Hepatotoxicity Associated with Illicit Use of Anabolic Androgenic Steroids in Doping
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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2017; 21 (1 Suppl): 7-16 Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping R. SOLIMINI, M.C. ROTOLO, L. MASTROBATTISTA, C. MORTALI, A. MINUTILLO, S. PICHINI, R. PACIFICI, I. PALMI Department of Therapeutic Research and Medicines Evaluation, Drug Abuse and Doping Unit, Istituto Superiore di Sanità, Rome, Italy Abstract. – Anabolic Androgenic Steroids Since then , several synthetic analogs of testos - (AAS) abuse and misuse is nowadays a harmful terone, known as Anabolic Androgenic Steroids habit involving both professional or recreational (AAS) or designer steroids (e.g . methyltestos - athletes, as well as general population. AAS are also frequently present in over-the-counter di - terone in 1935 , nandrolone in 1950 and 1953, etary supplements without being declared in the testosterone esters from mid-1950s, stanozolol list of ingredients, leaving consumers unaware and oxymetholone in 1959 , oxandrolone in 1962) of the risks of adverse effects. Indeed, health have been produced in the attempt to minimize risks of AAS consumption in pharmaceutical the androgenic effects and improve the anabolic preparations or dietary complements seem still ones 1,2,7-9 . However , a successful complete sepa - underestimated and under-reported. The variety of complications due to AAS misuse involves ration of the anabolic and the androgenic proper - cardiovascular, central nervous, musculoskeletal ties has never been realized in the synthetic de - and genitourinary systems of both males and fe - rivatives of testosterone 1,2,10,11 . Among those, nan - males; psychiatric and behavioral effects, dam - drolone was the first compound which showed a ages to metabolic system, skin and mainly liver. partial dissociation between anabolic and andro - For instance, relevant concern has been raised genic properties and therefore , it started to be by the AAS hepatotoxicity including adenoma, 2,12 hepatocellular carcinoma, cholestasis, and pelio - used in the medical practice . sis hepatis. After the Second World War, the use of AAS The present review reports the information for performance improvement started to be available on the hepatotoxic effects of AAS use widely spread in the sports circles and progres - in professional and amateur athletes . sively turned into a business since almost all Key Words: sports showed an economic importance strictly Anabolic androgenic steroids, Doping, Hepatotoxi - linked to the image of the power of the coun - city, Illicit use. tries 9. The introduction of AAS in medical practice induced elite athletes to use them “off-label” Introduction with the aim of increasing muscle mass and en - hancing sports performance 6, but with a dosage Testosterone is the male sex hormone and the usually much higher than the therapeutic one, typical endogenous anabolic steroid with specific with consequent serious health risks 2,9,13,14 . properties of stimulating muscle mass growth In the 1950s , the use of AAS by Soviet and (anabolic aspect ) and enhancing male sexual USA weightlifters was reported 2,4 . During the characteristics (androgenic aspect) 1-5 . 1960s , the Council of Europe introduced the con - Testosterone was first isolated from bull testes cept of doping in sports after the deaths of a cou - in 1935 by David and co-workers 1,2,6 and in the ple of competitive athletes and the spread of same year , it was chemically synthesized by Bu - harmful drugs use 2,15 . tenandt in Göttingen (Germany) and Ruzicka in The International Olympic Committee (IOC) Basel (Switzerland) 7. In 1940s testosterone was started doping control tests in the Olympics of supposedly used by Germans in war contexts 4,6 , 1968 and subsequently AAS were introduced in and it was prescribed in psychiatry for depression the list of prohibited substances in 1976 4,6,10 . and andropause until the introduction of new In the 1970s competitive athletes and body treatments in 1950s 6. builders were largely using AAS 4,6 and in 1988 Corresponding Author: Renata Solimini; e-mail: [email protected] 7 R. Solimini, M. C. Rotolo, L. Mastrobattista, C. Mortali, A. Minutillo, S. Pichini, R. Pacifici, I. Palmi the sprinter Ben Johnson was prosecuted for be - AAS Mechanism of Action ing found positive for anabolic steroid stanozolol Synthetic AAS are compounds derived from at Seoul Olympics and his gold medal was with - the natural testosterone from which they differen - drawn by IOC 4. In the 1980s the exclusive use tiate because of several modifications of the basic confined to elite sport up to then dangerously testosterone structure 2. Endogenous androgens as shifted to amateur athletes and even to non-ath - testosterone have both skeletal muscle-building letes (mostly adolescents and young men) and (anabolic) and masculinizing (androgenic) ef - recreational drug users 1,4,6,8,9 . fects, while, as above reported, most of the syn - Since 1991 , in the USA, AAS have been DEA thetic AAS have been developed with the aim to (Drug Enforcement Administration) Schedule III separate the anabolic from the androgenic prop - substances under Controlled Substances erties, preferring synthetic androgens that have Act 2,4,6,13,16 . preferential anabolic activity and no androgenic The focus on AAS misuse in sports increasing - one. Testosterone acts as an androgen either di - ly raised to the point that today the antidoping rectly by binding to the androgen receptor or in - authorities monitor and control the phenomenon directly by conversion to 5alpha-dihydrotestos - both on elite and recreational athletes 16,17 . terone (DHT). The structural modification of AAS use prevalence in the general population AAS alters the relative anabolic or androgenic worldwide is 6.4% for males and 1.6% for fe - activity, the binding affinity for the androgen re - males 18,19 . Abuse and misuse of AAS to boost ceptor and metabolic clearance 4. muscles and sculpt the body also involves adoles - Testosterone and AAS pass into the blood sys - cents and young adults affected by body image tem, through the target cell membrane, linking disturbance or eating disorders, who use them for with intra-cytoplasmic receptors. This complex cosmetic purposes and showing increased mas - hormone-receptor is later transported into the nu - culinity 2,6,18,20 . cleus of the cell, where it links up with DNA. It AAS are illegally (meaning without a med - results in the production of RNA, DNA and the ical prescription) sold through the black mar - subsequent enhancement of protein synthesis (in - ket, websites, gyms, body building competi - cluding increased amounts of actin and myosin tions, teammates, coaches, trainers and by inap - in skeletal muscles) 2,9 . propriate prescription or theft 1,13,16 . Street The main chemical substitutions occurring to names for illegally sold anabolic steroids in - testosterone are the 17 -beta-esterification and the clude Gear, Winny, Deca, EQ, Tren-A, Fina, 17alpha- alkylation. Whereas testosterone is me - Arnolds, Juice, Pumpers, Roids, Stackers, tabolized rapidly in the body, the esterification of Weight Gainers 13,14,21 . the 17 -beta-hydroxyl group makes the molecule Overall AAS include testosterone, its synthetic more hydrophobic. When these esters of testos - derivatives , and precursors also known as pro- terone (i.e . testosterone enanthate, cypionate , and hormones (weaker formulations of AAS) like de - decanoate) are administered in an oily suspen - hydroepiandrosterone (DHEA), dihydrotestos - sion, they are released very slowly into the aque - terone (DHT), 1-testosterone, 19-norandrostene - ous plasma because of their hydrophobicity. This dione, prostazonol and androstenedione, which extends their duration of action 4. are usually present in dietary supplements 2,3,21 . Indeed, an important metabolic pathway of Their administration can be oral, injectable (oil- testosterone and its synthetic derivative is oxida - based and water-based) and transdermal (testos - tion of the 17-beta-hydroxy group with the forma - terone cream )2-4 , buccal and sublingual (i.e. tion of the 17-keto metabolites. These polar tetrahydrogestrinone) 2. metabolites are biologically inactive. The 17 -al - Several side effects related to AAS abuse in - pha- alkylation induces the inhibition of metabolic volve mostly cardiovascular, reproductive, cen - deactivation by oxidation of the 17 -beta hydroxy tral nervous, and musculoskeletal systems, skin group in the liver, thus 17alpha-alkylated andro - and liver 2. The most relevant one is undoubtedly gens can be effectively administered orally. Often hepatotoxicity since it has been showed that pri - the alkylation of the C-17 position of testosterone marily the oral forms of AAS may damage liver alters the relative anabolic potency about the mas - function . culinizing effects (androgenic steroids) . This article reviews the mechanism of action The mostly used oral anabolic steroids are eth - and potential hepatotoxicity of AAS abuse and ylestrenol, fluoxymesterone, mesterolone, methan - misuse as a doping offense . dienone, methenolone, methandrostenolone, 8 Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping methyltestosterone, methenolone acetate, mi - Hepatotoxicity of AAS may be correlated to bolerone, norethandrolone, oxandrolone, individual susceptibility and genetic factors, and oxymetholone, stanozolol 3,4,22 . The oral forms are it is associated with an increase in infiltration of resistant to immediate degradation