Image- and performance-enhancing drugs include a wide range of substances used to promote physical changes to enhance appearance, increase musculature, and improve athletic performance, as well as perceived social opportunity, self-confidence, and self-esteem.1
Anabolic androgen steroids are the most widely used class of illicit image- and performance-enhancing drugs in competitive athletics, recreational sports, and bodybuilding, generally used to augment muscle mass. However, numerous studies have consistently shown that anabolic androgen steroids users typically ingest a wide variety of additional drugs, including other image- and performance-enhancing drugs and classic drugs of abuse as well as analgesic and psychiatric drugs without medical prescription.1–3
Uncontrolled anabolic androgen steroid abuse by adult athletes, professionals, and amateurs, whether taking part in sporting events or not, may be responsible for an increased incidence of cardiac deaths. This concerns mainly weightlifters and bodybuilders taking very high anabolic androgen steroid doses, often in combination with other image- and performance-enhancing drugs and illicit drugs.2,4
On the other hand, the fact that anabolic androgen steroid users may assume a bewilderingly large number of image- and performance-enhancing drugs in various forms, individually, simultaneously, and in various temporal combinations and sequences, as well as classic drugs of abuse, renders the interpretation of morphological and toxicological findings in fatal cases extremely difficult.5 Exhaustive macroscopic, microscopic, and toxicological investigations are mandatory in the evaluation of sudden unexpected deaths involving suspected image- and performance-enhancing drug users.
The study presented herein (case series) focuses on postmortem findings in a series of deaths involving image- and performance-enhancing drug (anabolic androgen steroid) users that underwent forensic investigations. Our aim was 2-fold: to identify the morphological changes pertaining to the cardiovascular system possibly involved in the pathogenesis of death and characterize the substances associated with anabolic androgen steroid use and their possible role in the occurrence of death.
MATERIALS AND METHODS
A retrospective review was performed of cases between 2010 and 2018 to identify deaths with anabolic androgen steroid use. Five cases (all males; mean age, 33 years) who had undergone forensic investigations were selected.
All cases included in this study originated from forensic practice and were admitted to the mortuary because of sudden, unexpected, and unwitnessed death. Personal data and medical records, when available, were collected from families, clinical patient databases, general practitioners, and local health services. According to available medical records, all these cases were void of any “officially” medically prescribed drug treatment at the time of death, including anabolic androgen steroid. Circumstantial elements (personal data collected from relatives and friends as well as house searches carried out by authorities) confirmed image- and performance-enhancing drug (including anabolic androgen steroid) use in all cases.
Systematic toxicological analysis included blood ethanol level determination, as well as general screening for volatile and nonvolatile drugs, poisons, and metabolites. Anabolic androgenic steroid screening (qualitative determination) was essayed in urine samples using recommended techniques for this analysis.
Table 1 summarizes the main results obtained in the selected cases. External examinations and autopsies allowed prominent muscular masses and various degrees of testicular atrophy to be noticed. At heart dissection, most coronary arteries were normal or revealed only slight intima thickening in their subepicardial portion. Scattered fatty streaks, as well as intima and media thickening, occasionally characterized the coronaries. Acute myocardial infarction was not observed in any of these subjects.
The main myocardial and coronary artery histological findings consisted of myocardial interstitial fibrosis (2 cases) and ventricular hypertrophy (left ventricular or left and right ventricular hypertrophy, 3 cases) (Fig. 1). Occasional myocyte necrosis within the left ventricle was observed.
Nandrolone and testosterone were the most frequently identified anabolic androgen steroids. The most commonly drugs found were non–medically prescribed tetrahydrocannabinol (4 cases), non–medically prescribed methadone (2 cases), non–medically prescribed opiates (2 cases), and non–medically prescribed benzodiazepines (2 cases). Ethanol, cocaine, non–medically prescribed barbiturate, and non–medically prescribed antidepressants were observed in 1 case.
In all cases, the morphological findings along with the toxicological data were considered sufficient to explain the death as related to the cardiac effects of anabolic androgen steroid abuse individually considered or in combination with drug concentrations potentially causing the death.
For years, individual case reports and small case series in both clinical and forensic literature have described a variety of possible anabolic androgen steroid effects on the cardiovascular system such as cardiomyopathy, arrhythmias, myocardial infarction, and cerebrovascular accidents, as well as coagulation abnormalities in known or suspected users. Larger controlled studies have more recently supported these findings in the clinical setting.2,3,5–9
Polypharmacy (use of multiple substances or agents in a complex drug regimen), including use of legal and illegal substances, is common among image- and performance-enhancing drug users. In anabolic androgen steroid users, this phenomenon typically presents as a range of ancillary substances designed to complement the effects of and counteract the unwanted side effects of anabolic androgen steroids (or other image- and performance-enhancing drugs taken simultaneously, eg, antiestrogens). The most common substances include other hormones (human growth hormone, insulinlike growth factor 1, thyroid hormones, and insulin), stimulants (amphetamine, ephedrine, pseudoephedrine, and especially β-agonist clenbuterol), drugs supposed to stimulate testosterone (anabolic androgen steroid augmenting drugs) or growth hormone secretion (peptidic growth hormone secretagogues) and decrease estrogen production, drugs for weight or fluid loss (diuretics, laxatives), and numerous other agents.5,10–12
It is worth noting that anabolic androgen steroid users frequently ingest a variety of “dietary supplements” or “nutraceuticals” in addition to the aforementioned drugs. Although these supplements are typically sold over the counter without regulation, numerous recent studies have shown that certain supplements actually contain potent androgens or other image- and performance-enhancing drugs such as clenbuterol. Conversely, a sizable proportion of drugs sold on the street or over the Internet as supposedly genuine androgens may be mislabeled, impure, or simply counterfeit. Thus, an individual's actual total burden of image- and performance-enhancing drug exposure may differ substantially from what he/she believes to have ingested.3
Numerous studies have also shown that illicit anabolic androgen steroid users frequently assume classic drugs of abuse in addition to anabolic androgen steroids. These include opioids/opiates, cocaine, and tetrahydrocannabinol, as well as other licit and illicit analgesic and psychoactive drugs. The mixture of pharmacologically distinct substances seems to be a common feature among image- and performance-enhancing drugs/anabolic androgen steroid users. It has been observed that the consumption of illicit psychoactive drugs among anabolic androgen steroid users is primarily associated with pathological anabolic androgen steroid users, for example, those who also engage in excessively long cycling.3,5,10,13–15
Thieme and Büttner16 reported that a substantial number of antihypertensive drugs of various classes were found in a series of relevant doping cases. The presumptive correlation between anabolic androgen steroid misuse and self-treatment of cardiovascular side effects was explicitly confirmed by detailed user statements.
Westerman et al17 observed that illegal drug use may occur in nearly all subjects before starting testosterone use. These authors highlighted that their own conclusions appeared to contrast others that had suggested testosterone as a plausible gateway to other drug abuse.14,18
In a report by Lood et al,14 polydrug abuse including analgesics, antidepressants, hypnotics, and other neuroleptics was found in 60% of urine samples obtained from anabolic androgen steroid users. According to the authors, all these substances are likely used as medical treatment for different side effects associated with anabolic androgen steroid use. Moreover, polydrug abuse in anabolic androgen steroid users would support the hypothesis of anabolic androgen steroid use as a gateway to other drug abuse and chronic anabolic androgen steroid intake as a risk factor for opioid dependence.
Current medicolegal literature pertaining to sudden death in image- and performance-enhancing drug users consists mainly of single case reports or small case series in anabolic androgen steroid users. In most situations, the cause of death was considered cardiac in origin based on the results of all investigations and the exclusion of alternative causes of death, thus supporting the hypothesis that cardiovascular changes possibly induced by chronic anabolic androgen steroid use may play a role in the pathogenesis of death. On the other hand, postmortem case series focusing on polydrug and anabolic androgen steroid/image- and performance-enhancing drug users have rarely been reported in the forensic setting.7,19–28
In a case series including 24 anabolic androgen steroid users described by Darke et al,29 the most common direct cause of death was drug toxicity. In 23 of 24 cases, psychoactive substances other than steroids were detected. The most prevalent drugs were psychostimulants (cocaine, methamphetamine, MDMA). Opioids/opiates (morphine, codeine, oxycodone, tramadol, and pholcodine) were detected in 37.5% of cases, with morphine present in all cases. Benzodiazepines were detected in nearly half of all cases, most commonly diazepam. Venlafaxine was present in 1 case, whereas no cases tested positive for cannabis.
As stated previously, the fact that anabolic androgen steroid users may assume other image- and performance-enhancing drugs in various forms, individually, simultaneously, and in various temporal combinations and sequences, as well as classic drugs of abuse, renders the interpretation of morphological findings in forensic cases quite challenging. For instance, chronic cocaine abuse has been demonstrated to be associated with increased left ventricular mass index and wall thickness. Left ventricular hypertrophy may provide an additional substrate facilitating the development of myocardial ischemia and/or fatal arrhythmia in cocaine abusers.5,30 Maceira et al31 observed a decreased systolic function of both left and right ventricles, an increased left ventricular mass, and the presence of local fibrosis in 71% of a cohort of 94 consecutive cocaine abusers, with a probability of left ventricular systolic function related to mean duration of cocaine abuse.
The results of the study presented herein tend to confirm clinical observations on this topic and corroborate previous suggestions of associations between image- and performance-enhancing drug/anabolic androgen steroid use and the consumption of a wide range of other licit and illicit substances.
On the other hand, the main limitations of our study must be clearly outlined and considered. The most important is the small study sample, which may limit the possibility of drawing conclusions based on a very limited number of studied cases, although comparable with other researches examining the same topic.
The second limitation concerns the fact that several other factors, such as genetics, could theoretically be involved in the pathogenesis of sudden death in image- and performance-enhancing drug/anabolic androgen steroid users. These factors were not considered in our research and should be taken into account in the future when assessing the possible “pathways” leading to cardiac events in such forensic population.
Third, as already highlighted by Petersson et al,26 most cases of sudden death among individuals younger than 40 years are subjected to forensic examinations even in the absence of obvious signs of unnatural death, although forensic autopsy and toxicology are not systematic in these situations.
Moreover, toxicological analyses regarding performance-enhancing drugs/anabolic androgen steroids/illicit drugs are usually performed on the suspicion of the forensic pathologists.
As a consequence, additional cases of sudden deaths in performance-enhancing drug/anabolic androgen steroid users might have been missed in our research, because of either lack of toxicological investigations or the fact that some cases could have been diagnosed with terminal cardiac event in the clinical setting, with no forensic investigations, or even in the forensic setting with no toxicological investigations/no anabolic androgen steroid research.
Globally considered, all these limitations might have led to underestimate the effective role that anabolic androgen steroids might play in the pathogenesis of sudden cardiac deaths and therefore limit the accuracy of our research.
From a forensic point of view, sudden and unexpected deaths in suspected image- and performance-enhancing drug/anabolic androgen steroid users raise significant issues pertaining to the interpretation of morphological findings and toxicological results.
The toxicological identification of anabolic androgen steroids, anabolic androgen steroid releasers/boosters, blood pressure regulators, diuretics, psychostimulants, opiates/opioids, tetrahydrocannabinol, benzodiazepines, and antidepressants in the same blood/urine samples, along with the macroscopic and microscopic identification of potentially significant cardiovascular abnormalities, must be intensely evaluated in order to assign the proper weight to each of these findings in the pathogenesis of death.
Potentially significant morphological changes pertaining to the myocardium and coronary arteries may be observed in fatalities involving chronic anabolic androgen steroid/ image- and performance-enhancing drug users. The high incidence of polydrug abuse in these cases corroborates the observation that image- and performance-enhancing drugs/anabolic androgen steroids are commonly taken together with other drugs of abuse, which is in accordance with the drug abuse pattern of the average drug user/addict, and confirms that these individuals are at high risk of death by intoxication.
Results obtained from postmortem investigations should therefore be meticulously evaluated in order to understand the weight that each identified substance may have played in the occurrence of death.
Based on the above, it is challenging to identify the most suitable forensic “strategy” to decide in which cases anabolic androgen steroids and other image- and performance-enhancing drugs should be screened in situations of sudden cardiac death or when anabolic androgen steroid use should be considered a contributing factor in the cause/pathogenesis of death in sudden cardiac death cases.
Numerous steroid-related pathophysiological mechanisms may play a role in determining a cardiac pathology and predispose young individuals to myocardial injury and subsequent sudden cardiac death. Based on the reviewed literature and our own findings, we strongly support the hypothesis that sudden cardiac death cases should always be investigated from a forensic point of view and always include broad toxicological investigations preceded, when possible, by a careful evaluation of personal information (clinical data and anamnestic data), in order to identify possible cases of anabolic androgen steroid consumption, as already emphasized by former researchers.20,21,32
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