could be explained by the pharmacology of AAS: gynaecomastia, infertility, testicular dysfunction, and skin disorders such as cutaneous abscesses, furuncles, carbuncles. Our review of the somatic side effects of AAS will therefore primarily focus on disorders arising from these organs, but we will also briefly discuss the effect of AAS on the cardiovascular system and the liver. Furthermore, strong signals were detected with disorder which were primarily attributed to weightlifting such as hernias, shoulder lesions, and dorsalgia.18
AAS have a profound effect on testicular function.9 The excessive amount of AAS taken by bodybuilders disturb the bodies’ hypothalamic-pituitary-gonadal axis, resulting in low levels of gonadotropins, leading to decreased endogenous testosterone production and reduced spermatogenesis.19,20 Rasmussen et al. studied 70 current and former AAS abusers and found their testicular volume to be significantly lower compared to healthy controls. Testosterone production was low in former abusers even years after cessation; however, markers of spermatogenesis (inhibin-B and anti-Müllerian hormone) tended to normalize after discontinuation of the AAS use.20 Our recent register-based study of 545 AAS users showed these had twice risk of being diagnosed with infertility compared to the background population.18
Sexual disturbances are another common problem in male AAS users.11,19 Testosterone plays a key role in erectile function and libido.21 Su et al.22 investigated the acute neuropsychiatric effects of high dose AAS in 20 male volunteers and reported of increased sexual arousal. Similarly, Moss and colleagues found that current users of AAS have a high sexual activity compared to healthy nonuser peers and past-users.23 AAS is often used in intermittent courses, termed cycles, and papers from different research groups indicate that sexual decline commonly occurred in the drug-free periods.24,25 Armstrong et al.25 found that 27% of AAS-users experienced erectile dysfunction during abstinence and 57% reported of a decreased libido. Thus, a common hypothesis is that low levels of sex-hormones during AAS abstinence explain the sexual disturbances.21,26 So-called postcycle therapy aims at restoring testicular function and is often used by AAS-abusers,24 and according to Armstrong et al.25 postcycle therapy tended to protect against sexual dysfunction. Postcycle therapy agents typically include tamoxifen, clomiphene or human chorionic gonadotropin (hCG). Both tamoxifen and clomiphene antagonize the negative feedback of estradiol thereby increasing FSH and LH secretion from the pituitary gland, which leads to an increased testosterone synthesis and spermatogenesis,27 whereas hCG directly stimulates the Leydig cells.28
Supraphysiological levels of estrogens are created through the metabolism of AAS,19 and the accompanying gynaecomastia is a side effect feared by many AAS-users. Testosterone and steroids with an unsaturated C4,5 bond can be converted to estradiol by the aromatase, whereas DHT or and 5-alpha synthetic derivates are not subjects to this conversion.19,29 The breast development is often sought counteracted using the estrogen receptor antagonists such as tamoxifen.9,24 Among Danish AAS-users one in seven had been treated for this condition in the official healthcare system and around half of those had received a breast surgery.18
Effects of anabolic steroids in women
AAS use is predominantly a male phenomenon,13 but experiences from the German Democratic Republic (DDR) clearly indicate that AAS use in women is associated with virilising effects such as hirsutism, deepening of voice and clitoris hypertropia.11 Furthermore, amenorrhea and infertility commonly occur, but may also be side effects of strenuous exercise.19 Otherwise, it is expected that women experience the same side effects as men.
Effects on skin
The androgens play a central role in the development of acne, and skin manifestations may be the first sign of AAS abuse.19,30 In our Danish cohort study we found that a quarter of the AAS users had been treated for this disorder, and the incidence of hospital contacts due to cutaneous abscesses and carbuncles was much higher than anticipated. Experiences from other countries seem to be similar: 38% of the patients at a Dutch AAS clinic suffered from acne, and approximately 18% of callers to a Swedish doping hotline reported this side effect.24,31
Effects on the cardiovascular system
AAS use has an adverse cardiovascular profile. The incidence of nonischaemic heart diseases such as cardiomyopathy and atrial fibrillation, is around three times higher among AAS users than in the controls (HR = 2.9, 95% CI = 1.7–5.0).18 In line with this, Rasmussen et al.32 found that current AAS use was associated with increased 24-hour blood pressure and increased aortic stiffness, which are known risk factors for cardiovascular events and death. Additionally, the incidence of thromboembolic disorder (thrombophlebitis and pulmonary embolism) is five times higher than among healthy controls (HR 5.0 (1.7–14.6)).18 Chang et al.33 recently demonstrated that current and former AAS abusers have an augmented thrombin generation, and AAS use has been associated with a decrease in HDL cholesterol and an increase in LDL cholesterol and secondary erythrocytosis.9,34 All these are factors are anticipated to contribute to an increased risk of cardiovascular disease.
Effects on the liver
17-alpha alkylated steroids have a retarded hepatic inactivation and can therefore be administered orally, and this subgroup of AAS have been associated with hepatotoxicity.29 In our study of Danish AAS users, the incidence of liver diseases was around six times than in the general population. However, the absolute risks were low and the association did not withstand the correction for multiple comparisons.18
Along with the increased nonmedical use of AAS in the 1980s, reports regarding mood and behavioural changes in association with AAS use started to appear. The early case reports described schizophrenic episodes,35 hypomania,36 aggressive and violent behaviour,37 as well as depressive symptoms and suicidal thoughts after withdrawal.38 Subsequently, various research teams sought to clarify the effects of AAS on CNS functions, psyche and behaviour.
In the late 1980s, Pope and Katz conducted a smaller interview-based study in 41 athletes who had previously used AAS. They reported that nine subjects (22%) met diagnostic criteria for a manic or depressive episode during/or after withdrawal from AAS use while five subjects (12%) had experienced psychotics symptoms.39 Later, Su and colleagues investigated the acute neuropsychiatric effects of AAS in a placebo-controlled study including 20 healthy male volunteers. They found that high doses of AAS increased self-confidence, forgetfulness, distractibility, mood swings, and violent feelings.22
The above-mentioned studies and several other reports on associations between AAS use and psychiatric symptoms and cognitive deficits40–42 further encouraged researchers to investigate the effect of AAS on CNS structure and function.
From an animal study of chronic exposure to AAS throughout adolescence, Carillo et al. reported altered function and expression of the glutamatergic system as well as changes in hypothalamic neural connections in hamsters.43 In human studies, long-term use of AAS was found to be associated with amygdale enlargement and poorer visual special function in AAS using male weightlifter compared to nonusing controls.44 Likewise, Bjørnebekk et al.45 compared the brains of AAS users and nonusing weightlifters with magnetic resonance imaging technique and found that AAS users had thinner cortex in various regions as well as reduced total grey matter, cerebral cortex and putamen.
The observed neural alterations might explain the impaired impulse control, extreme mood swings and increased aggressiveness that have been associated with AAS use. Further, it has been suggested that this aggressiveness and impaired impulse control occasionally trigger violent behaviour in certain individuals.42,46
Some studies indicate a dose-dependent effect on the occurrence and severity of mood and behavioural disturbances and that the effect is varying across individuals. Thus, certain susceptible individuals appear to develop serious psychological changes, whereas others show only little impact of AAS.22,47 This also might explain why only some individuals appear to be prompted to aggressive and violent behaviour when using AAS. During the last decades this possible association of AAS with aggression, violent behaviour and criminal acts has been examined. In a register-based study on individuals referred to the Swedish Doping Laboratory, Klötz et al. compared 241 subjects who tested positive for AAS with 1199 subjects who tested negative and found that the conviction rate for weapons offences or fraud was significantly higher in the AAS positive group. In contrast, they did not find a significant difference regarding violent crimes or crimes against property.46 Lundholm and colleagues reported a strong association between self-reported AAS use and conviction of violent crimes from a large cross-sectional register study of male twins, but the association lost statistical power when controlling for polysubstance abuse. Underestimation of the true association is, however, likely as the nonresponders (40%) more often were criminally convicted, treated for psychiatric conditions, had lower IQ, and lower education level.48 Likewise, Beaver et al. found a small but significant association between involvement in serious violent behaviour and self-reported AAS use in a recent American nationally representative survey. In contrast to the findings by Lundholm et al.,49 the association remained significant after adjusting for polysubstance use and previous violent behaviour.
As opposed to aggressive and agitated mood changes, several reports have also described depressive symptoms in users of AAS. Predominantly, these symptoms appear to be associated with withdrawal from AAS as an ‘end-of-cycle’ phenomenon, which might be attributable to suppression of the hypothalamic-pituitary-gonadal axis.47,50,51
Anabolic steroid dependence
The other potential psychiatric side effect is the risk of development of dependence upon AAS. The syndrome of AAS dependence has been recognized since the late 1980s; however, the mechanism behind remains uncertain. Most users appear to use AAS only a few times during a lifetime, whereas it is estimated that around 30% of AAS users develop dependency with sustained use despite adverse effects.52 Several models for development of AAS dependency have been proposed. One theory is a two-stage model in which, initially, the reinforcing actions of AAS are thought to derive from the muscle-active effects of AAS. At this first stage, it is a highly goal-directed desire to attain large muscle size and increased strength that motivate and drive AAS use in combination with a rigorous diet and training regimen. At a second stage, the long-term supraphysiological administration of AAS is believed to activate brain-mediated reward system, analogously to more classical addictive drugs and hereby augment the muscle-active dependence of AAS.50 Another hypothesis is that the AAS dependence might be driven by a form of body dysmorphic disorder termed ‘muscle dysmorphia’ in which a paradoxical increasing dissatisfaction with muscularity despite growing muscles triggers the dependence upon AAS.53 Yet another hypothesis is that some individuals are more biological vulnerable to the dysphoric effects associated with AAS withdrawal and these AAS users therefore become progressively prone to continue AAS use to prevent these symptoms.52
As reviewed above, the literature suggests that use of AAS is associated with a variety of psychiatric disorders and effects, and antisocial behaviour. It is, however, less clear whether AAS play a causal role in the development of such. It might be that these psychiatric symptoms solely are attributable to underlying personality traits, or psychosocial factors associated with AAS use. Unfortunately, it is difficult to examine this association by prospective, randomized controlled trials as it is unethical to mimic the extreme doses and regimes of AAS taken by the illicit users.
The lifetime prevalence of AAS use among men is estimated to be around 6%, and accumulating evidence suggests that these drugs are associated with a broad range of side effects. The most common somatic adverse drug reactions are gynaecomastia, infertility, testicular dysfunction, and acne. Furthermore, the literature suggests that use of AAS is associated with a variety of psychiatric disorders and antisocial behaviour.
Conflicts of interest
There are no conflicts of interest.
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