Cardiovascular Effects of Anabolic Androgenic Steroids

Cardiovascular Effects of Anabolic Androgenic Steroids Table of Contents ABSTRACT INTRODUCTION BODY: ANABOLIC ANDROGENIC STEROIDS Effects Desired Effects Adverse Effects CONCLUSION ACKNOWLEDGEMENTS BIBLIOGRAPHY ABSTRACT Doping is a global phenomenon present in international sporting events. International sports federations, led by the International Olympic Committee, and the World Anti-doping agency (WADA), have for the past half century attempted to prohibit the spread of this problem, however, there is still a lot left to be desired. The apparent lack of information with respect to the cardiovascular effects of anabolic steroid usage in competitive sports precipitated the need for a literature review to present scientific knowledge of the possible effects to the general public. The literature review led to detailed explanations of the cardiovascular effects of anabolic androgenic steroids, their mechanisms of actions and delved into the basis underlying why long-term abuse of these substances leads to physiologic malfunctions such as left ventricular hypertrophy, myocardial infarctions and sudden cardiac death. INTRODUCTION The creed of the Olympics states that: â€Å"The important thing in games is not winning but taking part. The essential thing is not conquering, but fighting well†1. While the objective above is lofty and conveys a sense of discipline and integrity, little of it can be found in the reality of today’s sports world. Doping, which can be explained as the use of a substance (such as an anabolic steroid or erythropoietin) or technique (such as gene doping – the use of modified or normal genetic cells) to illegally enhance athletic performance, has become an essential topic in almost every sport and has somehow been exposed in athletes of all ages and at every level of competition2. Doping substances are not unique to modern sports competitions. Their inception dates back to 776 BC when plants and mixtures of wine and herbs were used by the early Greek Olympic athletes and Roman gladiators competing in Circus Maximus. Not only were they used for their stimulating effects in speed and endurance events, but also for their ability to mask pain, permitting injured athletes to continue competing. This was a familiar practice that continued until heroin and cocaine became legally accessible by prescription in the 1920s. At this point, there was an upsurge in the number of athletes using stimulants as doping substances. During the 1930s, amphetamines also evolved and emerged as the stimulant of choice for athletes. By the time Ben Johnson’s gold medal was stripped off in the 1988 Seoul Olympics for using the steroid stanazalol, the world had become much aware of the incidence of doping in sport. The Medical Commission, under the International Olympic Committee (IOC), established a list of illegal substances in 1967 and introduced anti-doping testing of athletes in the 1972 Munich Games. It was clear at this point that doping substances did perform their expected functions and, if allowed to continue unchecked, would wreak havoc not only to the integrity of sports, but also to the health of sportsmen. A number of world class sportspeople, including sprinters like Tyson Gay, Justin Gatlin and Asafa Powell, cyclists like Lance Armstrong and Floyd Landis, footballers like Kolo Toure and Adrian Mutu and fast bowlers like Shoaib Akhtar and Mohammed Asif, have been associated with doping. During sports, the rate at which blood is pumped from the heart to the various organs increases and this translates to an increased cardiac output. Cardiac output can be determined by the heart rate (beats per minute) and stroke volume (volume of blood pumped per beat or stroke). Doping drugs exert their influence on these parameters either by downplaying or exceeding normal heart function. Some doping drugs cause irregular heartbeats, tachycardia (a rapid heart rate of more than 100 beats per minute) and increased blood pressure. Other drugs have the capacity of blocking fast sodium channels competitively in nerve cells, hence reducing the amplitude of the action potential and rate of depolarisation, which can cause cardiac dysrhythmias.3 The stark reality of today’s sports industry, rife with heavy investments and large cash prizes, makes it unsurprising to see athletes and coaches going several lengths to gain competitive advantages and enhance performance at all costs, even to the detriment of the athletes’ health1. Worldwide, there are varying forms of doping substances being misused by professional sportsmen, with some being more common and others being potentially unknown. This paper will focus on the respective cardiovascular effects of anabolic agents (anabolic androgenic steroids)4 BODY: ANABOLIC ANDROGENIC STEROIDS Anabolism can be defined as the synthesis of substances in the body. The word â€Å"anabolic† is derived from the Greek word â€Å"anabole† meaning â€Å"something which is thrown up† or â€Å"mound.† An androgen is a sex hormone responsible for the development of male sexual characteristics. The word â€Å"androgen† is also from the Greek word â€Å"andros† meaning â€Å"of a man†. Anabolic androgenic steroids are drugs that are structurally related to the cyclic rings characteristic of steroids and fall under anabolic agents according to WADA. They are therefore compounds that have the ability to induce higher rates of anabolism in organisms5. The first serious research into anabolic androgenic steroids commenced in the 1930s by the German Chemist Adolf Butenandt, who isolated androstenone from a thousand litres of urine. Further research on the effects of AASs was conducted by 1939 by the World Scientific community. Its use spread among athletes and body builders by the 1940s and 1950s and resulted in an embargo on its use by the time of the 1972 Olympics. In humans, anabolic androgenic steroids (AASs) affect protein synthesis positively and protein breakdown negatively. Androgenic anabolic steroids are synthetic derivatives of the male hormone testosterone. According to the World Anti-Doping Agency (WADA), there are two main classes of anabolic androgenic steroids: endogenous and exogenous. The endogenous anabolic androgenic steroids include testosterone, dihydrotestosterone and androstenedione while exogenous anabolic steroids include boldenone, formebolone, metabolome, stanozolol, furazabol and metandienone.6 Anabolic androgenic steroids are used by athletes through oral or intramuscular routes in three widespread routines: stacking, cycling and pyramiding. Stacking refers to an AAS administration routine in which more than one steroid is used at a time to cause a cumulatively higher effect. Cycling is a routine that involves the administration of an AAS for 6 to 12 weeks, followed by abstinence from steroids for 10 to 12 weeks and then returning to administration for another 6 to 12 weeks, effectively â€Å"cycling† the steroid. Pyramiding is another routine, one which stipulates that individuals begin with low doses of AASs and progressively increase the doses over a period of time. Use of AASs was initially envisioned as treatment of HIV-associated muscle wasting, sarcopenia (gradual age-related loss of skeletal muscle) and hypogonadal males. In recent years, however, about 5% to 14% of American college athletes have been using AAS for purposes unrelated to the intended purposes of the compound. A survey conducted in the United States of America also indicated that AAS use among community weight trainers attending gyms and health clubs was about 15% to 30%7 Mechanism Of Action Testosterone, the active component in AASs and its synthetic analogues, acts on target cells (usually skeletal muscles) by adhering to intracellular androgen receptors (AR)8. The AR-steroid complex binds to DNA in the nucleus, leading to transcription of various genes which lead to the production of a host of proteins that work to increase the size of muscles and the rate of muscle growth.8 After the binding of the AR-steroid complex, additional messenger RNA (mRNA) are formed. These mRNA move out of the nucleus and into the muscle cell cytoplasm where they bind to ribosomal RNA (rRNA), thus initiating translation, which will cause the synthesis of proteins in the Golgi apparatus12. These extra proteins are then integrated into the muscle cell, increasing its size. Studies have shown that androgen receptors on cells can be up-regulated in response to AAS exposure and by strength training. Upon exposure to testosterone and its analogues, there is hypertrophy of muscles that is as a re sult of an increase in the number of myocytes nuclei and the cross-sectional area of muscle fibres. Another mechanism by which AASs act is through glucocorticoid antagonism and growth hormone (GH) and insulin-like growth factor-1 (IGF-1) stimulation, which leads to an increase in muscle size and strength.7 Also, AASs act on the heart and major arteries by promoting the release of endothelial nitric oxide and the inhibition of smooth muscle tone of the vessels. This particular effect occurs only when physiologic amounts of testosterone and other AASs are present. Effects Desired Effects An amount of testosterone higher than the normal range (a supraphysiologic dose) has the tendency to increase muscle strength and mass by increasing protein synthesis (resulting in muscle hypertrophy) and increasing blood pressure, thereby enhancing the performance of athletes in sports2. It is also used in order to improve upon one’s physical appearance and also improve performance in body building. Due to these effects, anabolic androgenic steroids are used mainly by athletes taking part in sports such as baseball, rugby, competitive bodybuilding, competitive cycling and sprinting. Under normal circumstances, androgens are required for physiologic developmental and biological processes involving cardiac myocytes9. Cardiovascular effects of androgens include relaxation of vascular beds, reduction of afterload and quick increase in cardiac contractility, causing an increase in cardiac output9 hence, an increase in the supply of oxygen for oxidative phosphorylation in muscles. This results in a rise in the supply of ATP to the muscles, which will in turn enhance endurance and overall performance as more energy is available to the active muscles. Adverse Effects Major adverse effects that occur from prolonged anabolic steroid usage are hypertension, myocardial hypertrophy (especially left ventricular hypertrophy) myocardial infarction, arrhythmias and thromboembolic incidents. The basis of these effects is the action of androgen receptors on the cardiac myocytes as a result of the supraphysiologic AAS doses. At high doses, the vasodilatory effects of physiologic AAS are inhibited, along with an increase in the growth of cardiac tissue under the influence of GH and IGF-1. The actions of AR-steroid complexes are such that they increase the quantities of secondary messengers, in this case, calcium. Increased amounts of calcium in the cytoplasm of cardiac myocytes causes the release of apoptosis-causing factors such as apoptosis-inducing factor, caspase-9 and holocytochrome C. This initiates apoptosis, otherwise known as cell death, of the cardiac cells, which will in turn lead to myocardial infarctions.10 Another effect of supraphysiologic AAS doses is the elevation of blood pressure that results from renal sodium retention10. Retention of sodium would lead to increase in blood volume as sodium would create an osmotic gradient to draw water to itself. This process will increase venous return and eventually, stroke volume. Prolonged use of AASs will cause an increase in the diameters of the heart’s chambers and also change diastolic function and ventricular relaxation stemming from the continuous increase in venous return (preload). Another effect of the increased preload is left ventricular hypertrophy, which is found in a large number of AAS abusers. Left ventricular hypertrophy (LVH) can be explained as increase in size of the muscles in the left ventricle of the heart due to excess action. LVH remains a strong predictor of cardiovascular mortality and morbidity and could alternately be caused by direct action of AASs on the myocardium.10 The hypertrophy of the left ventricle is associated with the stimulatory effect of AASs on Growth Hormone (GH), which is directly linked to an increase in the inelastic elements (collagen) and cellular infiltration of the cardiac myocytes. Anabolic androgenic steroids have direct influence on the formation of thrombosis (blood clot resulting from platelets aggregation in a living organism). Thromboxane A2, a powerful platelet aggregator, and fibrinogen are positively affected by AASs. Production of prostacyclin, a form of prostaglandin I2 that acts as a platelet aggregator antagonist, however, is decreased. By these actions, AASs increase the risk of developing thrombosis as fibrinogen, which is a major factor in clot formation, and thromboxane A2 are increased in circulation while prostacyclin, which prevents the aggregation of platelets, is reduced in circulation. With increased aggregation of platelets, a free moving structure known as an embolus is produced. In the event that this embolus lodges in the lumen of a blood vessel and causes a halt in blood flow, thromboembolism is said to have occurred. The risk for this to occur is highly increased in AAS users and may cause myocardial infarctions and sudden cardiac d eath.10 AASs also catalyse various changes in lipid metabolism; the most noticeable being increases in LDL (low density lipoprotein) levels by approximately 20% and reductions in HDL (high density lipoprotein) levels by values ranging from 20% to 70%. Though the mechanism of this action is inadequately understood, it has been postulated that LDL levels increase due to the action of the enzyme hepatic triglyceride lipase (augmented by AASs) that causes increased catabolism of VLDL (very low density lipoproteins). These changes in lipoproteins (dyslipidaemia) will result in significantly increased risks of coronary artery disease.10 The above effects therefore suggest that there is increased risk for cardiovascular diseases among anabolic steroid users11. CONCLUSION From the information presented in this paper, it is clear that while anabolic androgenic steroids provide undue advantages to their users, they simultaneously predispose their users to a plethora of cardiovascular problems including, but not limited to, hypertension, arrhythmias, acute myocardial infarctions, thromboembolic episodes and sudden cardiac death. There is marked paucity of information on the cardiovascular effects and anabolic androgenic steroids among sportsmen and it is thus imperative that organisations, anti-doping agencies and providers collect and supply as much information as possible from and to athletes, physicians, coaches and parents in order to help in furthering the education of the risks involved in the use of anabolic androgenic steroids (AASs). ACKNOWLEDGEMENTS BIBLIOGRAPHY 1. Baron DA, Martin DM, Abol Magd S. Doping in sports and its spread to at-risk populations: an international review. World Psychiatry. 2007;6(2):118-123. 2. Press D. Drug Abuse In Athletes. 2014:95-105. 3. Sherwood L. Human Physiology: From Cells to Systems.; 2010. doi:9781111577438. 4. Doping Prevention: Anabolic agents. http://www.doping-prevention.sp.tum.de/substances-and-methods/anabolic-agents/anabolic-agents.html. Accessed June 3, 2015. 5. Sturmi JE, Diorio DJ. Anabolic agents. Clin Sports Med. 1998;17(2):261-282. doi:10.1016/S0278-5919(05)70080-6. 6. Urhausen A, Albers T, Kindermann W. Are the cardiac effects of anabolic steroid abuse in strength athletes reversibleà ¢Ã¢â€š ¬Ã‚ ¯? 2004:496-501. doi:10.1136/hrt.2003.015719. 7. Evans NA. American Journal of Sports Team Physician ’ s Corner. 2004. doi:10.1177/0363546503262202. 8. Wilson C, Maass R, Estrada M. Cardiovascular Effects of Androgens. 1998. 9. Doping Prevention: Mode of action. http://www.doping-prevention.sp.tum.de/substances-and-methods/anabolic-agents/mode-of-action.html. Accessed June 3, 2015. 10. Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm. Am J Cardiol. 2010;106(6):893-901. doi:10.1016/j.amjcard.2010.05.013. 11. Vanberg P, Atar D. Androgenic anabolic steroid abuse and the cardiovascular system. Handb Exp Pharmacol. 2010;(195):411-457. doi:10.1007/978-3-540-79088-4_18. Page 1