Abuse of anabolic androgenic steroids and related substances in sport and exercise

Michael S Bahrke and Charles E Yesalis

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 increasing strength, lean body mass and sexual performance. However, there is no research indicating that androstenedione, or its related compounds, signicantly increases strength and/ or lean body mass in humans by increasing testosterone levels. The long-term 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. However, research demonstrates that DHEA supplementation does not increase serum testosterone concentrations or increase strength in men, and may acutely increase testosterone levels in women, thus producing a virilizing effect.
Addresses Human Kinetics, 1607 North Market Street, Champaign, Illinois 61825-5076, USA e-mail: mikeb@hkusa.com

in the biosynthesis pathway. This review briey discusses why AASs and related substances are used in sport and exercise, the incidence of their use, and the adverse health effects associated with their use.

Anabolic androgenic steroids

AASs are synthetic derivatives of testosterone. Because virtually every cell in the body has receptor proteins for AASs, the anabolic or androgenic response is determined by the location and type of cell, and not by the nature of the steroid [1]. Consequently, a pure anabolic steroid has yet to be discovered, and thus the formal name for this group of drugs is anabolic androgenic steroids (Boxes 1 and 2).
Mechanism of action

Current Opinion in Pharmacology 2004, 4:614620 This review comes from a themed issue on Endocrine and metabolic diseases Edited by Julia Buckingham and Brian Furman Available online 3rd October 2004 1471-4892/$ see front matter # 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2004.05.006

Anabolic steroids have effects on a wide variety of body tissues. Their fundamental physiological action is thought to occur through hormone binding to an intracellular protein in target tissue. This hormone-receptor complex then translocates to binding sites on chromatin, promoting gene transcription and subsequent synthesis of mRNA. The effects of steroids vary in different tissues according to the local environment, such as the types of enzyme (e.g. 5 alpha-reductase and aromatises) and receptor present. However, the specic biological mechanisms responsible for changes in strength and body composition are far from clear.
Reasons for use

Abbreviations AAS anabolic androgenic steroid Andro androstenedione DHEA dehydroepiandrosterone HDL-C high-density lipoprotein cholesterol

Introduction
Testosterone is the primary male sex hormone and is responsible for the androgenic and anabolic effects observed during male adolescence and adulthood. Related substances include anabolic androgenic steroids (AASs) as well as prohormones, androstenedione (Andro) and dehydroepiandrosterone (DHEA), which are steroids
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Testosterone itself is relatively ineffective when taken orally or injected in an aqueous solution because it is susceptible to relatively rapid breakdown by the liver before it can act on the target organ that, in the case of athletes, is skeletal muscle. Consequently, the chemical structure of testosterone has been modied to surmount this problem. Most commonly, AASs are taken orally or by intra-muscular injection. More recently, gels and creams are being used by elite athletes for the purpose of circumventing drug testing. The goals of individuals who use AASs and related substances in sport and exercise are dependent upon the activity in which they participate. Bodybuilders desire more lean mass and less fat. Weightlifters desire to lift the maximum amount of weight possible. Field athletes want to put the shot, or throw the hammer, discus or javelin, farther than their competitors or holders of previous records. Swimmers and runners hope to be able to perform frequent, high intensity, long duration workouts without physical breakdown. American football players want to increase lean mass
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Abuse of anabolic androgenic steroids and related substances in sport and exercise Bahrke and Yesalis 615

Box 1 Common US anabolic androgenic steroids.

Dianabol Fluoxymesterone Metandren Nortestosterone Oxandrolone Oxymetholone Stanozolol Testosterone

and years) administration of AASs on physique or physiological capacities have not been documented. Likewise, residual effects of AASs on physiological capacities after termination of use have not been established. Furthermore, although dose-response effects have been shown in males, the results of any dose response on physical/physiological capacities or performance in females are unknown.
Adverse health effects

and strength, so that they can be successful at the high school, university or professional level. Other AAS users simply want to look good which to many people means being big and muscular.
Incidence of use

Multiple US local, state and national level studies show that 4% to 6% (range of 3% to 12%) of high school males admit to using AASs at some time in their life [2]. Some of these studies also examined the use of AASs among high school females, nding that 1% to 2% reported having used AASs, with use by females having signicantly increased during the past decade [2]. According to results from the 2003 Monitoring the Future Study, 3.5% of high school seniors (males and females) have used AASs at some point in their lives with a dramatic increase in use by females over the past few years [3]. The use of AASs by adolescents is not limited to the US [2]. Surveys conducted in Canada, Sweden, England, Australia and South Africa have reported overall prevalence rates for highschool-aged students to range between 1% and 3% (males and females). Several surveys of Olympic competitors [2] suggest high levels of AAS use among athletes in a variety of sports.
Effectiveness

The short-term health effects of AASs have increasingly been studied, and several authors have reviewed the physiological and health effects of these drugs [610]. Although AAS use has been associated (mainly through case reports) with several adverse and even fatal effects, the incidence of serious effects reported has been extremely low [9]. However, for decades experts have consistently stated that the long-term health effects of AAS use are unknown [11]. Specically, long-term health effects related to type of steroid, dose, frequency of use, age at initiation and concurrent drug use have not been elucidated. Assessment of health consequences is confounded by the fact that many individuals use other performanceenhancing and illicit drugs concurrent with AASs and/or use large doses of AASs for prolonged periods of time, whereas others use therapeutic doses intermittently [1214]. Although the role of AASs in the etiology of various diseases in both animals and humans is still uncertain, steroid use in clinical trials and in laboratory studies is associated with numerous acute deleterious changes in risk factors for cardiovascular disease, liver tumors and infertility, and in the physiology of various sundry organs and body systems, suggesting potential for subsequent health problems (see also Update) [1,7,9,15]. The bestdocumented effects are those on the liver, serum lipids and reproductive system. Other areas of concern include the psyche and behavior, cardiomyopathy, coronary artery disease, cerebrovascular accidents, prostatic changes and immune function [9]. AAS use has been related to cardiovascular risk factors. The most important are changes in lipoprotein fraction, increased triglyceride levels, increased concentrations of several clotting factors, changes in the myocardium such as increased left ventricular mass and dilated cardiomyopathy [16], and hyperinsulinism and diminished glucose tolerance [6,7,9,1719]. Although these effects vary signicantly between different types and doses of AAS, and between individuals and situations [1], all of the effects (except postulated changes in the myocardium) are fully reversible within several months after cessation of AAS use [6,7,9]. Acute thrombotic risk has been linked to AAS use in case reports of non-fatal myocardial infarction and stroke in
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Individuals who are experienced in weight training and who continue training during AAS administration consistently experience increases in strength beyond those observed in control individuals from training alone [4 7] (see also Update). However, in the large majority of studies, most participants who were given AASs but were not experienced or pre-trained with weights gained no more strength than control individuals. Additionally, the effects of exceptionally high doses or prolonged (months
Box 2 Common non-US anabolic androgenic steroids.
Clostebol Drostanolone Ethylestrenol Mesterolone Methenolone Norethandrolone Oral turinabol Oxymesterone Stenbolone

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several athletes who were using AASs [19]. Although there is no direct evidence that AAS are thrombogenic in humans [20], the clinical circumstances of these reports suggest a possible causal relationship. These reports further suggest that if a causal relationship exists AASs could have serious short-term effects. Liver structure and function are also altered by administration of AASs; these changes include cholestatic jaundice, peliosis hepatis, hepatocellular hyperplasia and hepatocellular adenomas [9,21,22]. It has not been demonstrated convincingly that AAS can cause, at least with therapeutic doses, development of hepatocellular carcinomas. Virtually all histological changes in the liver are associated with use of 17 a-alkylated (oral) AASs [1,7,9,10], and the cause-and-effect relationship between oral AASs and these conditions is strengthened by the return of normal blood values and excretory function, the regression of tumors, general recovery and a return towards normal liver function following cessation of AAS use [9]. The effects of AASs on the male reproductive system include reductions in the levels of endogenous testosterone, gonadotrophic hormones and sex hormonebinding globulin; reductions in testicle size, sperm count and sperm motility; and alterations in sperm morphology [7,9]. When AAS use is stopped, the testes resume sperm production. In women, AASs are associated with several adverse effects, some of which are not reversible upon discontinuation of AAS use [23]. These adverse effects include menstrual abnormalities, deepening of the voice, shrinkage of the breasts, malepattern baldness and an increase in sex drive, acne, body hair and clitoris size. Premature halting of growth in younger users has not been systematically studied, although such effects have been described in case reports for decades [24]. A positive association between endogenous testosterone levels and aggressive behavior in males has increasingly been established [25]. Although studies using moderate doses of exogenous testosterone for contraceptive and clinical purposes reveal few adverse effects on male sexual and aggressive behavior, other investigations and case reports of athletes using substantially higher doses suggest the possibility of affective and psychotic syndromes (some of violent proportions), psychological dependence and withdrawal symptoms [25]. Whereas several recently published reports support a pattern of association between the use of AASs by athletes and increased levels of irritability, aggression, personality disturbance and psychiatric diagnoses, others do not [5,26]. Only a few prospective, blinded studies documenting aggression and adverse overt behavior resulting from AAS use have been reported [2730]. Although prevalence of AAS dependency is difcult to determine, and
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there might be as many as 300 000 AAS users yearly in the US [31], it appears that only a small percentage of users experience psychological dependence requiring clinical treatment.

Androstenedione
Andro is an AAS produced either by the gonads and adrenal glands, or from DHEA by peripheral transformation [32]. Along with DHEA, Andro is often described as a prohormone or hormone precursor. Andro is marketed to increase blood testosterone concentrations for the purposes of increased strength, lean mass and sexual performance. Andro does not have any known clinical applications. Recommended daily dosages for oral preparations range from 1001200 mg/d. Although Andro is the most popular street name, numerous brands of supplements containing androstenedione and other related compounds are available. Other substances chemically and pharmacologically related to Andro include 5-androstendione, 4-androstendiol, 5-androstendiol, 19-norandrost-4-enedione, 19-norandrost-5enediol and 19-norandrost-4-enediol [33]. Andro and its analogs are also available as sublingual sprays, patches and percutaneous gels. By itself, Andro is a relatively weak steroid whose anabolic activity is one-fth to one-tenth that of testosterone. Womens production of Andro is approximately one-third greater than that of men [32]. In both genders, Andro is an immediate precursor of testosterone, as well as estradiol and estrone [32]. Aromatase, the enzyme that converts androstenedione to estrone and estradiol, is found in various cells, including skeletal muscle and fat. Consequently, increased levels of Andro could be accompanied not only by increased testosterone levels but also by increased production of estrogens. The conversion of Andro to testosterone is accomplished by means of the enzyme 17-dehydrogenase, which is also found in most cells of the body [32]. This enzymatic process is regulated by the negative feedback mechanisms that maintain homeostasis. Thus, if a male with normal testosterone levels ingested large amounts of Andro, one would predict from this feedback loop that the body would produce only enough 17-dehydrogenase to, at best, result in a modest increase in testosterone production. The remainder of the Andro would be metabolized and excreted. If, however, Andro does signicantly increase serum testosterone levels, one would expect, in conjunction with strength training and/or conditioning, signicant increases in anabolism and anti-catabolism commonly associated with testosterone administration [4,5]. Although there is generally a lack of national-level data on the incidence of Andro use, according to a 2002 US Department of Health and Human Services survey approximately one in 40 high school seniors reported that they had used Andro during the past year [34].
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There have been several studies [3544] that have administered 72 mg to 300 mg oral Andro and/or its related compounds daily for periods of 128 days, primarily to assess the effect on serum testosterone levels. In some of these studies, serum testosterone levels increased [36,38,4044], whereas in others they did not [35,37, 39]. Undoubtedly, many Andro users consume daily doses substantially higher than those used in the above studies. However, in a recent investigation [45], four weeks of Andro supplementation (200 mg/d) diminished the treatment response (serum androstenedione) in middleaged men. More importantly, no study has shown that Andro or its related compounds signicantly increases strength and/or lean mass by way of increasing blood testosterone levels. Five studies [4650] lasting 812 weeks, using healthy males (ages 1960) who were given 100 mg or 300 mg oral Andro or its related compounds per day in conjunction with strength training regimens, failed to detect significant increases in strength or muscle mass. The long-term health effects of prolonged Andro (or its related compounds) supplementation are unknown. However, recent studies have noted acute adverse effects [35,38,4143,4648,50]. At least seven studies [35,38,41 43,46,48] have reported a signicant increase in blood estrogen levels (estrone and estradiol) in healthy males with oral Andro supplementation. Elevated estrogen levels in males are associated with gynecomastia and other feminizing effects, as well as an increased risk of cardiovascular disease [9]. Several studies [43,46,48,50] found that Andro and/or its related compounds adversely affected blood lipid levels through a signicant reduction in high-density lipoprotein cholesterol (HDL-C). This reduction in HDL-C is highly consistent with ndings from numerous studies into the effects of anabolic steroids on blood lipid levels [9]. If decreased HDL-C levels were maintained, an increased risk of cardiovascular disease would result. The literature clearly supports the hepatotoxicity of many oral anabolic steroids. As the oral Andro-related decrease in HDL-C is probably the result of an increase in hepatic triglycerol lipase activity, it is prudent to assume prolonged use at high doses could adversely affect other aspects of liver structure and function [9]. There are only two studies into the effects of Andro on women [51,52]. An early study administered 100 mg/d to two women and found a signicant increase in blood testosterone levels. In the most recent investigation [52], 100 mg or 300 mg administered daily to women was found to increase testosterone concentrations. The use of Andro by women should be avoided, given the possibility of signicant increases in blood testosterone levels and the attendant risk of virilization [23]. Sustained
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elevated testosterone levels in children have been associated with precocious puberty and premature epiphyseal closure leading to diminished adult height [24]. Because Andro can pose long-term health risks for young people, athletes and other consumers, the US Food and Drug Administration recently sent letters to 23 companies that manufacture or distribute Andro, warning the companies that they will have to cease production unless they can prove that Andro is safe [53]. As of May 2004, legislation to ban over-the-counter sales of muscle-building supplements and other steroid-related substances is awaiting passage by the US Congress.

Dehydroepiandrosterone
DHEA is a weak androgen secreted by the adrenal glands (with small amounts produced by the ovary) and is a precursor of testosterone and estrogen [32]. Athletes use it in an attempt to elevate testosterone levels and ultimately to increase muscle mass and strength. In addition, it is advertised as an anti-obesity and anti-aging supplement also capable of improving libido, vitality and immunity levels [5456]. However, research to support these claims is limited. Although the prevalence and incidence of DHEA usage are unknown, it is a commonly used dietary supplement. Transdermal DHEA patches have recently been developed to enhance bioavailablity [57]. Between 50 mg/d and 100 mg/d is the most commonly recommended dosage of DHEA. However, dosages of up to 1600 mg/d have been investigated in men without increasing serum testosterone levels [58]. More importantly for athletes, additional studies suggest that DHEA ingestion neither enhances serum testosterone concentration nor does it cause adaptations associated with resistance training in young men [59,60]. In women, larger doses have been shown to increase serum testosterone levels and cause adverse virilizing effects such as hirsuitism and acne [61]. Much of the research examining the anti-obesity effects of DHEA has been conducted using rats. One study shows that DHEA is protective against accumulation of visceral fat and development of muscle insulin resistance in rats fed a high-fat diet [62]. DHEA has also been found to exert a small independent effect on leptin levels in obese rats [63]. In addition, long-term administration of DHEA has been shown to have different effects on energy intake of young, lean and obese male rats, with only the obese rats exhibiting less energy intake relative to body weight compared with controls of the same body size [64]. A recent investigation examining the chronic effects of DHEA administration on rat adipose tissue metabolism suggests that the anti-obesity action of DHEA may be related to changes in lipase activities and in b3-adrenoceptor density, and is dependent upon the ovarian status of the animal [65].
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In humans, one study failed to demonstrate any effect of DHEA on total weight, body fat mass, fat distribution, insulin sensitivity or lipid status in obese young men [66]. In a related study, DHEA did not inuence energy or protein metabolism in healthy men [67]. Other investigations show no effect of DHEA supplementation on serum lipids, bone markers, body composition or exercise capacity [68,69,70]. Although there is potential for positive immune effects of DHEA in elderly humans [55,56], the effects are not well documented, and a recent study of chronic intake of a dietary supplement containing DHEA, Andro and herbal extracts reported a minimal effect on immune function in middle-aged men [71]. Beyond the virilizing effects mentioned above, short-term use of DHEA by women can result in reduced HDL-C, impaired insulin sensitivity and glucose tolerance [61]. Adverse effects have not been thoroughly investigated in young and middle-aged men. However, owing to the potential for androgenic effects, the use of DHEA is not recommended for young children and women. The longterm effects of DHEA use are unknown, especially in athletes using large doses in conjunction with other performance-enhancing substances.

might be able to inject genes to enhance performance and appearance. In the upcoming few decades, genetic engineering could profoundly alter the course of competitive sport by allowing scientists to create the perfect athlete, although risks for doing so may be high.

Update
Herbst and Bhasin [72] highlight recent data demonstrating the direct anabolic effects of androgens on mammalian skeletal muscle and review the mechanisms by which testosterone regulates body composition. Profound unfavorable effects on lipids and lipoproteins, leading to an increased atherogenic lipid prole that persisted after AAS withdrawal, have recently been reported by Hartgens et al. [73].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest 1. 2. Kruskemper HL: Anabolic steroids. New York: Academic Press; 1968. Yesalis CE, Bahrke MS, Kopstein AN, Barsukiewicz CK: Incidence of anabolic steroids use: a discussion of methodological issues. In Anabolic Steroids in Sport and Exercise, Second Edition. Edited by Yesalis CE. Champaign: Human Kinetics; 2000: 73-115.

Conclusions
AASs are synthetic derivatives of testosterone. They are usually administered orally or by injection, and are used by athletes to enhance performance and appearance. Research ndings indicate that AAS use results in increased body weight and muscular strength. Although the long-term effects of AASs are still unknown, the bestdocumented physiological effects are those on the liver, serum lipids and reproductive system. Increased levels of irritability, aggression, personality disturbance and psychiatric diagnoses are among some of the adverse psychological effects of AASs. Androstenedione is an anabolic steroid produced primarily in the testes, ovaries and adrenal cortex. It has also become a very popular dietary supplement. However, research does not support the use of Andro to enhance performance. There is a lack of research regarding the long-term health effects of Andro supplementation. DHEA is a weak anabolic steroid secreted by the adrenal glands. It is used as a nutritional supplement because of its purported effects on serum testosterone levels. However, research demonstrates that DHEA supplementation does not increase serum testosterone concentrations or increase strength in men, and it may have virilizing effects on women. Some experts believe the current use of AASs and related substances could soon become passe, because athletes
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3. Monitoring the Future Study. Ann Arbor: University of Michigan;  2003. [URL:http://www.monitoringthefuture.org]. Monitoring the Future is an ongoing study of behaviors (including drug use), attitudes and values of American secondary school students, college students and young adults. Each year, a total of about 50 000 8th, 10th and 12th grade students are surveyed. 4. Friedl KE: Effect of anabolic steroid use on body composition and physical performance. In Anabolic Steroids in Sport and Exercise, Second Edition. Edited by Yesalis CE. Champaign: Human Kinetics; 2000:139-174. Bhasin S, Storer T, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R: The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996, 335:1-7. Haupt H, Rovere G: Anabolic steroids: a review of the literature. Am J Sports Med 1984, 12:469-484. Wright JE: Steroids and athletics. Exerc Sport Sci Rev 1980, 8:149-202. Lamb D: Anabolic steroids in athletics: how well do they work and how dangerous are they? Am J Sports Med 1984, 12:31-38. Friedl KE: Effect of anabolic steroids on physical health. In Anabolic Steroids in Sport and Exercise, edn 2. Edited by Yesalis CE. Champaign: Human Kinetics; 2000:175-225.

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15. American College of Sports Medicine, Position stand on the use of anabolic-androgenic steroids in sports. Sports Med Bull 1984, 19:13-18. 16. Urhausen A, Albers T, Kindermann W: Are the cardiac effects of  anabolic steroid abuse in strength athletes reversible? Heart 2004, 90:496-501. Several years after discontinuation of anabolic steroid abuse, strength athletes still show a slight concentric left ventricular hypertrophy in comparison with steroid-free strength athletes. 17. Glazer G: Atherogenic effects of anabolic steroids on serum lipid levels. Arch Intern Med 1991, 151:1925-1933. 18. Sullivan ML, Martinez CM, Gennis P, Gallagher EJ: The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis 1998, 41:1-15. 19. Rockhold R: Cardiovascular toxicity of anabolic steroids. Annu Rev Pharmacol Toxicol 1993, 33:497-520. 20. Ansell J, Tiarks C, Fairchild V: Coagulation abnormalities associated with the use of anabolic steroids. Am Heart J 1993, 125:367-371. 21. Dickerman RD, Pertusi RM, Zachariah NY, Dufour DR, McConathy WJ: Anabolic steroid-induced hepatotoxicity: is it overstated? Clin J Sport Med 1999, 9:34-39. 22. Soe K, Soe M, Gluud C: Liver pathology associated with the use of anabolic steroids. Liver 1992, 12:73-79. 23. Elliot DL, Goldberg L: Women and anabolic steroids. In Anabolic steroids in sport and exercise, edn 2. Edited by Yesalis CE. Champaign: Human Kinetics; 2000:225-246. 24. Rogol A, Yesalis CE: Anabolic-androgenic steroids and the adolescent. Pediatr Ann 1992, 21:175-188. 25. Bahrke MS: Psychological effects of endogenous testosterone and anabolic-androgenic steroids. In Anabolic Steroids in Sport and Exercise, edn 2. Edited by Yesalis CE. Champaign: Human Kinetics; 2000:247-278. 26. Yates WR, Perry PJ, MacIndoe J, Holman T, Ellingrod VL: Psychosexual effects of three doses of testosterone cycling in normal men. Biol Psychiatry 1999, 45:254-260. 27. Hannan CJ, Friedl KE, Zold A, Kettler TM, Plymate SR: Psychological and serum homovanillic acid changes in men administered androgenic steroids. Psychoneuroendocrinology 1991, 16:335-342. 28. Pope HG, Kouri EM, Hudson JI, TM: Effects of supraphysiologic doses of testosterone on mood and aggression in normal men. Arch Gen Psychiatry 2000, 57:133-140. 29. Kouri EM, Lukas SE, Pope HG, Oliva PS: Increased aggressiveness responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate. Drug Alcohol Depend 1995, 40:73-79. 30. Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, Rubinow DR: Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 1993, 269:2760-2764. 31. Kenney J: Extent and nature of illicit trafcking in anabolic steroids. In Report of the International Conference on the Abuse and Trafcking of Anabolic Steroids. Washington, DC: United States Drug Enforcement Administration Conference Report; 1994:34-35. 32. Yen S, Jaffe R: Reproductive endocrinology. Philadelphia: Saunders; 1978. 33. Yesalis CE: Medical, legal, and societal implications of androstenedione use. JAMA 1999, 281:2043-2044. 33. Yesalis CE: Medical, legal, and societal implications of androstenedione use. JAMA 1999, 281:2043-2044. 34. CNN Com: FDA begins crackdown on supplement andro. March 11, 2004. [URL: http://www.cnn.com/2004/HEALTH/03/11/ andro.crackdown/index.html]. 35. Rasmussen BB, Volpi E, Gore DC, Wolfe RR: Androstenedione does not stimulate muscle protein anabolism in young healthy men. J Clin Endocrinol Metab 2000, 85:55-59. www.sciencedirect.com

36. Uralets V, Gilette P: Over-the-counter anabolic steroids 4-androsten-3,17-dione; 4-andeosten-3,17-diol; and 19-nor-4-androsten-3, 17-dione excretion studies in men. J Anal Toxicol 1999, 23:357-366. 37. Ballantyne CS, Phillips SM, MacDonald JR, Tarnopolsky MA, MacDougall JD: The acute effects of androstenedione supplementation in healthy young males. Can J Appl Physiol 2000, 25:68-78. 38. Leder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS: Oral androstenedione administration and serum testosterone concentrations in young men. JAMA 2000, 283:779-782. 39. Colker CM, Antonio J, Kalman D: The metabolism of orally ingested 19-nor-4-androstene-3,17-dione and19-nor-4androstene-3,17-diol in healthy, resistance-trained men. J Strength Cond Res 2001, 15:144-147. 40. Leder BZ, Catlin DH, Longcope C, Ahrens B, Schoenfeld DA, Finkelstein JS: Metabolism of orally administered androstenedione in young men. J Clin Endocrinol Metab 2001, 86:3654-3658. 41. Brown GA, Vukovich MD, Martini ER, Kohut ML, Franke WD, Jackson DA, King DS: Effects of androstenedione-herbal supplementation on serum sex hormone concentrations in 30- to 59-year-old men. Int J Vitam Nutr Res 2001, 71:293-301. 42. Brown GA, Martini ER, Roberts BS, Vukovich MD, King DS: Acute hormonal response to sublingual androstenediol intake in young men. J Appl Physiol 2002, 92:142-146. 43. Brown GA, Vukovich MD, Martini ER, Kohut ML, Franke WD, Jackson DA, King DS: Endocrine and lipid responses to chronic androstenediol-herbal supplementation in 30 to 58 year old men. J Am Coll Nutr 2001, 20:520-528. 44. Earnest C, Olson MA, Broeder CE, Breuel KF, Beckham SG: In vivo 4-androstene-3,17-dione and 4-androstene-3,17-diol supplementation in young men. Eur J Appl Physiol 2000, 81:229-232. 45. Beckham SG, Earnst CP: Four weeks of androstenedione  supplementation diminishes the treatment response in middle aged men. Br J Sports Med 2003, 37:212-218. Continued androstenedione supplementation resulted in a diminished treatment response. 46. King D, Sharp RK, Vukovich MD, Brown GA, Reifenrath TA, Uhl NL, Parsons KA: Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men. JAMA 1999, 281:2020-2028. 47. Wallace MB, Lim J, Cutler A, Bucci L: Effects of dehydroepiandrosterone vs. androstenedione supplementation in men. Med Sci Sports Exerc 1999, 31:1788-1792. 48. Brown GA, Vukovich MD, Reifenrath TA, Uhl NL, Parsons KA, Sharp RL, King DS: Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab 2000, 10:340-359. 49. Van Gammeren D, Falk D, Antonio J: The effects of supplementation with 19-nor-4-androstene-3,17-dione and19-nor-4-androstene-3,17-diol on body composition and athletic performance in previously weight-trained male athletes. Eur J Appl Physiol 2001, 84:426-431. 50. Broeder CE, Quindry J, Brittingham K, Panton L, Thomson J, Appakondo S, Breuel K, Byrd R, Douglas J, Earnest C et al.: The Andro Project: physiological and hormonal inuences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program. Arch Intern Med 2000, 160:3093-3104. 51. Mahesh V, Greenblatt R: The in vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol (Copenh) 1962, 41:400-406. 52. Brown GA, Dewey JC, Brunkhorst JA, Vukovich MD, King DS:  Changes in serum testosterone and estradiol concentrations Current Opinion in Pharmacology 2004, 4:614620

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following acute androstenedione ingestion in young women. Horm Metab Res 2004, 36:62-66. Results from this study indicate that, in contrast to men, androstenedione intake in women increases serum testosterone concentrations. 53. Kaufman M: FDA seeks to halt sales of supplement. Washington DC: The Washington Post; March 12 2004: A03. 54. Yen SS, Morales AJ, Khorram O: Replacement of DHEA in aging men and women. Potential remedial effects. Ann N Y Acad Sci 1995, 774:128-142. 55. Khorram O, Vu L, Yen SS: Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men 2. J Gerontol A Biol Sci Med Sci 1997, 52:M1-M7. 56. Ledochowski M, Murr C, Jager M, Fuchs D: Dehydroepiandrosterone, ageing and immune activation. Exp Gerontol 2001, 36:1739-1747. 57. Minghetti P, Cilurzo F, Casiraghi A, Montanari L, Santoro A: Development of patches for the controlled release of dehydroepiandrosterone. Drug Dev Ind Pharm 2001, 27:711-717. 58. Nestler JE, Barlascini CO, Clore JN, Blackard WG: Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 1988, 66:57-61. 59. Brown GA, Vukovich MD, Reifenrath TA, Uhl NL, Parsons KA, Sharp RL, King DS: Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab 2000, 10:340-359. 60. Brown GA, Vukovich MD, Sharp RL, Reifenrath TA, Parsons KA, King DS: Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men. J Appl Physiol 1999, 87:2274-2283. 61. Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS: The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol 1998, 49:421-432. 62. Hansen PA, Han DH, Nolte LA, Chen MM, Holloszy JO: DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol 1997, 273:R1704-R1708. 63. Richards RJ, Porter JR, Svec F: Serum leptin, lipids, free fatty acids, and fat pads in long-term dehydroepiandrosterone-treated Zucker rats. Proc Soc Exp Biol Med 2000, 223:258-282. 64. Richards RJ, Porter JR, Svec F: Long-term oral administration of dehydroepiandrosterone has different effects on energy

intake of young lean and obese male Zucker rats when compared to controls of similar metabolic body size. Diabetes Obes Metab 1999, 1:233-239. 65. Mauriege P, Martel C, Langin D, Lacaille M, Despres JP,  Belanger A, Labrie F, Deshaies Y: Chronic effects of dehydroepiandrosterone on rat adipose tissue metabolism. Metabolism 2003, 52:264-272. Results from this investigation suggest that the anti-obesity effects of DHEA may be related, in part, to changes in lipase activities and in b3adrenoceptor density, and it is dependent upon the ovarian status of the animal. 66. Usiskin KS, Butterworth S, Clore JN, Arad Y, Ginsberg HW, Blackard WG, Nestler JH: Lack of effect of dehydroepiandrosterone in obese men. Int J Obes 1990, 14:457-463. 67. Welle S, Jozefowicz R, Statt M: Failure of dehydroepiandrosterone to inuence energy and protein metabolism in humans. J Clin Endocrinol Metab 1990, 71:1259-1264. 68. Arlt W, Callies F, Koehler I, van Vlijmen JC, Fassnacht H, Strasburger CJ, Seibel MJ, Huebler D, Ernst M, Oettel M et al.: Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion. J Clin Endocrinol Metab 2001, 86:4686-4692. 69. Sulcova J, Hill M, Hampl R, Ceska R, Novacek A, Hampl R, Starka L: Effects of transdermal application of 7-oxo-DHEA on the levels of steroids, gonadotropins and lipids in men. Physiol Res 2000, 49:685-693. 70. Jedrzejuk D, Medras M, Milewicz A, Demissie M:  Dehydroepiandrosterone replacement in healthy men with age-related decline of DHEA-S: effects on fat distribution, insulin sensitivity and lipid metabolism. Aging Male 2003, 6:151-156. Results of this study did not reveal any signicant changes in fat distribution, insulin sensitivity and lipid metabolism following DHEA replacement; however, there was a statistically signicant increase in DHEAsulphate levels following DHEA treatment. 71. Kohut ML, Thompson JR, Campbell J, Brown GA, Vukovich MD,  Jackson DA, King DS: Ingestion of a dietary supplement containing dehydroepiandrosterone (DHEA) and androstenedione has minimal effect on immune function in middle-aged men. J Am Coll Nutr 2003, 22:363-371. Results from this investigation suggest that although chronic intake of a complex dietary supplement containing DHEA, androstenedione and herbal extracts increases serum androgen levels it has minimal effect on immune function in middle-aged men. 72. Herbst KL, Bhasin S: Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care 2004, 7:271-277. 73. Hartgens F, Rietjens G, Keizer HA, Kuipers H, Wolffenbuttel BH: Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a). Br J Sports Med 2004, 38:253-259.

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