Effects of Long Term Supplementation of Anabolic Androgen Steroids on Human Skeletal MuscleThe problem of anabolic-androgenic steroid AAS abuse tseroids recently generated widespread public and media attention. Most AAS abusers, however, are not elite athletes like those portrayed in the media, and many are not competitive athletes at all. This larger but less visible propionate enanthate kuru of ordinary AAS users began anwbolic emerge in about The senior members of this population are now long term effects anabolic steroids middle age; they represent the leading wave of a new type of aging former substance abusers, with specific medical and psychiatric risks. We reviewed the evolving literature on long-term psychiatric and medical consequences of AAS abuse.
Long-Term Psychiatric and Medical Consequences of Anabolic-Androgenic Steroid Abuse
The problem of anabolic-androgenic steroid AAS abuse has recently generated widespread public and media attention. Most AAS abusers, however, are not elite athletes like those portrayed in the media, and many are not competitive athletes at all. This larger but less visible population of ordinary AAS users began to emerge in about The senior members of this population are now entering middle age; they represent the leading wave of a new type of aging former substance abusers, with specific medical and psychiatric risks.
We reviewed the evolving literature on long-term psychiatric and medical consequences of AAS abuse. Long-term use of supraphysiologic doses of AAS may cause irreversible cardiovascular toxicity, especially atherosclerotic effects and cardiomyopathy. In other organ systems, evidence of persistent toxicity is more modest, and interestingly, there is little evidence for an increased risk of prostate cancer.
High concentrations of AAS, comparable to those likely sustained by many AAS abusers, produce apoptotic effects on various cell types, including neuronal cells - raising the specter of possibly irreversible neuropsychiatric toxicity.
Finally, AAS abuse appears to be associated with a range of potentially prolonged psychiatric effects, including dependence syndromes, mood syndromes, and progression to other forms of substance abuse. However, the prevalence and severity of these various effects remains poorly understood. As the first large wave of former AAS users now moves into middle age, it will be important to obtain more systematic data on the long-term psychiatric and medical consequences of this form of substance abuse.
AAS should not be confused with other types of steroids such as corticosteroids e. When taken in supraphysiologic doses, AAS allow users to greatly increase muscle strength and athletic performance, often well beyond the limit attainable by natural means Kouri et al. As a result, many elite competitive athletes have used AAS - and this phenomenon has recently generated much publicity, as evidenced by burgeoning media reports around the world Ewing, ; Fainaru-Wada and Williams, ; Magnay, ; Swartz, and recent investigations by the United States Congress th United States Congress, ; Mitchell, The great majority of illicit AAS users, however, are not elite athletes; indeed many are not competitive athletes at all, but simply individuals who want to become more muscular Buckley et al.
This much larger population of ordinary AAS abusers started to grow in the late s and early s as detailed below , but has remained less visible than most other populations of substance abusers, because AAS users rarely seek treatment Pope and Brower, in press , rarely come to the attention of physicians in general Dawson, ; Kutscher et al.
These latter doses are times greater than the natural weekly production of testosterone by the normal male testis Reyes-Fuentes and Veldhuis, Over the last years, illicit AAS use has grown into a widespread substance abuse problem in the United States Buckley et al.
Although many of these older men no longer use AAS, accumulating evidence suggests that they may still be vulnerable to long-term psychiatric and medical effects from their former drug use.
In this paper, we suggest that these effects may pose a growing public health concern, as large numbers of these men move into middle age and beyond.
As a foundation for this discussion, we begin with a more detailed chronology of the AAS epidemic, illustrated in Figure 1 , and explained in the following paragraphs. Time points in the evolution of anabolic-androgenic steroid abuse. See text for further discussion and references. AAS were apparently first used by the Russians at the weightlifting championships in Vienna in Wade, , and quickly spread into competition bodybuilding, track and field events such as the shot put, and other sports where performance depended on muscle strength or speed of recovery during training Fitzpatrick, The efficacy of AAS remained a well-kept secret among athletes; sports physicians and medical texts were still widely proclaiming that AAS were ineffective for gaining muscle Casner et al.
Fitness and bodybuilding magazines, usually with an AAS-using male model on the front cover, began to proliferate, and increasing numbers of young men became aware of the dramatic muscle gains that they could achieve with AAS Pope et al.
This book contained detailed information on how to obtain and use AAS, including instructions about how to self-administer injections; it quickly became a bible in the bodybuilding underground and appeared in successively larger revised editions in in Duchaine, , In this climate, AAS use began to break out from the domain of elite athletics and into the general community. In a widely cited paper, Buckley and colleagues Buckley et al. Since a large majority of AAS users were boys see Johnston et al.
This survey produced lower estimates of AAS use than the anonymous questionnaire studies, for reasons that we have discussed elsewhere Kanayama et al. This chronology has important implications for assessing the long-term medical and psychiatric consequences of AAS use. But this number will now grow rapidly; even using the conservative figures from the NHS, it would follow that about half a million American men with a lifetime history of AAS use will have passed the age of 45 by the year This cohort of aging AAS users is the first of its kind - the leading wave of a new epidemiologic phenomenon.
Although many of these older men have discontinued AAS use, and evolving literature suggests that they may be vulnerable to a range of psychiatric and medical effects that may persist long after last AAS exposure. These are briefly summarized in Table 1 ; we review the relevant literature in the following sections. Supraphysiologic doses of AAS appear to produce a range of adverse cardiovascular effects, including hypertension Kuipers et al. Some of these effects, such as hypertension, dyslipidemia, and coagulation abnormalities, remit after AAS use is discontinued, but effects such as atherosclerosis and cardiomyopathy are likely irreversible Hartgens and Kuipers, ; Sullivan et al.
Older former AAS users, who are now entering the age of increased risk for cardiovascular morbidity and mortality, might therefore be expected to display an increased rate of serious cardiovascular events. At present, it is difficult to estimate the prevalence or severity of cardiovascular pathology in older AAS users, since there are few empirical studies.
Parssinen and colleagues Parssinen et al. Three of the 8 deaths among powerlifters were ascribed to myocardial infarction, and the authors speculate that these deaths may have been attributable to AAS use.
Of course, it must be remembered that there was no direct evidence, either from self-report or body-fluid analysis, that these athletes had used AAS - but the excess mortality among powerlifters appears unlikely to be attributable to powerlifting itself, since weightlifters and power sports athletes studied before the AAS era showed survival curves similar to male controls Parssinen and Seppala, Similarly, Thiblin and colleagues noted chronic cardiac changes in 12 of 34 medically investigated deaths of male AAS users Thiblin et al.
In a cross-sectional study, Di Bello and colleagues performed videodensitometry measures on 10 weightlifters reporting AAS use mean [SD] age The authors speculate that these findings may reflect focal increases in myocardial collagen as a reparative mechanism against myocardial cellular damage in the AAS users - a potentially irreversible effect. Recent cross-sectional studies of similar design in France Nottin et al. Although the precise origin of these effects is uncertain, one possible mechanism is suggested by a recent study finding that AAS, in a dose-dependent manner, can induce apoptotic cell death in myocardial cells in a rat model Zaugg et al.
Although HPT function usually recovers spontaneously within a few weeks to a few months, the authors have encountered several men where hypogonadism persisted for more than a year after discontinuing AAS, and several recent published reports have documented post-AAS hypogonadism of similar duration Boyadjiev et al. Persistent suppression of HPT function may have serious clinical consequences, including infertility de la Torre Abril et al.
Even in users who recover HPT function uneventfully, there are concerns about the effects of prolonged, markedly supraphysiologic levels of AAS on other tissues sensitive to androgens, such as the prostate.
High doses of AAS may contribute to prostatic hypertrophy, Jin et al. However, both of these latter case reports appeared more than 15 years ago; the apparent absence of any similar reports since argues against an association of AAS use with prostatic neoplasia. This conclusion is congruent with recent endocrinological reports arguing that there is no adequate scientific basis for the long-held belief that testosterone stimulates prostate cancer to grow Morgentaler, , However, to our knowledge, no systematic studies have assessed the prevalence of prostate pathology in a population of AAS users as compared to age-matched control men.
The long-term effects of supraphysiologic doses of AAS on other organ systems are incompletely understood, and most of the available literature consists either of animal studies or small case reports in humans. Use of alpha alkylated AAS which are orally active is definitely, albeit rarely, associated with adverse hepatic effects, such as peliosis hepatis Karasawa et al.
Adverse hepatic effects with nonalpha alkylated AAS, such as testosterone, appear to be extremely rare, but have been described Carrasco et al. The risk of these hepatic effects is presumably greater with increasing duration of AAS exposure, as suggested for example by reports of hepatocellular adenomas developing after years of therapeutic AAS treatment for certain anemias Nakao et al.
However, AAS-induced hepatic pathology is often reversible upon discontinuation of AAS Modlinski and Fields, , and the overall prevalence of adverse hepatic effects among long-term illicit AAS users is likely low. However, it is not clear whether these findings can be extrapolated to older populations. Also disquieting are studies suggesting that supraphysiologic levels of AAS produce dose-dependent apoptotic cell death.
In a rat model, supraphysiologic levels of testosterone and stanozolol were found to induce apoptotic death of myocardial cells - prompting the authors to speculate that this mechanism might account for cardiac pathology in human AAS users Zaugg et al. Recently, another study has found that supraphysiologic levels of testosterone can produce apoptosis in neuronal cells Estrada et al.
Although this study was in vitro, the levels of testosterone causing significant apoptosis were within the range that might plausibly be reached by illicit human AAS users, who may ingest doses equivalent to times the level of endogenous testosterone production Fudala et al. Thus, the authors suggest that their findings might have clinical significance in humans. To our knowledge, however, no studies have systematically assessed older long-term high-dose AAS users for signs of dementia or specific neuropsychological deficits.
Even if supraphysiologic AAS do not prove to have a clinically significant toxic effect on human neuronal cells, these drugs are known to be associated with a variety of psychiatric effects Pope and Katz, Among illicit AAS users, it may be difficult to judge which of these psychiatric effects are attributable to AAS themselves, as opposed to underlying personality attributes of the user, or psychosocial factors surrounding AAS use Bahrke and Yesalis, ; Bahrke et al.
Nevertheless, both experimental studies Pope et al. However, not all studies have documented such mood changes Bahrke et al. These studies have included several reports of suicides Agren et al. Depressive symptoms, like hypomanic symptoms, appear to be idiosyncratic, with occasional individuals showing marked symptoms and others showing none Schmidt et al. Most of the above studies, however, describe short-term mood changes, measured in weeks or months, during or shortly after AAS use.
It is less clear whether mood changes may persist longer. However, recent Scandinavian studies offer some cause for concern. Petersson and colleagues found that suicide was significantly more common among deceased former AAS users than among other types of substance users Petersson et al. Also, in the study of older powerlifters by Parssinen et al. Recently, a Swedish research group has presented preliminary results from a structured questionnaire mailed to former Swedish elite male athletes who placed 1 st though 10th in Swedish championships between and in wrestling, track and field throwing events , power lifting, and Olympic lifting Lindqvist et al.
Among the respondents, answered the question about AAS, and of these, The former users were much more likely to report seeking treatment for psychiatric symptoms; for example, 19 Of course, the above studies do not establish that AAS played a causal role in the development of long-term depression or other psychiatric symptoms - but there are several reasons to suspect that AAS users might be at increased risk for depression even into middle age.
First, some individuals become dependent on AAS, repeatedly taking these drugs to prevent hypogonadal symptoms, and thus may continue to use AAS well into middle age. Second, even among those who discontinue AAS use in their 20s or 30s, HPT suppression and consequent hypogonadal symptoms may persist in some cases for prolonged periods.
The prevalence of this phenomenon among AAS users, and its contribution to depressive symptoms, remains unknown. Third, AAS users may suffer from prominent body-image disorders, such as muscle dysmorphia, a form of body dysmorphic disorder in which individuals become preoccupied that they do not look sufficiently big and muscular Cafri et al.
Specifically, men with body-image concerns may be motivated to use AAS initially, and then paradoxically become increasingly concerned about their muscularity even as they are growing bigger on AAS. Muscularity becomes central to their self-esteem, and loss of muscularity triggers anxiety.
This phenomenon frequently contributes to the syndrome of AAS dependence Brower, ; Brower et al. Also as a result of their body image concerns, AAS users may abuse a wide range of additional substances to gain muscle, lose fat, or otherwise affect body appearance.
Individuals wishing to use these substances can obtain detailed advice from comprehensive underground guides Gallaway, ; Llewellyn, ; Roberts and Clapp, or from countless Internet websites, forums, and discussion groups devoted to AAS and other body-image drugs for some examples, see a list of representative sites at http: Many of these substances have been studied under legitimate medical conditions, but their effects when used illicitly, alone or in combination with AAS, are little studied.
Among the various illicit drugs ingested by AAS users, opioids may represent a particular problem. Specifically, two reports have described illicit use of the opioid agonist-antagonist nalbuphine among AAS users McBride et al. Another study of consecutive men admitted to an inpatient substance abuse treatment facility suggested a similar link between AAS and opioids: Interestingly, animal studies also suggest possible links between AAS and opioids; for example, hamsters will self-administer testosterone, sometimes even to the point of death Wood, , and several lines of evidence suggest that opioidergic mechanisms may be involved in this self-administration process Peters and Wood, Thus, there may be a neurobiological basis for the progression from AAS use to opioid use in humans.
Little is known about the lifetime prevalence of the various medical and psychiatric consequences of AAS use described above. It might be speculated that publication bias exaggerates the apparent magnitude of AAS-associated pathology, in that rare cases of cardiac or hepatic toxicity, or of psychiatric effects such as violence or suicide, find their way into published case reports, while the great majority of long-term illicit AAS users are healthy.