coNseQUeNces oF ANABoLIc steRoIDs ABUse

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The reports of abuse with steroids begins at the time when bodybuilding gane ... but also young people who practice fitness and want to look like a bodybuilder. Anabolic steroid ... ed to Schedule III of the Controlled Substances Act. This action ...
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S. Ivanova, K. Ivanov, S. Pankova, L. Peikova

CONSEQUENCES OF ANABOLIC STEROIDS ABUSE S. Ivanova1, K. Ivanov1, S. Pankova2, L. Peikova2 Medical University Plovdiv, Faculty of Pharmacy, Department Pharmacognosy and Pharmaceutical Chemistry, Plovdiv, Bulgaria 2 Medical University Sofia, Faculty of Pharmacy, Department Pharmaceutical Chemistry, Sofia, Bulgaria 1

Abstract. Many cases of anabolic steroid abuse are reported nowadays. Anabolic androgenic steroids are used to enhance athletic performance and appearance. Not only athletes take anabols but also young people who practice fitness and want to look like a bodybuilder. Anabolic steroid abuse can be associated with a wide range of adverse side effects ranging from some that are physically unattractive, such as acne and breast development in men, to others that are life threatening, such as heart attacks and liver cancer. Most are reversible if the abuser stops taking the drugs, but some are permanent, such as voice deepening in females. Most data on the long-term effects of anabolic steroids in humans come from case reports rather than formal epidemiological studies. Steroid abuse disrupts the normal production of hormones in the body, causing both reversible and irreversible changes. Changes that can be reversed include reduced sperm production and shrinking of the testicles (testicular atrophy). Irreversible changes include male-pattern baldness and breast development (gynecomastia) in men. In one study of male bodybuilders, more than half had testicular atrophy and/or gynecomastia.In this study we make review of the most important side effects of use of steroids. Key words: anabolic androgenic steroid; androstenedione; dehydroepiandrosterone; steroids; side effects, sport medicine Abbreviation: anabolic-androgenic steroids (AAS); low-density lipoprotein (LDL); cardiovascular diseases (CVD); high-density lipoprotein (HDL); anabolic androgenic steroids (AASs)

Introduction The roots of bodybuilding go all the way back to ancient Greece. It was the athletes of ancient Greece who used to train in the gymnasiums. They did not use resistance training as a form of body modification but rather a means to improve at the sport they participated in. It was in 11th century India that bodybuilding as we know it first arrived on the scene. It was back then the Indians would use primitive dumbbell weights carved from stone for the sole purpose of getting bigger and stronger, it is also reported that by the 16th century weight lifting had become a national past time in India. By the mid-19th century weight training as a means of improving health and increasing strength was becoming increasingly popular. Born 1867 in Prussia by the name Friedrich Muller, Eugene Sandow later became referred to as “The Father of Modern Bodybuilding”. In 1970 Schwarzenegger won the competition Mr. Olympia, making him the

youngest ever Mr. Olympia at the age of 23, a record he still holds to this day. Bodybuilding had a new star and the bodybuilding became the new star of the 20-th century. The 80’s ushered in a new era of massive bodybuilders. The reports of abuse with steroids begins at the time when bodybuilding gane more and more popularity. Sociocultural standards of beauty for males emphasize strength and muscularity. The broad-shouldered, narrow hipped male body is idealized in the modern society. Weight machines and performance enhancing supplements are widely advertised in health and fitness centers [17]. Nowadays there is a big demand of food supplements with androgenic effects or product with steroids, however the steroids are forbidden substances in food additives. Most athletes use anabolic-androgenicsteroids (AAS) to obtain a well-trained, athletic, and healthy looking body [19]. Users of anabolic steroids can be divided into two groups: first who use these products

Consequences of anabolic steroids abuse

for medical purposes (anabolic steroids are prescribed for a small number of legitimate medical purposes) and the second group include those who use them to enhance their strength and athletic ability, and/or enhance their physical appearance by adding muscle mass. There are different groups that use performance enhancing drugs and abuse with steroids [22]. The first group - elite athletes who have a definite plan to achieve their goal, the second - people who practice fitness and want to look good. Very often these people have only a crude knowledge about the pharmacological databases and the serious side effects regarding these drugs. Proponents of their use claim that the drugs increase muscle strength and mass, endurance, decrease recovery time between workouts and improve physique. Critics claim that these beneficial effects are due primarily to expectancy and other factors associated with training; many doctors also claim that their use is actually quite dangerous. Regardless of their efficacy, the use and abuse of anabolic-androgenic steroids has escalated such that in 1990 the US Congress enacted the Anabolic Steroids Control Act requiring that anabolic steroids be added to Schedule III of the Controlled Substances Act. This action placed compounds such as testosterone cipionate and nandrolone decanoate in the company of various opioid drugs, amphetamines and barbiturates. As chair of the American Society for Pharmacology and Experimental Therapeutics’ Committee on Substance Abuse, Scott Lukas advocates continued research on the effectiveness, toxicity and natural

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Fig. 1. Basic structure of steroid hormones and the possibilities of chemical derivatization.

history of anabolic-androgenic steroid abuse [2]. All androgens posses the cyclopentanophenanthrene nucleus, typical of steroid hormones. The structures of testosterone and some selected derivatives used as anabolics are shown in Figure 2. These compounds have been synthesized and used to maximize the bioavailability, and to prolong the androgenic effects. Clinical studies about side effects of AAS Anabolic androgenic steroids are synthetic derivatives of testosterone, which is the primary male sex hormone. Anabolic androgenic steroids are used to enhance athletic performance and appearance. Adverse effects include those on the liver, serum lipids, psyche/behavior and reproductive system. Androstenedione is an anabolic androgenic steroid used to increase blood testosterone levels for the purposes of

Fig.2. Structures of testosterone and some of the most common synthetic derivatives used as anabolics

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increasing strength, lean body mass and sexual performance. However, there is no research indicating that androstenedione, or its related compounds, significantly increases strength and/or lean body mass in humans by increasing testosterone levels. The longterm health effects of prolonged androstenedione supplementation are unknown. Dehydroepiandrosterone (DHEA) is a weak androgen also used to elevate testosterone levels, and is advertised as an anti-obesity and anti-aging supplement capable of improving libido, vitality and immunity levels [1]. The health consequences of steroid abuse are very serious. Rising levels of testosterone and other sex hormones normally trigger the growth spurt that occurs during puberty and adolescence and provide the signals to stop growth as well. Cardiovascular side effects Adverse cardiovascular effects induced by anabolic steroids include hypertension, left ventricular hypertrophy, impaired diastolic filling, polycythaemia, and thrombosis.[13]Steroid abuse has been associated with cardiovascular diseases (CVD), including heart attacks and strokes, even in athletes younger than 30. Steroids contribute to the development of CVD, partly by changing the levels of lipoproteins that carry cholesterol in the blood. Steroids, particularly oral steroids, increase the level of low-density lipoprotein (LDL) and decrease the level of high-density lipoprotein (HDL). High LDL and low HDL levels increase the risk of atherosclerosis, a condition in which fatty substances are deposited inside arteries and disrupt blood flow. If blood is prevented from reaching the heart, the result can be a heart attack. If blood is prevented from reaching the brain, the result can be a stroke .Steroids also increase the risk that blood clots will form in blood vessels, potentially disrupting blood flow and damaging the heart muscle so that it does not pump blood effectively .Steroid abuse has been associated with liver tumors and a rare condition called peliosis hepatis, in which blood-filled cysts form in the liver. Both the tumors and the cysts can rupture, causing internal bleeding .Steroid abuse can cause acne, cysts, and oily hair and skin .Many abusers who inject anabolic steroids may use nonsterile injection techniques or share contaminated needles with other abusers. In addition, some steroid preparations are manufactured illegally under nonsterile conditions. These factors put abusers at risk for acquiring lifethreatening viral infections, such as HIV and hepatitis B and C. Abusers also can develop endocarditis, a bacterial infection that caus-

S. Ivanova, K. Ivanov, S. Pankova, L. Peikova

es a potentially fatal inflammation of the inner lining of the heart. Bacterial infections also can cause pain and abscess formation at injection sites. Since the Bodybuilding became also and a female sport many female bodybuilders began to use steroids. In the female body, anabolic steroids cause masculinization. Breast size and body fat decrease, the skin becomes coarse, the clitoris enlarges, and the voice deepens. Women may experience excessive growth of body hair but lose scalp hair. With continued administration of steroids, some of these effects become irreversible.Bonetti et all from the University of Parma Italy have made a 2 year study for the side effects of steroids. Long-term side effects of high doses of anabolic androgenic steroids self-administration were evaluated in this study. Twenty male bodybuilders, voluntarily starting steroid self-administration, were followed every 6 months over 2 years. Physical examination, haematological, metabolic and endocrine variables, semen analysis, hepatic and prostate ultrasound and echocardiographic evaluations were performed. LH values (baseline 3.43 ± 1.75) were suppressed at 18 (1.98 ± 1.99) (p = 0.026) and 24 (2.43 ± 2.17) (p = 0.026), and FSH (3.95 ± 2.01) at 6 (3.01 ± 2.16) (p = 0.031), 12 (2.45 ± 2.54) (p = 0.029), 18 (2.02 ± 2.29) (p = 0.032) and 24 (3.42 ± 2.64) (p = 0.032) months and SHBG (34.11 ± 10.88) values significantly lowered at 12 (24.81 ± 12.49) (p < 0.05), 18 (21.28 ± 11.15) (p < 0.01), 24 months (25.42 ± 11.16) (p < 0.01). A significant decrease in spermatozoa count (p < 0.01), and fertility index (p = 0.01) occurred. HDL-cholesterol (baseline 56.94 ± 13.54) was reduced at 18 (41.86 ± 14.17) (p < 0.01) and 24 (43.82 ± 18.67) (p < 0.05) months and Apo A-1 at 12 (p < 0.001), 18 (p = 0.05) and 24 (p = 0.05) months. The most important long-term adverse effects were lower fertility and the impairment of lipid profile associated with an increased cardiovascular risk.[3] It has been consistently shown that anabolic steroid use is associated with abnormal lipid profiles: a decrease in high density lipoprotein cholesterol and a variable increase in low density lipoprotein cholesterol and total cholesterol [14,15]. Infertility side effect Abuse of anabolic androgenic steroids (AASs) may be an aetiological factor in male infertility among recreational power athletes [5]. Large doses of exogenous androgenic agents induce apituitary hypogonadal state, associated with decreasedsecretion of follicular stimulating hormone and luteinizing hormone [13].

Consequences of anabolic steroids abuse

Neuropsychiatric side effects Thomas A. Pagonis et all have made a very important study for the Psychiatric side effects of anabolic steroids correlate to the severity of abuse. The study includes a substantial group of AAS abusing athletes and two more groups demographically similar to the first, one composed of athletes not using any substance and a placebo group. All athletes were stratified according to the severity of AAS abuse. Psychometric instruments were applied to all athletes in specific time intervals, dependent to the AAS abusers’ regimens, providing us with a final psychological profile that was to be compared to the pre-study profile. All results were comparable (within and between groups) for statistically significant differences and correlated to the severity of the abuse. Homogeneity of all groups was safeguarded by random doping controls, monitoring of drug levels and analysis of all self obtained drugs by method of liquid chromatography/mass spectrometry. All athletes were provided with a common exercise and dietary regime, so common training and nutritional conditions were achieved. We studied a cohort of 320 body-building, amateur and recreational athletes, of whom 160 were active users of AAS (group C), 80 users administering placebo drugs (group B) and 80 not abusing any substance (Group A). Group C athletes were stratified according to AAS abuse parameters, thus providing us with three subgroups of “light, medium and heavy abuse”. Athletes of groups A and B were included in a “no abuse” subgroup. The psychometric instruments used were the Symptoms Check List-90 (SCL-90) and the Hostility and Direction of Hostility Questionnaire (HDHQ). The psychometric evaluations took place within a time interval of 13 months. Statistical analysis was performed by using the Mann–Whitney/Wilcoxon two-sample non-parametric test (Kruskal–Wallis test for two groups) for data that were not normally distributed and Linear regression analysis was used to ascertain the correlation between severity of use and escalation of side effects. The study showed a statistically significant increase in all psychometric subscales recorded in group C, and no statistically significant difference in group C and A. There was a significant increase in the scorings of group C for all subscales of SCL-90 and HDHQ. Correlation of abuse severity and side effects showed that there was a statistical significant increase in Δ values of all SCL-90 and HDHQ subscales that escalated from light abuse to medium and heavy abuse/consumption patterns [4]. A 2005 review determined that some, but not all, ran-

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domized controlled studies have found that anabolic steroid use correlates with hypomania and increased aggressiveness, but pointed out that attempts to determine whether AAS use triggers violent behavior have failed, primarily because of high rates of non-participation [6]. A 2008 study on a nationally representative sample of young adult males in the United States found an association between lifetime and past-year self-reported anabolic-androgenic steroid use and involvement in violent acts. Compared with individuals that did not use steroids, young adult males that used anabolic-androgenic steroids reported greater involvement in violent behaviors even after controlling for the effects of key demographic variables, previous violent behavior, and polydrug use.[7] A trial conducted in 2000 using testosterone cypionate at 600 mg/week found that treatment significantly increased manic scores on the YMRS, and aggressive responses on several scales. The drug response was highly variable. However: 84% of subjects exhibited minimal psychiatric effects, 12% became mildly hypomanic, and 4% (2 subjects) became markedly hypomanic. The mechanism of these variable reactions could not be explained by demographic, psychological, laboratory, or physiological measures [9]. A 1996 review examining the blind studies available at that time also found that these had demonstrated a link between aggression and steroid use, but pointed out that with estimates of over one million past or current steroid users in the United States at that time, an extremely small percentage of those using steroids appear to have experienced mental disturbance severe enough to result in clinical treatments or medical case reports.[8] Anabolic-androgenic steroids may both relieve and cause depression, and that cessation or diminished use of anabolic-androgenic steroids may also result in depression[11].

Fig.3 Stanozol (Winstrol)

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Hepatotoxicity There are numerous reports of liver dysfunction associated with anabolic steroid use. These include asymptomatic elevations in serum aminotransferases, cholestasis, peliosis hepatitis (an uncommon condition characterized by small blood filled cystic spaces distributed throughout the liver parenchyma), hepatocellular carcinoma, hepatic adenomas, and hepatic haematomas.[13] Hepatotoxicity is usually associated with the C17 alkylated compounds [20,21]. Good example for this is stanozolol, commonly sold under the name Winstrol (oral) and Winstrol Depot (intramuscular), is a synthetic anaboli steroid derived from dihydrotestosterone. It was developed by Winthrop Laboratories (Sterling Drug) in 1962, and has been approved by the FDA for human use. Feminization There are also sex-specific side effects of anabolic steroids. Development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), may arise because of increased conversion of testosterone to estradiol by the enzyme aromatase (fig.4)

Fig.4. Conversion of testosterone to estradiol

Gynaecomastia occurs in about 40% of male users of anabolic steroids [17]. Another male-specific side-effect that can occur is testicular atrophy, caused by the suppression of natural testosterone levels, which inhibits production of sperm (most of the mass of the testes is developing sperm). This side-effect is temporary: The size of the testicles usually returns to normal within a few weeks of discontinuing anabolic steroid use as normal production of sperm resumes [10]. Masculinization Just like the males atlets all professional female bodybuilders are taking anabolic steroids. We don’t recommend anabolic drugs to females. AAS destroy woman femininity and helth. Anabolic steroids are designed to copy the muscle-building effects of testosterone but with fewer of the accompanying

S. Ivanova, K. Ivanov, S. Pankova, L. Peikova

“masculinization” effects. Masculinization occurs in females, leading to menstrual irregularities, clitoral enlargement, hirsutism, deepening of voice, oily skin and breast atrophy, increased hair growth on face, legs and arms. Of these, clitoral enlargement and voice changes are usually permanent [23]. Endocrine aspects of anabolic steroids The unwanted consequences of AAS abuse are most damaging in females and adolescents: irreversible virilization and stunting of linear growth, respectively. Suppression of the hypothalamic–pituitary– gonadal axis that results in disturbances in menstrual function and infertility is, in contrast, reversible. Stimulation of the sebaceous glands appears to be dose-related: Increasing testosterone beyond the physiological range in normal men results in further increases in the sebum excretion rate. Consequently AAS users tend to suffer from severe acne [12].

Fig.5. Dose – response relation of biological responses to increasing concentrations of circulating testosterone charavteristic of various clinical situations and therapeutic indications [12].

Testosterone concentrations encountered in AAS abuse are typically orders of magnitude higher than physiological concentrations [12]. The discontinuation of long-term anabolic steroid use can cause unexpected withdrawal symptoms in addition to the endocrine hypofunction [18]. An important side effect to mention for high school athletes because steroids can cause the premature closure of the growth plate, leading to stunted growth. When a child or adolescent takes anabolic steroids, the resulting artificially high sex hormone levels can prematurely signal the bones to stop growing. Conclusion For the past 50 years anabolic-androgenic steroids have been used by a wide variety of people with the

Consequences of anabolic steroids abuse

hope of improving their performance and their body shape. The wide use of AAS continues to be a problem because of the large number of side effects of these products. The long-term consequences result from the abuse of anabolic androgenic steroids are side effects on the cardiovascular system, mental health, endocrine system. Infertility, growth defects, feminization and masculanization are very often irreversible side effects. The proportion benefit – risk shows that any kind of abuse with AAS drugs is extremely dangerous. References 1. B a h r k e M, Yesalis C.Abuse of anabolic androgenic steroids and related substances in sport and exercise Current Opinion in Pharmacology; Volume 4, Issue 6; Pages 614-620 2. L u k a s S. Current perspectives on anabolic-androgenic steroid abuse; Trends in pharmacological science , Volume 14, Issue 2, February 1993, Pages 61–68 3. B o n e t t i  A, Tirelli F, Catapano A, Dazzi D, Dei Cas A , Solito F, Ceda G , Reverberi C, Monica C, Pipitone S , Elia G, Spattini M, Magnati G; Side Effects of Anabolic Androgenic Steroids Abuse; Int J Sports Med 2008; 29(8): 679-687 4. T h o m a s A. Pagonis , Nikiforos V. Angelopoulos, George N. Koukoulis, Christos S. Hadjichristodoulouc, Psychiatric side effects induced by supraphysiological doses of combinations of anabolic steroids correlate to the severity of abuse, European PsychiatryVolume 21, Issue 8, December 2006, Pages 551– 562 5. K a r i l a T, Hovatta O, Seppälä T; Chorionic Gonadotrophin Impairs Spermatogenesis in Power Athletes; Int J Sports Med 2004; 25(4): 257-263 6. T h i b l i n I, Petersson A (February 2005). “Pharmacoepidemiology of anabolic androgenic steroids: a review”. Fundam Clin Pharmacol 19 (1): 27–44. doi:10.1111/j.14728206.2004.00298.x. PMID 1566095 7. B e a v e r KM, Vaughn MG, Delisi M, Wright JP (December 2008). “Anabolic-Androgenic Steroid Use and Involvement in Violent Behavior in a Nationally Representative Sample of Young Adult Males in the United States”. Am J Public Health 98 (12): 2185–7.doi:10.2105/ AJPH.2008.137018. PMC 2636528. PMID 18 923108

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8. B a h r k e MS, Yesalis CE, Wright JE (1996). “Psychological and behavioural effects of endogenous testosterone and anabolic-androgenic steroids. An update”. Sports medicine (Auckland, N.Z.) 22 (6): 367–90. doi:10.2165/00007256199622060-00005 9. P o p e HG, Kouri EM, Hudson JI (February 2000). “Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial”.Arch. Gen. Psychiatry 57 (2): 133–40; discussion 155– 6. doi:10.1001/archpsyc.57.2.133 10. A l é n M, Reinilä M, Vihko R (1985). “Response of serum hormones to androgen administration in power athletes”. Medicine and science in sports and exercise 17 (3): 354–9.  11. U z y c h L (February 1992). “Anabolic-androgenic steroids and psychiatric-related effects: a review”. Can J Psychiatry 37 (1): 23–8. 12. F. C. W. Wu , Endocrine aspects of anabolic steroids , Clinical ChemistryJuly 1997 vol. 43 no. 7 1289-1292 13. K a m P, Yarrow M. Anabolic steroid abuse: physiological and anaesthetic considerations; Anaesthesia; 2005, 60, pages 685–692 14. B a k e r PJ, Ramey ER, Ramwell PW. Androgen mediated sex differences of cardiovascular responses in rats. American Journal of Physiology 1978; 235: H 242–6. 15. D i c k e r m a n RD, McConathy WJ, Zachariah NY. Testosterone,sex hormone-binding globulin, lipoproteins and vascular disease risk. Journal of Cardiovascular Risk 1997; 4:363–6. 16. M o t t r a m DR, George AJ. Anabolic steroids. Baillieres Best Practice & Research: Clinical Endocrinology and Metabolism 2000;14: 55–69 17. K o p e r a H. Interactions of anabolic steroids. Wiener Medizinische Wochenschrift 1993; 143: 401–2. 18. A y o t t e C, Lévesque JF, Cléroux M, Lajeunesse A, Goudreault D, Fakirian A. Sport Nutritional Supplements: Quality and Doping Controls.Can.J.Appl.Physiol. Suppl 26: S 120-129 (2001) 19. D i c k e r m a n RD, Pertusi RM, Zachariah NY. Anabolic steroid induced hepatotoxicity: is it overstated?; Clinical Journal of Sports Medicine 1999; 9: 34–9.

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20. G r a h a m S, Kennedy M. Recent developments in the toxicology of anabolic steroids. Drug Safety 1990; 5:458–76. 21. S i l v e r MD. Use of ergogenic aids by athletes. J.Am.Acad.Orthop.Surg. 9: 61-70 (2001)



S. Ivanova, K. Ivanov, S. Pankova, L. Peikova

22. D i c k e r m a n RD, Pertusi RM, Zachariah NY. Anabolic steroid induced hepatotoxicity: is it overstated? Clinical Journal of Sports Medicine 1999; 9: 34–9.

Corresponding author: Stanislava Ivanova Department Pharmagognosy and Pharmaceutical Chemistry Faculty of Pharmacy, Medical University – Plovdiv, Plovdiv, Bulgaria Mobile: +359 (0)879 061053 e-mail: [email protected]