(from literature gather up to January 2016) From the Anti-Doping Library SIDE EFFECTS OF TESTOSTERONE AND OTHER ANABOLIC STEROIDS ON THE HEART AND VASCULAR SYSTEM A systematic collection of published scientific literature on “doping and exercise in sports” 2000-2015 Åke Andrén-Sandberg From the Department of Surgery, Karolinska Institutet at Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden CONTENT SUMMARY GENERAL ASPECTS OF SIDE EFFECTS OF ANABOLIC STEROIDS Many different bodily function are targeted Effects on the heart Cardiac muscle cells have receptors for androgens Is side effects of anabolic steroids an overstated problem? Self-reported adverse effects Female missuse Different effects of different anabolic steroids Toxicokinetics Impurities in illicit samples of anabolic steroids Explanatory models for adverse effects of anabolic steroids MORTALITY RATE AFTER USE OF ANABOLIC STEROIDS An increased mortality rate Swedish data Finnish data A national population-based cohort study Tour de France (1947-2012) ANABOLIC STEROIDS’ IMPACT ON THE CARDIOVASCULAR SYSTEM Overview Cardiologic adverse effects also of other doping substances Serious cardiovascular adverse effects from use of dietary supplements Cofactors for adverse events Changes in lipid metabolism Metabolic syndrome Other contributing factors Conflicting data TESTOSTERONE SUPPLEMENTATION IN (OLDER) HYPOGONADALA MEN Cardiovascular risk in older men on testosterone Testosterone deficiency Independence of the level of heart dysfunction Testosterone supplementation Experimental SPECIFIED CARDIAC PATHOLOGY AFTER USE OF ANABOLIC STEROIDS Myocardial hypertrophy Increased left-ventricular mass Right ventricular myocardial dysfunction after use of anabolic steroids Increased risk for ischemia Echocardiography Left ventricular hypertrophy independently predicts cardiovascular mortality Movement of the left ventricular wall Functional effects of left ventricular increased muscle thickness Effects of resistance training on left ventricular thickness Experimental Heart failure due to anabolic-androgenic steroids Acute cardiac failure Dilated cardiomyopathy Case report Atherosclorosis Coronary artery calcifications Myocardial infarction Case reports Thromboembolic disease Cardiac thrombosis Cerebral venous thrombosis Thrombosis Pulmonary embolism Cardiac arrhythmias and abnormal electrocardiography Increased atrial electromechanical delay Altered autonomic system regulation QT-interval Increased QT dispersion and short QT intervals Experimental Heart rate Arterial hypertension Vascular effects of anabolic steroids CARDIAC MORPHOLOGY ALTERATIONS DUE TO ANABOLIC STEROIDS Cardiac structure and functioning SUDDEN DEATH AFTER USING ANABOLIC STEROIDS Overviews Forensic cases During surgery Case reports LONG-TERM EFFECTS ON THE HEART OF ANABOLIC STEROIDS Conflicting results Experimental DYSLIPIDEMIA Two-ways action Postprandial triglyceridaemia, low-density lipoprotein and lipoprotein Total cholesterol High-density lipoprotein-cholesterol and its subfractions Triglycerides Apolipoproteins and lipoprotein Lipoprotein(a) MISCELEANOUS Multiple organ failure Effects on antioxidation after anabolic steroids Homocystein abnormalities Studies not showing any cardiotoxic effects Effects on the cardiovascular system of dehydroepiandrosterone (DHEA) Cardiac effects of anabolic steroids in different sports Combination with other substances Increased risk of diabetes A SUMMARY OF EFFECTS OF ANABOLIC STEROIDS ON THE HEART REFERENCES SUMMARY Since the 1970s anabolic androgenic steroids (AAS) have been abused at ever increasing rates in competitive athletics, in recreational sports and in bodybuilding. Anabolic androgenic steroids may have not only the desired effect, but also adverse side effects, resulting from the combination of different AASs in extremely high doses with other drugs and from duration of administration over periods ranging from months to many years – usually seen with abuse in sports. Due to the secret nature of this drug abuse type, doses and duration are mostly unknown and properly controlled clinical trials do not exist. Hence the scientific assessment of the sequelae of AASs abuse relies on case reports and on a few retrospective investigations. Proper diagnosis is further hindered by the reluctance of the doped patient to admit the consumption of AASs and being ignorant about their possible serious side effects. Abuse is not, or only reluctantly admitted to physicians, who must be aware of the multitude of serious side effects of AAS when confronted athletes with unclear symptoms. Since AAS abuse is not or only reluctantly admitted physicians should be aware of the multitude of serious side effects when confronted with unclear symptoms. Whilst attaining accurate data on the prevalence of their use has limitations, studies suggest the illicit use of doping agents by athletes and non-athletes may be 1-5 percent in the population and greater than 50 percent in some groups; with the prevalence being higher in males. The use of doping substances and methods is, however, extensive not only among elite athletes, but also among amateur and recreational athletes. Many types of drugs are used by athletes to enhance performance, to reduce anxiety, to increase muscle mass, to reduce weight or to mask the use of other drugs during testing. Among biomedical side-effects of doping, the cardiovascular ones are the most deleterious. Myocardial infarction, hyperlipidemia, hypertension, thrombosis, arrythmogenesis, heart failure and sudden cardiac death have been noted following drug abuse. A caveat is warranted when drawing conclusions from animal studies to human beings. There are a reasonable number of studies reporting potential adverse cardiovascular effects, while studies indicating an absence of adverse effects are not reported. Supplying information, whatever its validity, is not equivalent, however, to creating and sustaining needed, useable knowledge to enable health-promoting awareness, perceptions, expectations, judgments, decisions, which are implemented or not, and necessary learning, which is integrated into daily adapting and functioning in a range of roles, networks, contexts, situations, and environments – each with their own conditions and “demands.” Is side effects of anabolic steroids an overstated problem? Historically, the side effects of AAS use have probably been overstated. Serious health problems are rare, and the more common adverse effects are benign and reversible. The incidence of complications associated with the nonmedical use of AAS as performance- enhancing drugs is unclear because the denominator of drug use in athletes is not well defined. However, data from larger observational studies suggest that the majority (88-96 %) of AAS users experience at least one minor subjective side effect, including acne (40-54%), testicular atrophy (40-51 %), gynecomastia (10-34 %), cutaneous striae (34 %), and injection site pain (36 %). Prospective clinical studies report a good safety profile for pharmacologic and suprapharmacologic doses of AAS when used in the short term. With the exception of a few reversible laboratory abnormalities – decreased HDL, elevated hemoglobin, and raised liver enzymes – high doses of AAS administered for periods of up to 20 weeks rarely demonstrate any significant systemic toxicity. The side effects reported in at least 40 percent of the male subjects include increased sexual drive, increased body hair and an increase in aggressive behavior. Furthermore, sleeplessness, increased irritability, decreased libido, increased appetite, enhanced transpiration, increased feeling of well-being, depressive mood states, loss of head hair and the occurrence of gynaecomastia are also reported. Female missuse Data relating to female athletes are very scanty. In one study it was interviewed females who all reported lowering of the voice brought on by AAS use. Furthermore, nine of ten females admitted increased growth of facial hair, enlargement of the clitoris and an increase in aggressiveness and appetite. Other side effects reported were acne (50 %), fluid retention (40 %) and alteration of libido (50 %). Impurities in illicit samples of anabolic steroids There are few data on the purity of illicit amples of AASs as a result of the lack of regulation. Consequently, there are no assurances that the chronic AAS abuser knows the dose or type of AAS. The difficulty determining doses used by AAS abusers limits the ability of studies toelucidate the effect of AAS abuse. Frequently, illicit samples of AASs do not contain declared ingredients or concentrations of ingredients. Analysis of 70 products confiscated from illegal sources demonstrated 17 (35 %) of the 48 steroidal compounds did not contain labeled ingredients as measured by liquid chromatography-tandem mass-spectrometry, gas chromatography mass-spectrometry with nitrogen-phosphorus detection, gel- electrophoresis, and immunological tests. Visual inspection does not distinguish original products from counterfeits. Physiological effects on the heart of testosterone and its analogues Some of the effects of testosterone on the heart and the cardiovascular system are still a matter of debate, but some influences of testosterone on cardiac function and morphology have been established. This is primarily in regard to a nonphysiologic situation of testosterone misuse when the side-effects include left ventricular hypertrophy with systolic and diastolic dysfunction. However, in patients