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    Adverse Effects of Anabolic Steroids

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    © All Rights Reserved
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    ‘Mes Toxiool Adverse Drug Exp. 4 (4: 254271, 1989 4 113.s2e4asja0n7-0254808.00, (© ADIS Press Limited AML ight reserved Adverse Effects of Anabolic Steroids | Robert C. Hickson, Karen L. Ball and Michael T. Falduto Department of Physical Education, University of tin Illinois, USA ‘8 Chicago, Chicago, Contents Summary — — 1. Molecular Alterations in the Formation of Anabolic Steroids 2 Benefit of Therapeutic Use : 21 Replacement Therapy 22 Growth Disorders : 23 Angemias and Blood Disorders 24 Cancet Treatment... 25 Catabolic and Debiltatng States 3. Benefits to Athletes ~ 4 Adverse Effects 461 Classical Eects 4.14 Reproduetion 412 413 Liver alterations 42 Emerging Areas 42.1 Development of Diabetes 422 Lipoprotein Profiles a. 423 Cardiovascular Ets 4.2.4 Cerebral Dange 42'5 Musculoskeletal Injuries 426 Promatie Cancer Risk. 42.7 Other Adverse Effects | 5. Conelsions Summary ee a diel tt ed ety vi rie ede ei poly eran Reames cee ia | Eee weer meren meena oes gee | ee et per chee endear are | several years of steroid intake (i.e, liver carcinoma). More recent studies indicate that | glucose intolerance, insulin resistance, increased cardiovascular disease risk profiles, cere- eres secre res mance ile eee, oa an io er ok to support the claim that athletes are less susceptible to adverse effects than those indi- aati ear eto Mn Pe nn Adverse Effects of Anabolic Steroids 255 ‘mation which has accumulated primarily fr mal, short term maton whi from crase-setional, short term longitudinal id case studies, there isa need: (a) 10 develop a comprehensive batery of specific and sensitive markers of adverse effets, particularly chase that would be able 10 detect the ‘onset of adverse actions and (b) 10 conduet contralled long term longitudinal studies in ‘order to fully understand the extensivenes and mechanisms involved inthe occurrence of adverse eects. ‘The role of androgens as anabolic agents was initially recognised by the ability of the ‘male hor- ‘mone! to induce a positive nitrogen balance in cas- trated dogs (Kochakian 1935). Subsequent uses of androgens and later synthetic derivatives of these ‘compounds, termed anabolic steroids (or more ap- ropriately anabolic-androgenic steroids, because the androgenic effects cannot be entirely disso- ciated), were initially directed at the clinical level in growth restoration from the hypogonadal state. Additional clinical studies have employed these compounds in the treatment of a variety of dis- orders (table 1) 'A second area of anabolic steroid use began in the 1950s, Athletes, particularly those of national and Olympie calibre involved in strength-related events, began using anabolic steroids as ergogznic aids, More than 30 years later, use of these com- ‘pounds by athletes of all ages and at all levels of ‘competition has become so widespread that drug- testing procedures have been implemented as a de- terrent. The advent ofthe fitness boom in the 1970s hhas also produced a population of steroid users at the subcompetitive or recreational level who aspire to larger muscles and greater strength. ‘This review is subdivided into sections cover- ing: changes in the molecular structure of the an- drogen molecule leading to the development of various anabolic steroids, the intended benefits as- sociated with anabolic steroids in clinical use and in use by athletes, and finally the major emphasis is directed on evaluating adverse actions. When- ever possible, adverse effects are reported separ ately between the clinical and athletic studies, We have attempted to distinguish whether athletes were ‘more susceptible than individuals receiving drugs for medical reasons or whether they would exhibit ‘greater resistance to the unwanted effects. ‘A further goal of this work was initially to eval~ uate adverse effects of high-dose anabolic steroid use, However, in the course of the literature re- view, it became apparent that adverse effects were manifested at all dose levels. Therefore, no tempts have been made to clearly differentiate be- ‘ween high and low dosages within the text. Never- theless, at specific points, arbitrary designations of high or low are stated in order to place specific emphasis on an effect. 1. Molecular Alterations in the Formation of Anabolic Steroids Chemical modifications of the basic testoster- cone molecule (ig. 1) have formed the basis for the clinical application of synthetic anabolic steroids. Specifically, one sim was to develop longer acting ‘compounds in order to improve the efficacy of tes- tosterone itself, which is quickly degraded when administered orally (Foss 1939). Another import nt goal was the development of steroids with in- creased anabolic effects. The anabolic functions of testosterone include increased total body nitrogen retention, increased numbers of red blood cells, {improved calcium deposition in the bones and, pO- tentally, muscle enlargement. Androgenic effects are represented by the growth and development of the seminal vesicles, inereased body hair, thick- cening of the vocal chords, and the growth and de- velopment of the prostate gland. Because the ani bolic effeets differ from the androgenic effects only in their location and not in the mechanism of the hormone ection, no purely anabolic agent has ever been synthesised. It is important to note that for the purposes of replacement therapy. both andro~ genic and anabolic actions are desirable. In con- ‘ras, in certain debilitating conditions in which te 256 Med. Toxicol. Adverse Drug Exp. 4 (4) 1989 ‘Tale 1. General uses of ancrogen and anabote-ancrogeni steods (normation from manutscuers product iterate nd Physicians Desk Reteronce 1968) insiatone ‘Contaiciatons| To inoase nacrogiobin and red co mass ‘To promote weight gan ater wolght ss falowing surgery, von infections, or svere aura ‘To ost ine pron catabolism associated wth prolonged cortconeoid azminstation For rl of tone pain accampenyng ostenporeis ‘As scuncie therapy in sen and postmanopausel oxtooporosis For replacement therapy in condions associatod with a otiency or absece of endogenous testosterone (@) primary hypogonadism (2) Pypogonadetopaic ypogonadism (@) delayed puberty not eecencary to pathological locdar (@ Aor castaion gospermia Impotence de to inadequate sncrogen producto As secondary therapy for advancing naperble metastatic "mammary cancer pestmenopaiss women tn premengpausal wornen wih Sst caneer whose tuours ae hormeneesponcive ‘carcinoma of the prostate Carina of he male breast Pregnancy (etl masculnsaton) Nophross Carina of te b uta insutctoney Petenis wth a hisory of myocarsial infarction stn some fomstes Benign prostate nypertrophy versal of catabolic states or greater nitrogen retention is required, enhancement of anabolic po- tency is the primary aim, Substitution of the hydrogen atom with alkyl ‘groups at the Cl7a position renders testosterone orally active by slowing its metabolism by the liver, Many of these alkylated oral agents have been syn- thesised with various other modifications which, ‘on empirical observation, seem to improve the an- abolic to androgenic ratio (Overbeek et al. 1969) [table I). There are 3 major metabolites of testos- ferone (fig. 1) and they are excreted, in large part, as conjugates of glucuronic or sulphuric acids, Al- ‘kyl groups at the 17a position can alter the con- figuration of the molecule such that its capacity to serve as.a substrate for the metabolising enzymes is markedly reduced, One common feature of the 1Te-alkyl com- Pounds is an association with hepatotoxic effects (Farrell et al. 1975; Foss & Simpson 1959), possi- bly because degradation of these agents occurs with the alkyl group intact (Mosbach et al. 1968). Sim- ilar sido effects of oral contraceptives having 17o- alkylation have also been reported (Goldfarb 1976, Ishak 1981; Mays & Christopherson 1984), which suggests a common mechanism. Esterification with various carboxylic acids of the fchydroxy group at the I7a-position is the most common modification of testosterone for paren- teral administration. The duration of action of this class of anabolic steroid is related to the length of the carbon chain of the ester group (Junkman 1957) Larger carboxylic acids convey less polarity in the molecule, with a concomitant inerease in lipid so! ubility. The result is a slower release into the sys- ‘temic circulation (Honrath et al. 1963; James et al 1969), In contrast to the orally active 17ealkyl steroids which act in the modified form, the ester ‘Adverse Effects of Anabolic Steroids 287 group of esterified testosterone and testosterone derivatives must be hydrolysed before biological action can occur (Caminos-Torres ct al. 1977). Substitutions and alterations of testosterone esters other than at the C17 position have also been em= ployed in the development of high anabolic and low androgenic compounds. For instance, 19-nor- testosterone esters such as nandrolone decanoate, which have no methyl group at C19, are long-act- ing highly anabolic steroids (table 11). ‘The binding of androgens to specific intracell- ular receptor proteins is necessary for biological ac- tivity, However, binding to serum proteins may make the steroid temporarily unavailable to the target tissue receptor and may facilitate their con- version in the liver to inactive forms (Chatterton 1982). In healthy individuals 90% or more of cir- culating testosterone is bound to plasma proteins (cf Cheeseman 1982). Although most 178-hydroxy steroids bind to the major testosterone-binding slobulin, some synthetic hormones have low affin- ity for these proteins and thus are immediately available to intracellular receptors (Chatterton 1982), Derivatives of 19-nortestosterone and 17a- ‘methylated compounds have reduced binding to testosterone-binding globulin (Cheesman 1982; Toth & Zakar 1982) which may play a role in their enhanced biological potency relative to testoster- cone, Conversely, some steroids with high anabolic androgenic activity in vivo do not bind tightly to the intracellular androgen receptor. Saartok and coworkers (1984) have suggested that these steroids must work by an indirect mechanism such as transformation to active compounds or displace- ment of active steroids from serum binding pro- teins. As with the 17ealkyl function, substitutions at other positions in the testosterone molecule can also affect the stability for acting as substrate for tes- tosterone-metabolising enzymes. Specifically, 19- nortestosterone derivatives may bypass the action of Scereductase (Bergink et al. 1985; Liao et al. 1973), an enzyme present in prostate, kidney, thy- mus and spleen (Bergink et al. 1985), but absent in muscle; yet these steroid derivatives bind to the androgen receptor with equal or greater affinity than testosterone itself (Bergink et al. 1985; Saartok et al, 1984; Toth & Zakar 1982). 19-Nortestosterone is also less susceptible than testosterone for meta- bolic inactivation by 17-hydroxy steroid dehydro- on A Teste a on “ Ho es t a echelon osrone vcore Fig. Testosterone and its principal metabolites. 258 Med. Toxicol. Adverse Drug Exp. 4 (4) 1989 fe. Structural potency rlaionships of commonly used snabolesterids Major sroctral ‘Other sinctural Recommended ——Anabalijandrogenla_Relerence rmosication and rmoditeaton) eves dese range actvy® ‘tert name ‘kyation at C17 Oxandrlone ‘Onygen subsite 5-10 maidey 2026 Lennon & Saunders force (1964) Stanczole! Pyrazel ing tS malday 2os203 Pots ata. (1960, 3,2 potion Sala 1980) ‘onymetnolone Hycormethylene 5-10 mglday 821048 Dorian & kine sup at C2 (1969) Momanarostencions Double bond 5 mayety 2308 Camerine & Sala (1960, ater Sale (1980) Metntostosterone None 10-50 mgleay 1140 961.08 Dorian & kin! 1868) Testers Tenesterone Dortman & kine! (1869) cylonate None 50-4009 02902505 every 2-4 wat nant Nona 50-4009 vary 24 we propionate None 25-505 2.9 umask Nanetolone decane Lacks methyl group 50-100m= 8.20.492/031-041 Overdook & stoi very 3-4 ws Devsser (1961) | Rolatve (© mathyteststerono, estoctrone, or lsloslorone proplonsle as reference drug. information on addiions awrlds can be obtained from Pott aL (1976. genase (Bergink et al. 1985). In addition, steroid compounds vary in the effectiveness in which they resist aromatic conversion to oestrogen (Doerr & Prike 1974). Thus, the biochemical and molecular basis for steroid action and the dissociation of'an- abolic and androgenic potencies may be explained by the free hormone availability to tissue receptors, tissue specific enzymatic metabolism, and recep- torbinding parameters. 2. Benefits of Therapeutic Use 2.1 Replacement Therapy Anabolic-androgenic steroid treatment of hy- pogonadal adult men, particularly with parenteral administration of long-acting testosterone esters, can restore testosterone levels to within normal range in the circulation. Androgens are antigona- dotrophic and in healthy men with full gonadal ac- tivity anabolic agents suppress sperm production, (Mauss et al. 1975). In addition, testicular testos- terone concentrations must be at least 10 times higher than the peripheral testosterone levels 10 ‘maintain sperm production (Rommerts 1988). ‘Therefore, spermatogenesis is not restored with an- Ta, 1939 Fos GL, Simpson SL. Oral methytstoserone and jaundice Brith Medial Journal 255, 1959, Frankle MA, Eichber , Zachariah SB. Anabolic androgenic ‘oroids aha sioke in an athlete, Archives of Physi ed {sine and Rehabitation $5: 632€33, 1988 Freed DLI, Bunks AJ, Larson D, Busey [Anabolic seo in sles: crossover double in tl on weighs Beh Medial Jourat 2: 871-473, 1938 Goldity'S. Sox hormones snd hepetic neoplasia, Cancer Re- "seat 36:2584.2585, 1976 Golian B. Liver eareinomn in an athlete taking anabolic ste ‘oie Joueral ofthe American Oxeopthic Auossion 8556, 1985 ‘Geeeaor 8, George WR, Kadowits PJ, Wilton WR, Androgen- Taducd eahancement of vasealr etctvity. Canadian ogra of Physiology and Pharmacology 5212-22, 374 ‘Gribpin Hk, Flavell Matts SG. Made of action and wwe of ana- ‘bole stride British Joural of linia Pace 903.9, (976 Guyda H, Fieen H, Baley JD, Lebocut G, Beck JC. Medial ‘esearch Council Canada therapeutic ral of Ruma row Iormone: fist 5 years of therapy Canadian Medial Assoce Sion Journal 112, 1301-1308, 1973 athe SM, Hushwaba RS, Poster DM Siudles onthe metabolic ‘echanism of reduced high-density lipoproteins ing 488. olesterld therapy. Mtabola 32: 413420, 1983, Hagerman FC, Jone Witter P, Ranton R. The eft of a= oie steroid ingestion on serum enzyme and urine I elo eroid levels, Journal of Sports Medicine {3 207-295, 1973 Haromana G, Adicts K, Donike M, Schanzr W. Tesserone pplication nfuenees sympathcaeiviy of scar nerves {'non-rained and wained mice. Joural of Autonomic Nev us System 17 85100, 1986 Haupt Ha, Rovere GD. Aratlie steroid: review ofthe it erature, American Joural of Spars Medicine 1: 40-484 1984 Heath GW, Ehsan AA, Hagoerp JM, Hinder JM, Goldberg. ‘AP, Exercise training improves lipoprotein lipid roils a tients wih coronary artery disase, Americas Hoar Jourm Tos sao, 1983 Henderson JT, Richmond J, Sommerting MD, Androgeicana- bolle stefid therapy and hepateeear erinoma. Lancet 5h, 1973 ‘ermaidez-NitoL, Brugera M Bomb JA, Comacho L, Rozman ‘Banga ivercelladenomeaasoaie with longan adie isration ofan androgenioanabole steroid (mehendienone) Cancer a0: 1761-1764, 1977 Hersey GR, Knibos AV, Burkinshsw L, Morgan DB, Sones PRM, ‘al. Eloi of methandienone an the performance end Body fomposion of men undegaing ule waning. Cita Sc fence 0: 457-46, 18 ‘Hickson RC, Gals TM, Kurowsti TT, Daniels DG, Chaeton SIRT. Androgen and ghicocorboid mechani in exert induced cardia hypertrophy. American Joural of Physolony 246 (Heart Cireulauion and Physiology 13) HI-767, 1934 Hickson RC, Kurowat Anabolic sods tad taing, Cin in Spars Medicine 5: 461-169, (86 Hickson RC, Kurowskl TT, Andrews GH, Capacio JA, Chat terion Jr RT. Glucocortioid cytosol binding in exercise

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