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Sudden or unnatural deaths involving anabolicandrogenic steroids

Available online at: Shane Darke,1 Ph.D.; Michelle Torok,1 M.Soc.Sci.; and Johan Duflou,1,2,3,4 M.Med.Path. (Forens),F.R.C.P.A.
Sudden or Unnatural Deaths InvolvingAnabolic-androgenic Steroids* ABSTRACT: Anabolic-androgenic steroids (AASs) are frequently misused. To determine causes of death, characteristics, toxicology, and pathology of AAS positive cases, all cases (n = 24) presenting to the New South Wales Department of Forensic Medicine (1995–2012) wereretrieved. All were male, and the mean age was 31.7 years. Deaths were mainly due to accidental drug toxicity (62.5%), then suicide (16.7%)and homicide (12.5%). Abnormal testosterone/epitestosterone ratios were reported in 62.5%, followed by metabolites of nandrolone (58.3%),stanozolol (33.3%), and methandienone (20.8%). In 23 of 24 cases, substances other than steroids were detected, most commonly psychostimu-lants (66.7%). In nearly half, testicular atrophy was noted, as was testicular fibrosis and arrested spermatogenesis. Left ventricular hypertrophywas noted in 30.4%, and moderate to severe narrowing of the coronary arteries in 26.1%. To summarize, the typical case was a male polydruguser aged in their thirties, with death due to drug toxicity. Extensive cardiovascular disease was particularly notable.
KEYWORDS: forensic science, steroids, toxicology, psychostimulants, cardiovascular disease, demographics Anabolic-androgenic steroids (AAS) include exogenous testos- with increased risk of peliosis hepatitis, cholestasis, and hepatic terone, synthetic testosterone, and synthetic testosterone deriva- tumors (1,7,18). AAS are also psychotropic and are associated tives (1). While such drugs have valid medical applications, with increased aggressiveness, agitation, paranoid ideation, mood human and animal AAS are frequently misused to enhance ath- swings, and depression (1,11,12). In the few steroid positive case letic performance, strength, and image (e.g., body building) series that have been conducted, death by violence, from other or (2–7). Users of these drugs are mostly male, and aged predomi- to self, formed a substantial proportion of deaths (11,12).
nantly between the late teens and mid-thirties (2–8). Apart from One final factor that may contribute to premature mortality muscular development, the regular use of AAS is associated with among AAS users is polypharmacy. There is emerging evidence, a number of direct physiological changes, including testicular among both current users and fatalities, that substance use atrophy and arrested spermatogenesis, while females may experi- among this population extends far beyond AAS (3,5,20–22).
ence masculinization (1). There is also evidence of a dependence There appear to be increased rates of use of opioids and psycho- syndrome among regular users (9,10). Indeed, in one recent study stimulants in particular but, apparently, not of cannabis or of AAS users, 30% met DSM criteria for dependence (10).
There is emerging evidence that the use of AAS is associated Despite their widespread use, there are few case series of ste- with increased risk of premature mortality (7,11,12). Much of this roid positive cases of unnatural or sudden death. This study risk is thought to arise from the physiological and psychological aimed to determine the circumstances of death, demographic sequelae of AAS. There is mounting evidence that these drugs characteristics, toxicology, and major organ pathology of cases cause cardiovascular disease, including cardiomegaly, left ventric- presenting to the Department of Forensic Medicine (DOFM), ular hypertrophy, cardiomyopathy, ischemic heart disease, fibro- Sydney, over the period January 1, 1996 to December 31, 2012 sis, and contraction band necrosis (1,12–19). Indeed, it has been in which anabolic steroids were detected during quantitative noted that the profile of cardiovascular damage from AAS abuse is similar to the pathology seen from psychostimulant abuse(1,7,18). Liver disease also appears higher among AAS users, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia.
All cases autopsied at the DOFM between January 1, 1996 and Department of Forensic Medicine, South Western Sydney Local Health District, PO Box 90, Glebe, NSW, 2037, Australia.
December 31, 2012 were identified in which anabolic steroids 3School of Medical Sciences, University of New South Wales, Sydney, were detected in urine taken at autopsy. Police death investigation summaries and autopsy reports of all such cases were retrieved 4Sydney Medical School, University of Sydney, NSW, 2008, Australia.
from the database of the DOFM. The DOFM is located in central *The National Drug and Alcohol Research Centre at the University of Sydney and is the primary forensic pathology center in New South NSW is supported by funding from the Australian Government.
Wales (NSW), conducting between 2000 and 2500 autopsies per Received 18 Dec. 2012; and in revised form 25 April 2013; accepted 24 year during this time period. Permission to inspect the files was 2014 American Academy of Forensic Sciences received from the Sydney Local Health District Human Research TABLE 1––Characteristics of cases of sudden or unnatural death in which Ethics Committee. All cases were reviewed by the authors.
anabolic-androgenic steroids were detected.
In NSW, a case must be reported to the coroner where a per- son dies a violent or unnatural death. The majority of such casesundergo a standardized forensic autopsy, with examination of all major organs and quantitative toxicological analysis. Cause of death is determined by the forensic pathologist on the basis of circumstances of death, the autopsy findings, and the toxicologi- cal analyses. Circumstances of death, and case histories, were obtained from accompanying police reports to the coroner.
All autopsy blood samples were taken peripherally (femoral or alcohol, cannabis (determined by the presence of D-9-THC), opi- oids (e.g., morphine, methadone, buprenorphine, oxycodone, hydrocodone, tramodol), psychostimulants (methamphetamine, cocaine, benzoylecgonine, 3,4methylenedioxymethamphetamine [MDMA]), benzodiazepines (e.g., diazepam, oxazapam, temaze- pam, flunitrazepam, alprazolam), gammahydroxybutyrate (GHB), antidepressants (e.g., amitriptyline, citalopram, moclobemide,venlafaxine, sertraline, dothiepin, imipramine, fluoxetine), andantipsychotic medications (e.g., thioridazine, chlorpromazine,olanzapine, lithium). In cases where there was prolonged hospi- relationship. Two-thirds were employed, the most common occu- talization prior to death, antemortem toxicology taken at admis- pations being security guard (n = 5) and personal fitness trainer sion was reported, and drugs administered by hospital and (n = 4). Bodybuilding was noted in a fifth of cases. The mean medical staff excluded. All samples were screened by immuno- BMI was 29.6 kg/m2, with 45% exceeding the cutoff for obesity assay and either by gas chromatography or by high-performance (>30 kg/m2). Evidence of recent injecting drug use was noted in liquid chromatography (HPLC) for drugs of abuse and common 54.2% of cases. Two cases were hepatitis C virus (HCV) posi- therapeutic substances. All analyses of blood were conducted by tive, and one was HIV positive on serologic testing.
the Forensic Toxicology Laboratory of the NSW Forensic & The most common direct cause of death was drug toxicity Analytical Science Service (formerly the Division of Analytical which, in conjunction with combined drug toxicity/cardiovascu- lar disease, constituted two-thirds of cases. Psychostimulant tox- Urine samples taken at autopsy were screened for AAS metab- icity was the direct cause of death in eight cases (33.3%) and olites by the Australian Sports Drug Testing Laboratory, using opioid toxicity in 7 (29.2%). Arsenic poisoning was diagnosed gas chromatography and mass spectrometry, there being no cur- in one case – the manner of death in this case was not able to rent blood test. In addition, abnormalities in steroid profiles were be determined, but homicide was suspected. Violent death (sui- examined for evidence of exogenous testosterone use, with a tes- cide, homicide) constituted a quarter of cases. Three of the four tosterone/epitestosterone ratio of >4 considered evidence of suicides were by gunshot, with one hanging. All three definite exogenous use by the Australian Sports Drug Testing Laboratory homicides were gunshot victims. The sole accidental death was (23). As is the case in other forensic institutes (11,12), AAS are of a pilot of a light aircraft with controlled flight into terrain, not routinely screened for by the NSW Forensic & Analytical situational unawareness being the likely cause of the crash.
Science Service. Such tests are conducted at the request of the There were no deaths solely attributable to natural causes.
forensic pathologist when there are signs (e.g., a pronounced,overdeveloped musculature), or circumstances indicating sus- pected AAS use (e.g., substances discovered at the death scene).
It should be noted that the field of AAS use, and the detection Abnormal testosterone/epitestosterone ratios >4 were reported of such use, is in constant flux as new drugs are developed, and in 15 of 24 cases, indicative of exogenous testosterone use, the testing menus are likely to vary over time.
most common indicator of AAS, followed by with metaboliteswere of nandrolone, stanozolol, and methandienone (Table 2). Inone case, a significantly increased concentration of dehydroepi- androsterone was reported. Tamoxefin was also present, a drug For continuous distribution means, standard deviations (SD) frequently used in AAS steroid cycles (25). The presence of and ranges were reported. All analyses were conducted using increased dehydroepiandrosterone and of tamoxifen in this case is strongly suggestive of exogenous steroid use. Nandrolone maybe present in low concentrations in urine from exogenous andendogenous sources. We did not have access to more detailed data on nandrolone concentrations or specific metabolites. In 12of these 14 cases, however, metabolites of other AAS were detected and/or increased testosterone/epitestosterone ratios, con- A total of 24 cases were identified, all male, with a mean age sistent with AAS use, while in the remaining two cases, other in their early thirties (Table 1). The majority were in a sexual TABLE 2––Toxicology of cases of sudden or unnatural death in which TABLE 3––Major autopsy findings of cases of sudden or unnatural death in anabolic-androgenic steroids were detected.
which anabolic-androgenic steroids were detected.
Abnormal testosterone/epitestosterone ratio Moderate–severe atherosclerotic occlusion injection of tablet preparations or other insoluble materials) wasdetected in a quarter of cases. Other pulmonary pathology was Blood toxicology was available for all cases. In all but one noted in six cases (26.1%), most commonly bronchopneumonia.
case (95.8%), psychoactive substances other than steroids were Renal pathology was diagnosed in three cases (13.0%). No pre- detected. The most prevalent substances were psychostimulants, existing intracranial pathology was identified, and there were no present in two-thirds of cases. Opioids were detected in 37.5% tumors typically associated with AAS use.
of cases, with morphine present in all these cases. A quarter hadalcohol detected, with a mean concentration of 0.093 g/100 mL (SD 0.095, range 0.010–0.247 g/100 mL). Benzodiazepines weredetected in nearly half of cases, most commonly diazepam. Ven- The cases in this series were exclusively male and aged on lafaxine was present in one case, as was ketamine, while no case average in their early thirties, characteristics consistent with ear- lier case studies and series (7,11–13,15–17). There was extensivephysical evidence of steroid abuse, most notably testicular atro-phy, and fibrosis, as well as arrested spermatogenesis. Muscular overdevelopment was present in almost all cases, with half hav- Muscular physique was noted in 21 cases (87.5%). In nearly ing BMIs in the obese range. As reported elsewhere (4), these half of cases, testicular atrophy, testicular fibrosis, and arrested high BMIs were not due to obesity, but to muscle volume and spermatogenesis were noted (Table 3). No case exhibited density. A large proportion of cases were employed as security gynecomastia, acne, or prostate enlargement.
guards or as personal trainers, occupations in which AAS may Cardiac pathology was diagnosed in 11 cases (47.8%). The mean heart weight was 467.7 g (SD 107.7, range 304–760 g), Exogenous testosterone appeared to be the most frequent form with left ventricular hypertrophy present in seven cases (30.4%).
of AAS use, as evidenced by metabolites of nandrolone, stanozo- Moderate to severe stenosis (>50%) of the coronary arteries was lol, and methandienone. An outstanding feature of these cases diagnosed in a quarter of cases. Fibrosis of the myocardium was was their extensive polypharmacy. All but a single case had psy- noted in three cases (13.0%). Psychostimulants were present in choactive substances other than AAS detected in blood, and death all six cases who exhibited moderate–severe coronary artery ste- was due to drug toxicity nearly two-thirds. Half were injecting nosis, 6 of 7 cases of left ventricular hypertrophy, 2 of 3 cases substances other than steroids, and a quarter showed evidence of of fibrosis of the myocardium, 1 of 1 case of cardiomyopathy, 2 likely injection of tablet preparations. Most prominent were the of 3 cases of myocyte necrosis, and 2 of 2 cases of myocarditis.
psychostimulants, although opioids were also prevalent. In terms Clinically significant hepatic pathology was diagnosed in six of the latter, in eight of the nine morphine positive cases, the evi- cases (26.1%). Two cases had cirrhotic livers, one of which was dence was of the injection of opioids and of heroin in particular.
HCV positive on serological testing. Pulmonary edema was pres- In one case, it would appear that a codeine preparation was con- ent in 16 cases (69.4%), 14 of which were drug overdoses. Pul- sumed. It is clear that there is a strong association between the illicit use of AAS and the illicit use of other substances, and with injecting drug use more broadly. As is commonly seen among 5. Larance B, Degenhardt L, Copeland J, Dillon P. Injecting risk behaviour psychostimulant and opioid users (26), there was widespread use and related harm among men who use performance- and image-enhanc-ing drugs. Drug Alcohol Rev 2008;27:679–86.
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Title of abstract

Additive effect of rimonabant and citalopram on extracellular serotonin levels monitored with in vivo microdialysis in rat Ortega J.E.a,*, Gonzalez-Lira V.b, Horrillo I.a, Herrera-Marschitz M.b, aDepartment of Pharmacology, University of the Basque Country UPV/EHU and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Spain; bMillenium Institute BNI and Programme of

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