Risk Factors
Cardiovascular risk and androgenic anabolic steroids Nicholas Sculthorpe is Senior Lecturer, Department of Sport and Exercise Science, University of Bedfordshire, Bedford, MK41 9EA; Fergal Grace is Senior Lecturer, Institute of Clinical Exercise and Health Sciences, University of the West of Scotland; Peter Angell is Sport Science Support, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University; Julien Baker is Chair and Head of Sports and Exercise Science, Institute of Clinical Exercise and Health Sciences, University of the West of Scotland; Keith George is Chair and Head of Research Institute for Sport and Exercise Sciences, Liverpool John Moores University. Email:
[email protected]
T
he use of pharmacological agents to aid athletic performance is not a new phenomenon and over several centuries, athletes have ingested a surprising variety of compounds purported to improve performance (Dimeo, 2006). However, of these, androgenic anabolic steroids (AAS) have become the most notable and widely used (Evans, 2004). The reasons for the ‘success’ of AAS as the performance-enhancing drugs of choice are varied. That they could be discontinued during competition and the athlete still benefit from their use has played a part, as has the relative ease with which their use could be masked in the early years of their development. However the overriding reason for the widespread use of AAS is likely due to their aesthetic effects on the male physique. This in turn has meant that, unlike many other performanceenhancing drugs, AAS have made the leap from high-level sports performance to amateur, non-competitive and even recreational use. Consequently, while a drug such as
Abstract
Although several drugs are purported to improve exercise performance, androgenic anabolic steroids (AAS) are the most widespread. Furthermore, unlike other drugs, their use has expanded beyond competition, to non-competitive and recreational athletes. Correspondingly health professionals are more likely to come into contact with users of AAS than with users of other performanceenhancing drugs. While there are numerous reports outlining serious cardiovascular consequences to high-dose AAS abuse, this evidence is often limited by difficulties in gaining access to users due to the legal status of AAS. Additionally the co-abuse of other substances (as additional muscle mass enhancers, or to mitigate possible side effects) is a further confounding factor. This review examines the evidence for AAS having a negative effect on the cardiac and vascular tissue and the corresponding risk of developing cardiovascular disease. Possible mechanisms of action by which AAS bring about these changes are also discussed. Key words w Performance-enhancing drugs w Cardiovascular risk w Lipid profile w Sudden cardiac death Submitted for peer review 2 April 2012. Accepted for publication 23 May 2012. Conflict of interest: None
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erythropoietin (EPO) is highly effective, its use outside of high-level sporting performance is relatively rare and therefore so is the likelihood of health professionals coming in contact with cases of its abuse. Alternatively, the widespread use of AAS in both sporting and non-sporting spheres means that the abuse base is far higher and correspondingly so is the likelihood that users will come into contact with medical staff (Grace et al, 2001). As AAS use has increased so have concerns regarding the potential negative side effects (Parker and Thompson, 2010). Different types of AAS have been associated with a number of pathologies (Table 1) including cardiovascular disease, sudden cardiac death, renal and hepatic pathologies and cancer as well as well-reported adverse psychological effects (van Amsterdam et al, 2010). Furthermore, investigating the use of large doses of AAS in humans has specific limitations. Many studies are mainly offered as case reports or small studies that lack adequate control groups (Stergiopoulos et al, 2008) and frequently do not account for differing steroid type(s) or dose, as neither may be known or what is taken may even be counterfeit with little, no or unknown active ingredients (Graham et al, 2009). In addition, AAS users presenting as clinical cases for emergency treatment may also engage in the concomitant abuse of other drugs, which can confound data and increase the potential for adverse events (Table 2). As a result the research literature is lacking empirical epidemiological data that would show direct effects of AAS on mortality. In other words, while AAS users may suffer cardiac incidents or cancers (for example), so do a great number of people who have never used AAS. Unfortunately, due to the illicit nature of AAS use and the negative consequences that may result from admitting to their use (negative both in professional and legal terms) it is extremely unlikely that data of this type will ever be collected. Consequently, the majority of previous research has attempted to assess the consequences of AAS use by determining their impact on known risk factors for specific diseases (e.g. blood lipids). It is also worth noting that the overwhelming majority of research and case studies identified within the literature deals almost exclusively with male users of AAS. Correspondingly, where reference is made to
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Risk Factors the magnitude of effect that AAS are reported to have on any given variable, those values refer to males only. That is not to suggest that females do not use AAS or do not suffer from the increased cardiovascular risk outlined here. Indeed given that the normal circulating levels of androgens in females are so much lower than in males it would seem logical that any
risk from AAS use would be as great or greater in female users than in males. Female athletes have been shown to be similar to their male counterparts in that they use AAS (Harmer, 2010), often co-abuse other drugs along with AAS (Ip et al, 2010) and sadly have cases of sudden death that may be related to their AAS use (Thiblin et al, 2009).
Table 1. Differing classifications of androgenic anabolic steroids Classifications based on alterations to the testosterone molecule 17-alpha alkylated
Water soluble Usually orally administered Due to first-pass metabolism often considered more hepatotoxic
17-beta esterified
Lipid soluble Usually administered parenterally
Classification based on expected side effects Testosterone
Based on the testosterone molecule with some alterations Easily converted to both DHT and to oestrogen with high risk of associated side effects
Dihydrotestosterone (DHT)
Based on the DHT molecule Poorly esterified to oestrogen Associated with DHT side effects (hair loss, acne)
19-nortestosterone
Based on the nandrolone molecule Moderately convertible to oestrogen with low risk of associated side effects Not converted to DHT and hence a low risk of DHT side effects May have progestrogenic effects
Table 2. Drugs that are frequently abused alongside androgenic anabolic steroids Human growth hormone Insulin Tamoxifen Oestrogen receptor antagonist Clomifene (Clomid) Selective oestrogen receptor inhibitor
Usually used in combination with AAS in the belief that their combination is more potent than any individual effects Oestrogen receptor antagonists. Used ‘on-cycle’ in the belief that they reduce the risk of gynaecomastia. Used post cycle to promote normalization of luteinising hormone production
Arimidex Aromatase inhibitor
Inhibits the effect of aromatase enzymes that convert testosterone into oestrogen. Used ‘on-cycle’ in the belief that this reduces the risk of gynaecomastia
Human chorionic gonadatropin (HCG)
Acts on the hypothalamic-pituitary-gonadal axis to restore normal testosterone. Used ‘off-cycle’
Finesteride
Inhibits the conversion of testosterone to dihydrotestosterone (DHT). Used in the belief that it minimizes some side effects of AAS use including hair loss, acne and prostate growth
Clenbuterol
Beta 2 agonist. Used as thermogenic agent to aid reductions in body fat
2,4-dinitrophenol (DNP)
Uncouples energy metabolism and reduced efficient ATP production. Used to aid reductions in body fat
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Risk Factors With these caveats in mind the remainder of this review will discuss the available evidence with particular reference to the effect of abusing AAS with supratherapeutic doses, on a range of cardiovascular risk factors.
Physiological effects of testosterone
Most tissues within the body have been shown to have androgen receptors and consequently the physiological effects of testosterone are multifactorial affecting most physiological systems. Broadly however, the effects of testosterone are generally split between those that are considered to involve growth and development (anabolic) and those that are considered to be associated with masculine traits (androgenic) (Figure 1). It is worth noting that the interactions outlined above relate to the effects of testosterone when present in normal concentration (300–1000 ng/dl). The use of high doses of AAS will significantly increase these concentrations with effects on all of those systemic targets of testosterone. Furthermore testosterone must be carried in the blood bound to the carrier sex steroid hormone-binding globu-
lin (SHBG) with only 1–2% of total testosterone unbound and available to interact with androgen receptors. Males and females therefore have reference ranges for both total testosterone (9.0–35 nmol/litre and 0.5–3.0 nmol/litre in males and females respectively) and free testosterone (80–300 pg/ml and 1.1–6.3 pg/ml in males and females respectively). Of relevance to the current topic is that if the SHBG system is saturated then any further administration of AAS will cause large increases in free rather than bound testosterone and consequently even moderate (though still supraphysiological) doses may result in disproportionate effects.
Blood-borne markers of cardiovascular risk
Elevated concentrations of total cholesterol (TC) and lowdensity lipoprotein (LDL) as well as depressed levels of high-density lipoprotein (HDL) are all strongly associated with an increased risk of developing cardiovascular disease (Robinson et al, 2009). Consequently much of the early research into the possible side effects of AAS concentrated on alterations to blood lipid profiles. While the data
Androgenic effects
Anabolic effects
Psychological effects of ‘male’ characteristics e.g. aggression, competitiveness
Increased skeletal muscle mass
Improved T-lymphocyte production
Development and maintenance of libido (males and females)
Increased size of organs
Pubertal voice alterations (males)
Retention of electrolytes (particularly dietary sodium)
Increased secretions from sebaceous glands in skin Altered haemoglobin and red blood cell mass Increased density of facial and body hair Altered distribution of body fat Pubic hair development (males) Increased bone density Initial development of genitalia (males and females) Increased pubertal growth height (when present with human growth hormone)
Seminal vesicles and prostate development (males)
FRIEDRICH SAURER/SCIENCE PHOTO LIBRARY
Figure 1. Effects of testosterone on the body (in normal concentrations) 268
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Risk Factors on the effects of AAS abuse on TC are variable, the consequences on HDL and LDL are much more definitive. The extreme blood lipid alterations induced by AAS have been described as being more profound than any reported with other pharmacological or non-pharmacological agents (Thompson et al, 1989). A review of highdose oral AAS abuse (Lenders et al, 1988) found a weighted average decrease in HDL of 52% and average increase in LDL of 36%. Decreases in HDL were predominately in the HDL2 sub-fraction (78% reduction) with HDL3 changes showing much greater inter-individual variability. The changes in HDL2 are thought to be due to the effect of AAS on the enzyme hepatic triglyceride lipase (HTGL) which plays an important role in the breakdown of the HDL2 sub-fraction (Lenders et al, 1988). Evidence of increased HTGL activity has been identified previously in studies of therapeutic AAS use (Glueck, 1985; Thompson et al, 1989) and also in research where participants have used two or more AAS in supraphysiological doses (Király, 1988; Zuliani et al, 1989). Recently Achar et al (2010) performed a meta-analysis of 49 studies, which confirmed that AAS abuse in otherwise healthy young athletes was associated with reductions in HDL and elevated LDL. Further, it is interesting to note that even relatively low therapeutic doses of AAS can cause adverse blood lipid response. Analyses of 20 studies (Glazer, 1991) using therapeutic doses of testosterone enanthate (as a possible contraceptive agent) demonstrated an AAS-related decrease in HDL (mean 11%) and increases in LDL (mean 9%) indicating that even low doses of AAS result in lesser, though still adverse changes to blood lipids. Taken together, it is clear that there appears to be a dose-dependent effect of AAS on HDL and LDL in otherwise healthy individuals. Apolipoprotein AI (apo-AI) and to a lesser extent apolipoprotein AII (apo-AII) are the major apoproteins of HDL cholesterol and have an important role in plasma lipid metabolism (Cheung et al, 1980). The effects of AAS use on apo-AI and apo-AII have been investigated and shown to follow a similar reduction to that of HDL following therapeutic doses (Haffner et al, 1983; Webb et al, 1984) and supraphysiological doses of AAS (Dickerman et al, 1997; Singh et al, 2002). Similarly studies reporting on the effect of AAS on LDL and its major apolipoprotein (apo-B) consistently report elevations in serum values to a similar degree to that seen in LDL (Cohen et al, 1996; Singh et al, 2002; Hartgens et al, 2004). It is the orally-administered 17-alpha-alkylated AAS that are associated with producing a more deleterious effect on HDL, LDL and apolipoproteins (Grace et al, 2001; Whitsel et al, 2001). To an extent the monitoring of TC may be misleading. Although there is a marked increase in atherogenic profile with AAS-induced increases in LDL, these are frequently offset by the decreased HDL. Correspondingly there is often no overall effect of AAS use on TC concentrations. For example Lane et al (2006) observed no difference in total cholesterol levels between AAS users (4·0 ± 0·83 mmol/ litre) and non-users (3·8 ± 0·38 mmol/litre), while LDL was British Journal of Cardiac Nursing June 2012 Vol 7 No 6
significantly elevated (2·9 ± 0·7 vs 2·1 ± 0·3 mmol/litre) and HDL significantly decreased (0·7 ± 0·4 vs 1·3 ± 0·3 mmol/ litre) in the AAS users. It is of interest that the impact of AAS use on blood lipids appears to occur quickly but that the effects may be reversible. Available longitudinal literature would suggest that HDL levels begin to decrease immediately after the onset of AAS consumption (Lenders et al, 1988; Whitsel et al, 2001) and that they reach their nadir between 1 and 4 weeks after initiating AAS use (Haffner et al, 1983; Whitsel et al, 2001) and return to pre-treatment concentrations between 3 weeks (Kuipers, 1991; Hartgens et al, 2004) and 3 months later (Cohen et al, 1996). Other work suggests that recovery of blood lipids following AAS administration may take longer than 3 months (Király, 1988; Bonetti et al, 2008). The transitory effect of AAS on blood lipids and apolipoproteins makes it difficult to ascertain the long-term atherogenic risk to users. Additionally, AAS use is often intermittent in a practice known as ‘cycling’ (repeated bouts of AAS use (‘on-cycle’) followed by abstention (‘off-cycle’)) in the belief that this avoids developing drug tolerance and minimises potential side-effects. However cycling is often performed in 6–12 week periods, which as outlined above may not be sufficient to allow for normalisation of HDL concentrations during the ‘off-cycle’. Consequently such patterns of use are likely associated with greater risk of cardiovascular consequences. Furthermore, while any changes in lipid profile may be reversible, any vascular damage that occurs during the period of use may not be. Other blood-borne markers of cardiovascular risk have also been assessed in AAS users. Homocysteine, a thiolcontaining amino acid formed from methionine, is considered to be an independent marker of endothelial damage and consequently cardiovascular risk (Boushey et al, 1995). Although Zmuda et al (1993) did not find any effect of AAS on homocysteine concentrations, a more recent study (Graham et al, 2006) identified elevated homocysteine both in ‘on-cycle’ and ‘off-cycle’ (3-month abstention) long-term AAS users, suggesting that AAS may increase endothelial risk, which may persist for months following withdrawal. The differences in findings may be related to a number of factors: dietary folate is a particular modulator of homocysteine (Boushey et al, 1995) and differences in the diets of AAS users between studies may partly account for the discrepancy. High sensitivity C-reactive protein (hsCRP) is a marker of inflammation and has been associated with cardiovascular events including myocardial infarctions and stroke and has a direct effect on vascular endothelium (Ridker et al, 2002). Measurement of hsCRP is not routinely performed in the evaluation of cardiovascular risk and therefore limited attention has been paid to hsCRP in AAS users. Grace and Davies (2004) reported that hsCRP was elevated in AAS-using bodybuilders compared to both non AAS-using bodybuilders and sedentary controls. Arazi et al (2011) also demonstrated increased hsCRP in AAS users relative to non-using resistance-trained ath269
Risk Factors letes, and Severo et al (2012) reported elevated hsCRP in AAS-using athletes compared to non-users. Although the mechanism(s) for this observation is not known, and such findings require replication, the data highlights the possibility that AAS use could result in local or systemic inflammation that has the potential to damage cardiomyocytes and/ or the vascular endothelium. It is also worth noting that lower therapeutic doses (
