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Medico-legal aspects of doping
Jourt~al oj C/inical Forensic Me&cme ~1998) 5, 1 7
'~ APS/HarcourtBrace& Co. Ltd 1998
CA S E R E VIE W
Medico-legal aspects of doping B. Madea, W. Grellner, E Musshoff, R. Dettmeyer Institute of Forensic Medicine, University of Bonn, Germany SUMMARY. Abuse of anabolic steroids is an increasing problem not only among athletes but also bodybuilders and teenagers. A fast-developing black market has been established since the opening of the borders to eastern Europe. Medico-legal aspects of doping are addressed with particular reference to toxicology and pathology. Constituents of anabolic steroids bought on the black market were identified using gas chromatography/mass spectrometry; the products did not contain the expected ingredients in 35% of cases. Long-term effects and fatalities because of anabolic steroid abuse are reported here based on our own case material and a literature review. In our own cases, severe cardiovascular side-effects developed after long-term abuse of Dianabol (methandrostenolone) and Oral-Turinabol (chlordehydromethyltestosterone), i.e. myocardial infarction, stroke, organomegaly and/or severe atherosclerosis. The pathogenesis of cardiovascular complications (cardiotoxic effect, risk of atherosclerosis, thrombogenic risk) is discussed based on the available literature reports following fatal outcome after the abuse of anabolic steroids.
Journal of Clinical Forensic Medicine (1998) 5, 1-7 INTRODUCTION Anabolic steroids play an important role for athletes, body-builders and even the general population? -lz An estimated 1 3 million male and female athletes in the USA have used androgens. 9 Apart from competitive athletes, the largest group of users are recreational body-builders who take anabolic steroids for cosmetic reasons. An estimated 2% of college-age males, 9% of athletes and 38-99% of body-builders have been estimated to use anabolic-androgenic steroids. 9 A survey of common substances on the market is given in Table 1. Anabolic steroids are defined as substances that increase the size of muscle cells, muscle mass and strength and reduce the fat mass of the b o d y . l-' Body-builders are concerned with the appearance of their musculature; power weight-lifters wish to increase muscle strength; runners want to delay the onset of fatigue, a quicker recovery from injury, a higher pain threshold and a general increase in competitiveness?: Forensic medicine is involved in several different areas. The forensic pathologist examines doping-associated deaths) ~-33The forensic psychiatrist
B. Madea, W. Grellner, F. Musshoff, R. Dettmeyer, Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, D-53111 Bonn, Germany, Correspondence
to."
B. Madea, Fax: +49 228 738368
and forensic physician deal with affective and mood disorders including the results of aggressiveness and criminality9'34~0 and problems of dependence on anabolic steroids? ~43 The forensic toxicologist evaluates the composition of illicit drugs, products from the black market and urine samples. 44 This paper provides a review of medico-]egal aspects of doping predominantly from the forensic pathological point of view. Potentially fatal adverse effects are discussed by means of two autopsy cases when death was associated with long-term abuse of anabolic steroids. Some aspects of the illegal blackmarket of such substances are considered. CASE REPORTS Case 1
Case history A 41-year-old male, professional body-builder had used 'cycles' of two oral anabolic steroids before competitions for 8 years. Following a 4-week lasting cycle in 1993, he suffered a brainstem infarction with intermittent hemiparesis. Persistent dizziness and dysarthria subsequently developed. Posterolateral myocardial infarction was diagnosed with the differential diagnosis of toxic cardiomyopathy. The neurological diagnosis comprised multiple cerebellar and brainstem
2 Journal of Clinical Forensic Medicine Table 1 Ten most commonlyused anabolic androgenic steroids45 Rank
1 2 3 4 5 6 7 8 9 10
Generic name
Trade name*
% of users
Mean + SD dose (MD) (mglwk)
Therapeutic dose (TD) (mglwk)
Methandrostenolone Nandrolone decanoate?
Dianabol Deca-Durabolin Anabol LA Anavar Depo-Testosterone Anadrol-50 Equipoise Winstrol-V Finaject 30 Delatestryl Durabolin
55.1
210.4±166.2
35.0
44.9 34.7 30.6 20.4 18.4 16.3 12.2 10.2 10.2
565.7 _+1159.8 172.0 _+110.3 814.7 _+1401 9.4 _+4.0** 214.3 _+69.0 346.9 _+439.2 96.0 + 53.7 400.0_+i63.3 66.7+-_28.9
21.4 52.5 75.0 3.0** -~ ; * 75.0 37.5
Oxandrolone Testosterone cypionate-~ Oxymetholone Boldenone undecylenatet Stanozolol injection t Trenbolone~ Testosterone enanthate'~ Nandrolone phenpropionatet
MD/TD
6.0 26.4 3.3 10.9 3.1 5.3 1.8
*Representative trade names, not necessarily taken by subjects; **Units for oxymetholoneonly are mg/kg/wk;*Injectabledrug from. Finaject 30 might also signifybolasterone to some users; Weterinarydrug for which human dosage is unknown.
infarctions. The man lost his job as a trainer in a sport centre due to his physical condition. On the day of his death, he was found unconscious in a sport centre and taken to hospital. He discharged himself against the advice of the doctors. That evening, he was found dead at home by his wife, with a pistol beside him.
Autopsy findings Autopsy showed an athletic constitution with a body weight of 89.9 kg and a height of 177 cm (body-mass index: 28.7 kg/m 2, normal: 20-25 kg/m2). Old myocardial infarction of the anterior and posterior wall of the left chamber of the heart with aneurysm formation of the posterior wall was present. Fresh myocardial necrotic areas were present at the margin of the scar of the anterior wall (Fig, 1). Apart from the infarction scars, disseminated myocardial fibrosis was found. The heart was hypertrophied (heart weight: 470 g [normal: 0.4% of body weight = 360 g]; ventricular wall: left 1 8 m m [normal: l l - 1 4 m m ] , right 7 m m [normal: .o. 3 mm]). Only slight coronary atherosclerosis and no cerebral atherosclerosis were present. Encephalomalacia of the brainstem and cerebellum and an old infarction of the right kidney were present. The cause of death was a contact wound to the right temple with a skull-brain through and through shot.
Case 2
Fig. 1 An old myocardialinfarction of the anterior wall and
fresh marginal necrosis.
Case history For 13 years, a 28-year-old male had undertaken extensive body-building with simultaneous abuse of anabolic-androgenic steroids (Dianabol, OralTurinabol). Documented pre-existing disease due to the adverse effects of his substance use included arterial hypertension (210/120 m m Hg), m o o d disorders
with depression, bone fractures, rupture of the pectoralis major muscle, rupture of the quadriceps femoris muscle and secondary hypogonadism. Severe disturbances of lipid metabolism (decreased HDL-cholesterol and markedly raised LDL-cholesterol) were repeatedly diagnosed during sport medical
Medico-legalaspects of doping Table 2
3
C l i n i c a l - c h e m i c a l findings in case 2
Time
2/92
3/92
9/92
5/94
Reference values
Cholesterol (mmol/1) Triglycerides (mmol/1) [3-Lipoproteins (Units) Total lipids (mg/dl) HDL-Cholesterol (mmoi/1) LDL-Cholesterol (retool/l)
9.7
11.0
9.6
10.8
3.1-5.2
7.80
5.75
4.64
3.55
0.80 2.28
-
680
578
-
150 250
-
1350
1140
-
250 625
0-0.03
0.04
0.13
0.18
>1.42
-
-
10.3
<3.88
examinations (Table 2). In 1992, 2 years prior to death, the following diagnoses were made: marked obesity, arterial hypertension, damage of the liver parenchyma, hypertrophy of the left ventricnlar wall, disorder of the lipid metabolism. After a medical examination in 1992, the man had been warned of the dangers of anabolic steroid abuse and the risk factors to his health. Symptoms prior to death included dyspnoea, a feeling of a lump in the throat, inability to sleep in a horizontal position and marked peripheral oedema with an increase in body weight of 3 kg per day. Fig. 2
E x t e r n a l aspect of case 2.
Autopsyfindings Autopsy demonstrated a heavily muscled 28-year-old male with signs of marked obesity, a body weight of 136 kg and a body height of 178 cm (Fig. 2). The body-mass index was 42.9 kg/m2 [normal: 20-25 kg/ m-~]. Hypertrophy of nearly all inner organs except the brain was observed with the following organ weights: heart 800 g [critical heart weight = 500 g], liver 5710 g [reference: ~ 1500 g], kidney 910 g [reference: ~ 150 g]. The cardiac findings included a 'cor bovinum' with hypertrophy of the right and left ventricular wall and an additional dilatation of all chambers (Fig. 3). Histologically, disseminated interstitial and perivascular fibrosis and some spotty scars could be demonstrated. Signs of chronic heart insufficiency comprised chronic congestion of the liver and spleen. Oedema of the lower extremities and chronic and acute congestion of the lung with pulmonary oedema and interstitial fibrosis were present. Pulmonary siderosis was present. In addition, massive general atherosclerosis with fat pads of the aorta (Fig. 4), coronary and pulmonary atherosclerosis were observed. Numerous striae of the chest and upper extremities were present resulting from obesity. Toxicologic analysis revealed
diazepam and verapamil in therapeutic ranges. Cause of death was given as heart failure due to cor bovinum after long-term abuse of anabolic steroids. Consistent with advanced atherosclerosis repeated disorders of lipid metabolism were recorded with a depression of HDL-cholesterol and elevation of LDL-cholesterol (Table 2). This atherogenic lipid profile has been repeatedly reproduced as typical of anabolic steroid use both in animal and in human experimentss'4~SJ (Table 3). Group 1 in Table 3 (consumers of anabolic steroids) differs significantly from the control group regarding HDL- and LDL-cholesterol and the quotient, s°
DISCUSSION The potential adverse effects of anabolic steroids are listed in Box 1. These are divided into the classical adverse effects on reproduction, hepatic function, virilization and feminization~-48,38.47-49,~,2and the effects that have become more apparent in recent years. The first myocardial infarction due to anabolic steroid abuse
4
Journal of Clinical Forensic Medicine
Fig. 3 Cor bovinum with hypertrophy of the right and left ventricle and dilatation of all chambers (case 2).
Table 3
Alteration of blood pressure and lipoproteins after abuse of anabolic steroids (from Lenders:51group 1 (examined at the end of a course), group 2 (examined after stopping anabolic steroids for a mean of 5 months), controls (never used anabolic steroids). Factor
Group 1
Number (n) 20 Systolic blood pressure 120.6+ 1.8" (mm Hg) Heart rate (bts/min) 65,0 _+1.8 HDLC (mmol/L) 0.68 + 0.0T LDLC (mmol/L) 5.27 + 0.55** LDLC/HDLC ratio i4.4 + 3.6~
Group 2
Controls
42 13 119.2+ 1.6" 113.5+ 1.7 60.8 + 1.3 60.2 + 1.8 1.07 + 0.04 1.17+ 0.06 4.0 + 0.22 3.34_+0.33 4.4 + 0.4* 3.0 _+0.5
*P < 0.05 with respect to controls; **P > 0.05 with respect to controls and group 2; tp < 0.001 with respect to controls and group 2.
Fig. 4 Advanced aortic atherosclerosis (case 2).
Box 1 Potential side-effects of anabolic steroids Classical adverse effects
•
was described in 1988 -~9a n d the first fatal myocardial i n f a r c t i o n in 1990.19 A p a r t from the classical wellrecognized adverse effects of a n a b o l i c steroids, only a b o u t 20 clinical reports, m a i n l y c o n c e r n i n g myocardial infarction, a n d less t h a n 10 reports o n cardiac deaths, strokes a n d p u l m o n a r y e m b o l i s m after anabolic steroid abuse h a d been published. The two case histories reported in this paper reinforce the message that l o n g - t e r m , high-dose a n a b o l i c steroids have a n a l a r m i n g cardiotoxic potential. The p u b l i s h e d literature refers m a i n l y to y o u n g b o d y - b u i l d e r s in their early twenties with n o other cardiovascular risk factors apart from a n a b o l i c steroid abuse. I n m o s t cases where m y o c a r d i a l infarctions (Box 2) a n d strokes (Box 3) occurred, reports show that the vessels were n o r m a l with n o signs of atherosclerosis. Spasm, e m b o l i s m a n d t h r o m b o s i s were discussed as causes of the infarctions. I n some
• •
Reproduction: - - negative feedback on testosterone level, testicular atrophy; decline in spermatogenesis Virilization and feminization: - - lower voice, increased facial hair, clitoral enlargement, diminished breast size, menstrual dysfunction, acne Hepatic function: - - elevated enzyme levels, peliosis hepatis, hepatic cholestasis, hepatic tumours (adenomas, angiosarcomas, carcinomas)
Emerging areas
• • • • • • •
Development of diabetes Lipoprotein profiles: - - lowered HDL cholesterol, raised LDL cholesterol Cardiovascular effects Cerebraldangers Musculo-skeletalinjuries Prostatic cancer Mood disorders: - - 'Bodybuilders psychosis', violence
cases, clots a n d t h r o m b o s i s were verified angiographically a n d by echocardiography a n d the following processes were discussed as initiating factors:
Medico-legalaspects o f d o p i n g
5
Box 2 Cardiac insults in users of anabolic steroids (literature reports) Ventricular hypertrophy McKillop et al 1986
23-year-old bodybuilder with 8 years of use
Myocardial infarction McNutt et al 1988
22-year-old weightlifter, 6 weeks' use of oral and injectable androgens. Hypercholesterolaemia, acute myocardial infarction; coronary arteries normal Ferenchick and Adelman 1992 37-year-old weightlifter with intermittent use over 7 years, coronary arteries normal Ferenchick 1991 22-year-old weightlifter with hypercholesterolaemia: hyperactive platelet function; normal coronary arteries Dickhuth et al 1989 Lethal myocardial infarction of 29-year-old bodybuilder with secondary analphalipoproteinaemia Ferenchick 1991 22-year-old college athlete; sudden death. Autopsy revealed thrombotic occlusion of LCA and LDA Bowmann et al 1989 23-year-old bodybuilder with 5 years of use; acute transmural infarction of the side wall Cardiomyopathy Touchette 1990
Football player with long duration of abuse; cardiomyopathy with necessary heart transplantation
Box 3 Cerebrovascular insults in users of anabolic steroids (literature reports). Frankle et al 1988
34-year-old bodybuilder with 4 years of use; right-sided hemiparesis; dysarthria
Nagelberg et al 1986
Cerebrovascular insult in a 21-year-old hypogonadal man: treated with testosterone (artificial overdose)
Shiozawa et al 1986
22-year-old student who was treated since months with high doses of anabolic steroids for hypoplastic anaemia; haemorrhagic infarction left temporoparietal region
Shiozawa et al 1992
Thrombosis of superior sagittal sinus in three patients (26, 39, 52 years old) who were treated with high doses of anabolic steroids for hypoplastic anaemia
Laroche 1990
28-year-old bodybuilder, 3 years of use (~stacking') thrombosis of carotid artery with cerebral embolism; 3 years later, after continued abuse, disseminated thrombosis of right lower extremity
1. Raised aggregability o f platelets 2. Structural changes o f the vessel wall 3. Decreased activity o f vascular endothelial prostacyclin 4. Increased activity o f p r o c o a g u l a t o r y factors. Thrombosis as cause o f the infarction must be considered in case 1 as there were two large infarction scars o f the anterior and posterior wall. A p a r t from thrombosis, atherosclerosis and arterial hypertension as causes o f myocardial infarction and disseminated myocardial fibrosis, as f o u n d in case 2, the direct cardiotoxic effects o f anabolic steroids must also be considers and have been described in animal experiments.53 57 The following ultrastructural changes were found: • Swollen and elongated m i t o c h o n d r i a • Disintegration o f myofibrils with destruction o f the sarcomer • Increase o f non-myofibrillar, intermediate filaments • Decreased contractility • Increased fragility o f lysosomes • Decreased mitochondrial activity. In relation to the epidemiology o f anabolic steroid abuse, reports on severe cardiovascular long-term effects and fatal cases are still anecdotal 10 years after
the first description. One reason m a y be that, as in these and other reported cases, the d o c t o r will not necessarily be informed about the anabolic steroid abuse or the abuse itself will even be denied by the patient. Physicians should thus have a high index o f suspicious about anabolic steroid use in cases o f juvenile atherosclerosis, cardiac hypertrophy or dilatation in body-builders or weight-lifters, if other typical risk factors are not evident.
ANALYSIS OF ANABOLIC STEROIDS FROM THE BLACK MARKET D u e to the limited availability o f approved products, a black market for anabolic steroids has developed in Germany, particularly since the opening o f the East E u r o p e a n borders (Fig. 5), This market is still growing because the d e m a n d is m u c h higher than the supply. Reports o f counterfeit products with substituted or omitted ingredients are increasing. M a n y 'anabolic dealers' m a y not k n o w whether their products are authentic or counterfeit. M a n y counterfeit products contain completely different substances, are strongly underdosed, or do not contain anabolic substances. They m a y also be o f doubtful purity and sterility. A total o f 42 products obtained from illegal distribution channels were
6 Journal of Clinical Forensic Medicine Table 4
Counterfeit anabolic steroids found on the black market44
Product labelling
Expected ingredient(s)
Identified ingredient(s)
methandriole dipropionate; nandrolone decanoate
Masteron
drostanolone propionate
Primobolan Depot
metenolone enantate
tocopherole; progesterone; nandrolone phenylpropionate
Parabolan
trenbolone hexahydrobenzylcarbonate
testosterones; 17-methyltestosterone; nandrolone decanoate; no steroids
CYCTAHOH; Heptylate de Testosterone; Testoviron Depot 250
testosterones
nandrolone decanoate
Anapolon Synasteron
oxymetholone
metandienone
Table 5
Example of 'courses' with anabolic steroids44
Week Dianabol 5 mg tab.
1 2 3 4 5 6 7 8 9 10 11 12 13 14-20
15 mg/d 20 mg/d 25 mg/d 30 mg/d 35 mg/d 40 mg/d
Testosterone Deca Enanthate HCG 100 mg/ml 250 mg/ml 5000 i.u.
200 mg/w 200 mg/w 200 mg/w 200 mg/w 200 mg/w 200 mg/w 400 mg/w 500 mg/w 400 mg/w 500 mg/w 400 mg/w 500 mg/w 200 mg/w 500 mg/w 200 mg/w 500 mg/w 100 mg/w 250 mg/w 50 mg/w
Clenbuterol 0.02 mg tab.
7000 i.u./w 7000 i.u./w
7000 i.u./w 7000i.u./w 80 ~tg/d 7000 i.u./w 120 gg/d
guidelines for the taking of steroids, providing information about their effects, prices on the black market and known counterfeits. Additionally, these handbooks contain examples of 'courses' of anabolic steroids and these are illustrated in Table 5. REFERENCES
Fig. 5
Anabolic steroids from the black market in Germany.
analyzed by gas chromatography/mass spectrometry (GC/MS). Of these products, 15 did not contain the expected ingredients (Table 4). 44 Mainly, counterfeits of parabolan and primobolan products were found. Instead of trenbolone or metenolone, the cheaper agents nandrolone or testosterone derivatives were identified. In one product, the gestagen progesterone was found. In two other cases, no steroids were present or tocopherole was substituted. In addition to the anabolic steroid black market, special books are also available, which are intended as
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10. Tennant F, Black DL, Voy RO. Anabolic steroid dependence with opioid-type features (letter). N Engl J Med 1988; 319:578 11. Yesalis ChE, Kennedy NJ, Kopstein AN, Bahrke M S. Anabolic-androgenic steroid use in the United States. JAMA 1993; 270:1217 1221 13. Alpert BS. Steroid-induced hypertrophic cardiomyopathy in an infant. Pediatr Cardiol 1984: 5:117-118 14. Appleby M, Fisher M, Martin M. Myocardial infarction, hyperkalaemia and ventricular tachycardia in a young male body-builder. Int J Cardiology 1994; 44:171-174 15. Bowman SJ, Tanna S, Fernando S, Ayodeji A, Weathherstone RM. Anabolic steroids and infarction. BMJ 1989; 299:632 16. Crook D. Testosterone, androgens and the risk of myocardial infarction. BJCP 1996; 50:180 181 17. Dickerman RD, Schaller F, Prather I, McConathy WJ. Sudden cardiac death in a 20-year-old bodybnilder using anabolic steroids. Cardiology 1995; 86:172 i73 18. Ferenchick GS. Anabolic androgenic steroid abuse and thrombosis: Is there a connection? Med Hypotheses 1991; 35: 27-31 19. Ferenchick GS, Adelman S. Myocardial infarction associated with anabolic steroid use in a previously healthy 37-year-old weight lifter. Am Heart J 1992: 124:507-508 20. Fisher M, Appleby M, Rittoo D, Cotter L. Myocardial infarction with extensive intracoronary thrombus induced by anabolic steroids. BJCP 1996; 50:222-223 21. Frankle MA, Eichberg R, Zuachariah SB. Anabolic androgenic steroids and a stroke in an athlete. Arch Phys Med Rehabil 1988; 69:632-633 22. Goldman B. Death in the Locker Room Steroids and Sports. South Bend, Indiana: Icarus Press 1986: 1258:1 360 23. Huie M. An acute myocardial infarction occurring in an anaboiic steroid user. Med Sci Sports Exerc 1994: 26:408-413 24. Jaillard AS, Hommel M, Mallaret M. Venous sinus thrombosis associated with androgens in a healthy young man. Stroke 1994; 25:212-213 25. Laroche G. Steroid analoolic drugs and arterial complications in an athlete - a case history. Angiology 1990; 41:966 26. Luke JL, Farb A, Virmani R, Sample RHB. Sudden cardiac death during exercise in a weight lifter using anabolic androgenic steroids: Pathological and toxicological findings. J Forensic Sci 1990; 35:1441-1447 27. Lyngberg KK. Myokardieinfarkt og doed af bodybuilder behandlet reed anabole steroider. Myocardial infarction and death of a bodybuilder after using anabolic steroids. Ugeskr Laeger. 1991; 153:587-588 28. Madea B, Grellner W. Langzeitfolgen und Todesffille bei Anabolikaabusus. Rechtsmed 1996; 6:33-38 29. McNutt RA, Ferenchick GS, Kirlin PC, Hamlin HJ. Acute myocardial infarction in a 22-year-old world class weight lifter using anabolic steroids. Am J Cardiol 1988; 62:164 30. Montine TJ, Gaede JT. Massive pulmonary embolus and anabolic steroid abuse. JAMA 1992: 267:2328 2329 31. Nieminen MS, Prim5 MR Viitasalo M, Heikkiliit P, Kmjalainen J, M/intysaari M, HeikkilS~ J. Serious cardiovascular side effects of large doses of anabolic steroids in weight lifters. Eur Heart J 1996; 17:1576-1583 32. Shiozawa Z, Tsunoda S. Noda A, Saito M, Yamada H. Cerebral hemorrhagic infarction associated with anabolic steroid therapy for hypoplastic anemia. Angiology 1986; 725-730 33. Shiozawa Z, Yamada H, Mabuchi C, Hotta T, Saito M, Sobue I, Huang YR Superior sagittal sinus thrombosis associated with androgen therapy for hypoplastic anemia. Am Neurol Assoc 1992; 578-580 34. Bahrke MS, Yesalis III, Wright JE. Psychological and behavioural effects of endogenous testosterone and anabolicandrogenic steroids, Sports Med 1996; 22:367-390 35. Brower KJ, Eliopulos GA, Blow FC, Catlin DH, Beresford TR Evidence for physical and psychological dependence on
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anabolic androgenic steroids in eight weight litters. Am J Psychiatry 1990; 147:510-512 Corrigan B. Anabolic steroids and the mind. MJA 1990; 165: 222-226 Driessen M, Muessigbrodt H, Dilling H. Child sexual abuse associated with anabolic androgenic steroid use. Am J Psychiatry 1996; 153:1369 Lamb D. Anabolic steroids in athletics: How well do they work and how dangerous are they? Am J Sports Med 1984: 12:31 38 Su T-R Pagliaro M, Schmidt P J, Pickar D, Wolkowitz O, Rubinow DR. Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 1993; 269 (2i): 2760-2764 Touchette N. Meeting highlights. 'Roid rage at FASEB." The J NIH Res 1990; 2:42-44 Kennedy MC, Lawrence C. Anabolic steroid abuse and cardiac death. Med J Aust 1993; 158:346-348 Pope HG, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988: 145:487-490 Pope HG, Katz DL Homicide and near-homicide by anabolic steroid users. J Clin Psychiatry 1990: 51:28-31 Mul3hoff F, Daldrup T, Ritsch M. Anabole Steroide auf dem deutschen Schwarzmarkt. Arch Krim 1997; 199:152-158 Brower K J, Blow FC, Jonny JF, Hill EM. Symptoms and correlates of anabolic-androgenic steroid dependence. Br J Addict 1991; 86:759-763 Baumstark M, Berg A, Frey I. Rokitzki L, Keul J. Analphalipoproteinemea in body-builders induced by anabolic steroids. Int J Sports Med 1988; 9:400 Fogelberg M, BjSrkham I, Diczfalusy U, Henriksson R Stanozolol and experimentai athereosclerosis: athereosclerotic development and blood lipids during anabolic steroid therapy of New Zealand white rabbits. Scand J Clin Lab Invest 1990; 50:693-696 Glazer G. Atherogenic effects of anabollc steroids on serum lipid levels. Arch Intern Med 1991; 151:1925-1933 Hickson RC, Ball KL, Falduto MT. Adverse effects of anabolic steroids. Med Toxicol Adverse Drug Exp 1989: 4: 254-271 Lajarin F, Zaragoza R, Tovar I, Martinez-Hernandez R Evolution of serum lipids in two male bodybuilders using anabolic steroids. Clin Chem 1996; 42:970-972 Lenders JWM, Demacker PNM, Vos JA, Jansen PLM, Hoitsma AJ, Laar A van't. Deleterious effects of anabolic steroids on serum lipoproteins, blood pressure, and liver function in amateur body builders. Int J Sports Med 1988; 9: 19-23 Karch StB. The pathology of drug abuse, 2nd edn New York, London. Tokyo: CRC Press Boca Raton, Appell HJ, Heller-Umpfenbach B. Ultrastructural and morphometric investigations on the effects of training and administrations of anabolic steroids on the myocardium of guinea pigs. Int J Sports Med 1984; 4:268-274 Behrend H. Effect of anabolic steroids on rat heart muscle cells. Cell Tissue Res 1977: 180:303 315 Behrend H. Myocardial cell lesions caused by an anabolic hormone. Cell Tissue Res 1977; 181:423-426 Kinson GA, Layberry RA, Hebert B. Influences of anabolic androgens on cardiac growth and metabolism in the rat. Can J Physiol Pharmacol 1991; 69:1698-1704 Melchert RB, Herron TJ, Welder AA. The effect of anabolicandrogenic steroids on primary myocardial cell cultures. Med Sci Sports Exerc 1992; 24:206-212 Nagelberg SB, Laue L, Loriaux DL, Liu L, Sherins RJ. Cerebrovascular accident associated with testosterone therapy in a 21-year-old hypogonadal man. N Engl J Med 1986; 314: 649-650
'~ APS/HarcourtBrace& Co. Ltd 1998
CA S E R E VIE W
Medico-legal aspects of doping B. Madea, W. Grellner, E Musshoff, R. Dettmeyer Institute of Forensic Medicine, University of Bonn, Germany SUMMARY. Abuse of anabolic steroids is an increasing problem not only among athletes but also bodybuilders and teenagers. A fast-developing black market has been established since the opening of the borders to eastern Europe. Medico-legal aspects of doping are addressed with particular reference to toxicology and pathology. Constituents of anabolic steroids bought on the black market were identified using gas chromatography/mass spectrometry; the products did not contain the expected ingredients in 35% of cases. Long-term effects and fatalities because of anabolic steroid abuse are reported here based on our own case material and a literature review. In our own cases, severe cardiovascular side-effects developed after long-term abuse of Dianabol (methandrostenolone) and Oral-Turinabol (chlordehydromethyltestosterone), i.e. myocardial infarction, stroke, organomegaly and/or severe atherosclerosis. The pathogenesis of cardiovascular complications (cardiotoxic effect, risk of atherosclerosis, thrombogenic risk) is discussed based on the available literature reports following fatal outcome after the abuse of anabolic steroids.
Journal of Clinical Forensic Medicine (1998) 5, 1-7 INTRODUCTION Anabolic steroids play an important role for athletes, body-builders and even the general population? -lz An estimated 1 3 million male and female athletes in the USA have used androgens. 9 Apart from competitive athletes, the largest group of users are recreational body-builders who take anabolic steroids for cosmetic reasons. An estimated 2% of college-age males, 9% of athletes and 38-99% of body-builders have been estimated to use anabolic-androgenic steroids. 9 A survey of common substances on the market is given in Table 1. Anabolic steroids are defined as substances that increase the size of muscle cells, muscle mass and strength and reduce the fat mass of the b o d y . l-' Body-builders are concerned with the appearance of their musculature; power weight-lifters wish to increase muscle strength; runners want to delay the onset of fatigue, a quicker recovery from injury, a higher pain threshold and a general increase in competitiveness?: Forensic medicine is involved in several different areas. The forensic pathologist examines doping-associated deaths) ~-33The forensic psychiatrist
B. Madea, W. Grellner, F. Musshoff, R. Dettmeyer, Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, D-53111 Bonn, Germany, Correspondence
to."
B. Madea, Fax: +49 228 738368
and forensic physician deal with affective and mood disorders including the results of aggressiveness and criminality9'34~0 and problems of dependence on anabolic steroids? ~43 The forensic toxicologist evaluates the composition of illicit drugs, products from the black market and urine samples. 44 This paper provides a review of medico-]egal aspects of doping predominantly from the forensic pathological point of view. Potentially fatal adverse effects are discussed by means of two autopsy cases when death was associated with long-term abuse of anabolic steroids. Some aspects of the illegal blackmarket of such substances are considered. CASE REPORTS Case 1
Case history A 41-year-old male, professional body-builder had used 'cycles' of two oral anabolic steroids before competitions for 8 years. Following a 4-week lasting cycle in 1993, he suffered a brainstem infarction with intermittent hemiparesis. Persistent dizziness and dysarthria subsequently developed. Posterolateral myocardial infarction was diagnosed with the differential diagnosis of toxic cardiomyopathy. The neurological diagnosis comprised multiple cerebellar and brainstem
2 Journal of Clinical Forensic Medicine Table 1 Ten most commonlyused anabolic androgenic steroids45 Rank
1 2 3 4 5 6 7 8 9 10
Generic name
Trade name*
% of users
Mean + SD dose (MD) (mglwk)
Therapeutic dose (TD) (mglwk)
Methandrostenolone Nandrolone decanoate?
Dianabol Deca-Durabolin Anabol LA Anavar Depo-Testosterone Anadrol-50 Equipoise Winstrol-V Finaject 30 Delatestryl Durabolin
55.1
210.4±166.2
35.0
44.9 34.7 30.6 20.4 18.4 16.3 12.2 10.2 10.2
565.7 _+1159.8 172.0 _+110.3 814.7 _+1401 9.4 _+4.0** 214.3 _+69.0 346.9 _+439.2 96.0 + 53.7 400.0_+i63.3 66.7+-_28.9
21.4 52.5 75.0 3.0** -~ ; * 75.0 37.5
Oxandrolone Testosterone cypionate-~ Oxymetholone Boldenone undecylenatet Stanozolol injection t Trenbolone~ Testosterone enanthate'~ Nandrolone phenpropionatet
MD/TD
6.0 26.4 3.3 10.9 3.1 5.3 1.8
*Representative trade names, not necessarily taken by subjects; **Units for oxymetholoneonly are mg/kg/wk;*Injectabledrug from. Finaject 30 might also signifybolasterone to some users; Weterinarydrug for which human dosage is unknown.
infarctions. The man lost his job as a trainer in a sport centre due to his physical condition. On the day of his death, he was found unconscious in a sport centre and taken to hospital. He discharged himself against the advice of the doctors. That evening, he was found dead at home by his wife, with a pistol beside him.
Autopsy findings Autopsy showed an athletic constitution with a body weight of 89.9 kg and a height of 177 cm (body-mass index: 28.7 kg/m 2, normal: 20-25 kg/m2). Old myocardial infarction of the anterior and posterior wall of the left chamber of the heart with aneurysm formation of the posterior wall was present. Fresh myocardial necrotic areas were present at the margin of the scar of the anterior wall (Fig, 1). Apart from the infarction scars, disseminated myocardial fibrosis was found. The heart was hypertrophied (heart weight: 470 g [normal: 0.4% of body weight = 360 g]; ventricular wall: left 1 8 m m [normal: l l - 1 4 m m ] , right 7 m m [normal: .o. 3 mm]). Only slight coronary atherosclerosis and no cerebral atherosclerosis were present. Encephalomalacia of the brainstem and cerebellum and an old infarction of the right kidney were present. The cause of death was a contact wound to the right temple with a skull-brain through and through shot.
Case 2
Fig. 1 An old myocardialinfarction of the anterior wall and
fresh marginal necrosis.
Case history For 13 years, a 28-year-old male had undertaken extensive body-building with simultaneous abuse of anabolic-androgenic steroids (Dianabol, OralTurinabol). Documented pre-existing disease due to the adverse effects of his substance use included arterial hypertension (210/120 m m Hg), m o o d disorders
with depression, bone fractures, rupture of the pectoralis major muscle, rupture of the quadriceps femoris muscle and secondary hypogonadism. Severe disturbances of lipid metabolism (decreased HDL-cholesterol and markedly raised LDL-cholesterol) were repeatedly diagnosed during sport medical
Medico-legalaspects of doping Table 2
3
C l i n i c a l - c h e m i c a l findings in case 2
Time
2/92
3/92
9/92
5/94
Reference values
Cholesterol (mmol/1) Triglycerides (mmol/1) [3-Lipoproteins (Units) Total lipids (mg/dl) HDL-Cholesterol (mmoi/1) LDL-Cholesterol (retool/l)
9.7
11.0
9.6
10.8
3.1-5.2
7.80
5.75
4.64
3.55
0.80 2.28
-
680
578
-
150 250
-
1350
1140
-
250 625
0-0.03
0.04
0.13
0.18
>1.42
-
-
10.3
<3.88
examinations (Table 2). In 1992, 2 years prior to death, the following diagnoses were made: marked obesity, arterial hypertension, damage of the liver parenchyma, hypertrophy of the left ventricnlar wall, disorder of the lipid metabolism. After a medical examination in 1992, the man had been warned of the dangers of anabolic steroid abuse and the risk factors to his health. Symptoms prior to death included dyspnoea, a feeling of a lump in the throat, inability to sleep in a horizontal position and marked peripheral oedema with an increase in body weight of 3 kg per day. Fig. 2
E x t e r n a l aspect of case 2.
Autopsyfindings Autopsy demonstrated a heavily muscled 28-year-old male with signs of marked obesity, a body weight of 136 kg and a body height of 178 cm (Fig. 2). The body-mass index was 42.9 kg/m2 [normal: 20-25 kg/ m-~]. Hypertrophy of nearly all inner organs except the brain was observed with the following organ weights: heart 800 g [critical heart weight = 500 g], liver 5710 g [reference: ~ 1500 g], kidney 910 g [reference: ~ 150 g]. The cardiac findings included a 'cor bovinum' with hypertrophy of the right and left ventricular wall and an additional dilatation of all chambers (Fig. 3). Histologically, disseminated interstitial and perivascular fibrosis and some spotty scars could be demonstrated. Signs of chronic heart insufficiency comprised chronic congestion of the liver and spleen. Oedema of the lower extremities and chronic and acute congestion of the lung with pulmonary oedema and interstitial fibrosis were present. Pulmonary siderosis was present. In addition, massive general atherosclerosis with fat pads of the aorta (Fig. 4), coronary and pulmonary atherosclerosis were observed. Numerous striae of the chest and upper extremities were present resulting from obesity. Toxicologic analysis revealed
diazepam and verapamil in therapeutic ranges. Cause of death was given as heart failure due to cor bovinum after long-term abuse of anabolic steroids. Consistent with advanced atherosclerosis repeated disorders of lipid metabolism were recorded with a depression of HDL-cholesterol and elevation of LDL-cholesterol (Table 2). This atherogenic lipid profile has been repeatedly reproduced as typical of anabolic steroid use both in animal and in human experimentss'4~SJ (Table 3). Group 1 in Table 3 (consumers of anabolic steroids) differs significantly from the control group regarding HDL- and LDL-cholesterol and the quotient, s°
DISCUSSION The potential adverse effects of anabolic steroids are listed in Box 1. These are divided into the classical adverse effects on reproduction, hepatic function, virilization and feminization~-48,38.47-49,~,2and the effects that have become more apparent in recent years. The first myocardial infarction due to anabolic steroid abuse
4
Journal of Clinical Forensic Medicine
Fig. 3 Cor bovinum with hypertrophy of the right and left ventricle and dilatation of all chambers (case 2).
Table 3
Alteration of blood pressure and lipoproteins after abuse of anabolic steroids (from Lenders:51group 1 (examined at the end of a course), group 2 (examined after stopping anabolic steroids for a mean of 5 months), controls (never used anabolic steroids). Factor
Group 1
Number (n) 20 Systolic blood pressure 120.6+ 1.8" (mm Hg) Heart rate (bts/min) 65,0 _+1.8 HDLC (mmol/L) 0.68 + 0.0T LDLC (mmol/L) 5.27 + 0.55** LDLC/HDLC ratio i4.4 + 3.6~
Group 2
Controls
42 13 119.2+ 1.6" 113.5+ 1.7 60.8 + 1.3 60.2 + 1.8 1.07 + 0.04 1.17+ 0.06 4.0 + 0.22 3.34_+0.33 4.4 + 0.4* 3.0 _+0.5
*P < 0.05 with respect to controls; **P > 0.05 with respect to controls and group 2; tp < 0.001 with respect to controls and group 2.
Fig. 4 Advanced aortic atherosclerosis (case 2).
Box 1 Potential side-effects of anabolic steroids Classical adverse effects
•
was described in 1988 -~9a n d the first fatal myocardial i n f a r c t i o n in 1990.19 A p a r t from the classical wellrecognized adverse effects of a n a b o l i c steroids, only a b o u t 20 clinical reports, m a i n l y c o n c e r n i n g myocardial infarction, a n d less t h a n 10 reports o n cardiac deaths, strokes a n d p u l m o n a r y e m b o l i s m after anabolic steroid abuse h a d been published. The two case histories reported in this paper reinforce the message that l o n g - t e r m , high-dose a n a b o l i c steroids have a n a l a r m i n g cardiotoxic potential. The p u b l i s h e d literature refers m a i n l y to y o u n g b o d y - b u i l d e r s in their early twenties with n o other cardiovascular risk factors apart from a n a b o l i c steroid abuse. I n m o s t cases where m y o c a r d i a l infarctions (Box 2) a n d strokes (Box 3) occurred, reports show that the vessels were n o r m a l with n o signs of atherosclerosis. Spasm, e m b o l i s m a n d t h r o m b o s i s were discussed as causes of the infarctions. I n some
• •
Reproduction: - - negative feedback on testosterone level, testicular atrophy; decline in spermatogenesis Virilization and feminization: - - lower voice, increased facial hair, clitoral enlargement, diminished breast size, menstrual dysfunction, acne Hepatic function: - - elevated enzyme levels, peliosis hepatis, hepatic cholestasis, hepatic tumours (adenomas, angiosarcomas, carcinomas)
Emerging areas
• • • • • • •
Development of diabetes Lipoprotein profiles: - - lowered HDL cholesterol, raised LDL cholesterol Cardiovascular effects Cerebraldangers Musculo-skeletalinjuries Prostatic cancer Mood disorders: - - 'Bodybuilders psychosis', violence
cases, clots a n d t h r o m b o s i s were verified angiographically a n d by echocardiography a n d the following processes were discussed as initiating factors:
Medico-legalaspects o f d o p i n g
5
Box 2 Cardiac insults in users of anabolic steroids (literature reports) Ventricular hypertrophy McKillop et al 1986
23-year-old bodybuilder with 8 years of use
Myocardial infarction McNutt et al 1988
22-year-old weightlifter, 6 weeks' use of oral and injectable androgens. Hypercholesterolaemia, acute myocardial infarction; coronary arteries normal Ferenchick and Adelman 1992 37-year-old weightlifter with intermittent use over 7 years, coronary arteries normal Ferenchick 1991 22-year-old weightlifter with hypercholesterolaemia: hyperactive platelet function; normal coronary arteries Dickhuth et al 1989 Lethal myocardial infarction of 29-year-old bodybuilder with secondary analphalipoproteinaemia Ferenchick 1991 22-year-old college athlete; sudden death. Autopsy revealed thrombotic occlusion of LCA and LDA Bowmann et al 1989 23-year-old bodybuilder with 5 years of use; acute transmural infarction of the side wall Cardiomyopathy Touchette 1990
Football player with long duration of abuse; cardiomyopathy with necessary heart transplantation
Box 3 Cerebrovascular insults in users of anabolic steroids (literature reports). Frankle et al 1988
34-year-old bodybuilder with 4 years of use; right-sided hemiparesis; dysarthria
Nagelberg et al 1986
Cerebrovascular insult in a 21-year-old hypogonadal man: treated with testosterone (artificial overdose)
Shiozawa et al 1986
22-year-old student who was treated since months with high doses of anabolic steroids for hypoplastic anaemia; haemorrhagic infarction left temporoparietal region
Shiozawa et al 1992
Thrombosis of superior sagittal sinus in three patients (26, 39, 52 years old) who were treated with high doses of anabolic steroids for hypoplastic anaemia
Laroche 1990
28-year-old bodybuilder, 3 years of use (~stacking') thrombosis of carotid artery with cerebral embolism; 3 years later, after continued abuse, disseminated thrombosis of right lower extremity
1. Raised aggregability o f platelets 2. Structural changes o f the vessel wall 3. Decreased activity o f vascular endothelial prostacyclin 4. Increased activity o f p r o c o a g u l a t o r y factors. Thrombosis as cause o f the infarction must be considered in case 1 as there were two large infarction scars o f the anterior and posterior wall. A p a r t from thrombosis, atherosclerosis and arterial hypertension as causes o f myocardial infarction and disseminated myocardial fibrosis, as f o u n d in case 2, the direct cardiotoxic effects o f anabolic steroids must also be considers and have been described in animal experiments.53 57 The following ultrastructural changes were found: • Swollen and elongated m i t o c h o n d r i a • Disintegration o f myofibrils with destruction o f the sarcomer • Increase o f non-myofibrillar, intermediate filaments • Decreased contractility • Increased fragility o f lysosomes • Decreased mitochondrial activity. In relation to the epidemiology o f anabolic steroid abuse, reports on severe cardiovascular long-term effects and fatal cases are still anecdotal 10 years after
the first description. One reason m a y be that, as in these and other reported cases, the d o c t o r will not necessarily be informed about the anabolic steroid abuse or the abuse itself will even be denied by the patient. Physicians should thus have a high index o f suspicious about anabolic steroid use in cases o f juvenile atherosclerosis, cardiac hypertrophy or dilatation in body-builders or weight-lifters, if other typical risk factors are not evident.
ANALYSIS OF ANABOLIC STEROIDS FROM THE BLACK MARKET D u e to the limited availability o f approved products, a black market for anabolic steroids has developed in Germany, particularly since the opening o f the East E u r o p e a n borders (Fig. 5), This market is still growing because the d e m a n d is m u c h higher than the supply. Reports o f counterfeit products with substituted or omitted ingredients are increasing. M a n y 'anabolic dealers' m a y not k n o w whether their products are authentic or counterfeit. M a n y counterfeit products contain completely different substances, are strongly underdosed, or do not contain anabolic substances. They m a y also be o f doubtful purity and sterility. A total o f 42 products obtained from illegal distribution channels were
6 Journal of Clinical Forensic Medicine Table 4
Counterfeit anabolic steroids found on the black market44
Product labelling
Expected ingredient(s)
Identified ingredient(s)
methandriole dipropionate; nandrolone decanoate
Masteron
drostanolone propionate
Primobolan Depot
metenolone enantate
tocopherole; progesterone; nandrolone phenylpropionate
Parabolan
trenbolone hexahydrobenzylcarbonate
testosterones; 17-methyltestosterone; nandrolone decanoate; no steroids
CYCTAHOH; Heptylate de Testosterone; Testoviron Depot 250
testosterones
nandrolone decanoate
Anapolon Synasteron
oxymetholone
metandienone
Table 5
Example of 'courses' with anabolic steroids44
Week Dianabol 5 mg tab.
1 2 3 4 5 6 7 8 9 10 11 12 13 14-20
15 mg/d 20 mg/d 25 mg/d 30 mg/d 35 mg/d 40 mg/d
Testosterone Deca Enanthate HCG 100 mg/ml 250 mg/ml 5000 i.u.
200 mg/w 200 mg/w 200 mg/w 200 mg/w 200 mg/w 200 mg/w 400 mg/w 500 mg/w 400 mg/w 500 mg/w 400 mg/w 500 mg/w 200 mg/w 500 mg/w 200 mg/w 500 mg/w 100 mg/w 250 mg/w 50 mg/w
Clenbuterol 0.02 mg tab.
7000 i.u./w 7000 i.u./w
7000 i.u./w 7000i.u./w 80 ~tg/d 7000 i.u./w 120 gg/d
guidelines for the taking of steroids, providing information about their effects, prices on the black market and known counterfeits. Additionally, these handbooks contain examples of 'courses' of anabolic steroids and these are illustrated in Table 5. REFERENCES
Fig. 5
Anabolic steroids from the black market in Germany.
analyzed by gas chromatography/mass spectrometry (GC/MS). Of these products, 15 did not contain the expected ingredients (Table 4). 44 Mainly, counterfeits of parabolan and primobolan products were found. Instead of trenbolone or metenolone, the cheaper agents nandrolone or testosterone derivatives were identified. In one product, the gestagen progesterone was found. In two other cases, no steroids were present or tocopherole was substituted. In addition to the anabolic steroid black market, special books are also available, which are intended as
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