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Olympic Games

Newer drugs used to enhance sporting performance

Michael C Kennedy

MJA 2000; 173: 314-317

Controversy surrounding drug use in sport makes this a difficult area for rigorous research. However, it is striking that what data there are on drugs currently used for performance enhancement rarely indicate any clear benefit.

Testosterone precursors - 5 Alpha-dihydrotestosterone - Clenbuterol - Erythropoietin - Insulin - Growth hormone - Insulin-like growth factors - beta-Hydroxy-beta-methylbutyrate - Conclusions - Disclaimer - Acknowledgements - References - Authors' details
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  Historically, many different drugs have been used in attempts to enhance sporting performance. Strychnine, cocaine, heroin and ethyl alcohol were in common use at the turn of the century, but they were later supplanted by amphetamines, pseudoephedrines and anabolic steroids. Caffeine has remained popular for over a hundred years and anabolic steroids have been in steady use since the early 1960s.1

Nevertheless, the magic elixir of sporting performance remains elusive. The search continues in the face of unsatisfactory results, adverse reactions and drug control efforts within sport and through legislation. With advances in drug development there is also the further hope that new drugs will be difficult for laboratories to detect.

My aim in this article is to provide a brief review of some of the newer drugs that have become popular over about the past 10 years, providing, where possible, doses used, their International Olympic Committee (IOC) status, their adverse reaction profiles, and methods used to detect them. The best known of these newer drugs are the testosterone precursors, dihydrotestosterone, clenbuterol, growth hormone, insulin-like growth factor, insulin, erythropoietin and beta-hydroxy-beta-methylbutyrate. Unfortunately, there are few published data quantifying the present use of these drugs in Australia. The doses of drug taken are difficult to ascertain -- those in this article have been obtained largely from Internet searches.

There are many difficulties in deciding whether a drug actually enhances sporting performance. While a laboratory study may find a small change in strength or some other physiological parameter such as maximal oxygen uptake, this may not translate to increased performance in actual competition.

When considering adverse reaction profiles it must be remembered that most of the drugs mentioned here are not subjected to the postmarketing surveillance procedures used for newly released therapeutic drugs. It is necessary to rely almost entirely on reports by interested professionals or projections made from the known pharmacological properties of the drug. There are no data on the effects of these agents on developing fetuses, children or adolescents.


Testosterone precursors
The pathway of testosterone synthesis is shown in the Box. Testosterone precursors are taken with the aim of increasing testosterone levels without the need for testosterone injections, and also in the hope of foiling current drug detection methods. The most popular agents in this group of drugs are dehydroepiandrosterone and androstenedione.

Dehydroepiandrosterone (DHEA) has been the subject of a recent comprehensive review in the Journal.2 This drug is a weak androgen that circulates in two interconvertible forms -- unconjugated DHEA and DHEA sulfate, the latter in higher concentration. The physiological role of DHEA remains unclear. Concentrations fall with age and it has been trialled as therapy in a wide variety of conditions with little evidence of a positive effect, apart from increasing well-being and sexuality (term derived from a psychometric questionnaire) in women with adrenal insufficiency.3 While one study showed an increase in lean body mass, this was not confirmed in another. There is one study of the effects of DHEA on strength and aerobic performance; a comparison of DHEA, androstenedione and placebo in 40 healthy middle-aged men did not show any advantage of the steroid precursors over placebo.4 The effects of long-term, high-dose administration are unknown.2 In Australia, there has been one high-profile case involving a footballer receiving DHEA for chronic fatigue syndrome. After legal argument, the player was allowed to continue playing if he ceased taking the drug.2

Androstenedione and related compounds, such as 5-androstenedione, 4-androstenediol, 5-androstenediol, 19-norandrost-4-enedione, 19-norandrost-5-enediol and 19-norandrost-4-enediol, have become extremely popular in the United States since baseball home run record holder Mark McGwire admitted using androstenedione.5 As with DHEA, androstenedione is used in an attempt to increase testosterone concentrations.

There is a well-conducted, double-blind controlled trial evaluating the effects of androstenediones on endocrine function, body composition and strength. In the first part of this study, 10 people received 100 mg of androstenedione orally for two days, and then received the same regimen of placebo one week later; the effects on serum testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) were measured. In the second part of the study, 300 mg of androstenedione or placebo was given in a cyclical dosing regimen over eight weeks to 20 men, only one of whom had any previous experience in resistance training. Strength was assessed by a number of resistance exercises and training was standardised over eight weeks. Compared with placebo, androstenedione did not increase concentrations of free or total testosterone and did not increase strength or alter lean body mass, but it did increase serum concentrations of oestradiol. Levels of high-density lipoprotein (HDL) became depressed in the treatment group compared with pretreatment levels. While this study used lower doses than are often used by athletes, these results suggest it is unlikely that androstenedione increases sporting performance.6

While it did not evaluate sporting performance, one study found that 300 mg of oral androstenedione given to 14 volunteers caused a significant rise in testosterone levels.7 There was also considerable individual variation in the levels, which suggests variations in metabolism of the drug.

Dose: Up to 1100 mg/day of DHEA; athletes take doses of androstenedione which exceed the dose used in these studies.

IOC status: Banned (but androstenedione is not banned in major league American baseball).

Adverse reactions: There do not appear to be any immediate clinically detectable adverse effects. Long term administration of testosterone precursors will reduce HDL, and so predispose some athletes to coronary disease. Elevated levels of oestrone and oestradiol could have effects on malignant processes and also cause gynaecomastia.

Detection: The testosterone/epitestosterone (T/E) ratio in urine is used to detect exogenous testosterone. A ratio greater than 6:1 is usually taken as an indication of misuse. DHEA has been reported to increase the T/E ratio in some, but not all, studies. Doses as low as 50 mg for three days can alter the ratio to more than 6:1 in some, but not all, individuals, suggesting there may be individual differences in the metabolism of this drug.8 In addition to the T/E ratio there has been considerable progress in detecting exogenous testosterone by measuring the ratio of the carbon isotopes 12C and 13C. This method may become one of the major means of detecting steroid misuse in the near future.


5 Alpha-dihydrotestosterone
5 Alpha-dihydrotestosterone (DHT) is the principal active metabolite of testosterone and has a greater binding affinity to the androgen receptor than testosterone. It transforms more readily to the steroid receptor complex and dissociates from this complex more slowly than does testosterone. It is used to enhance performance in a variety of sports.

DHT has been a licensed pharmaceutical in some countries and gained considerable prominence when 11 Chinese swimmers were found to have taken the drug in the 1994 Asian Games in Tokyo. There are no published data showing there is any effect on sporting performance.

Dose: Probably greater than 25 mg twice daily, percutaneously.

IOC status: Banned.

Adverse reactions: While there are few data, it is reasonable to expect that typical androgenic adverse effects such as baldness in males, hirsutism in females and acne will occur.

Detection: DHT does not alter the T/E ratio, but it can be detected by determining the ratios of other steroids to epitestosterone and LH.9

Clenbuterol Clenbuterol is a beta2-agonist with a half-life of 35 hours which came to prominence during the Barcelona Olympics.10,11 It is marketed in some countries as a bronchodilator and is not approved for human use in Australia.

There are excellent data showing that other beta2-agonists allow asthmatic athletes to compete at international level, but few showing that these drugs improve strength or aerobic performance in people who do not have asthma. In animals large doses of clenbuterol have been shown to increase lean body mass.12 Athletes usually take clenbuterol to increase muscle mass, and it is taken orally in conjunction with anabolic steroids. There are no data showing clenbuterol alters athletic performance or strength in healthy people.

Dose: Up to 60-120 mg/day may be taken in cycles of 6-12 weeks' duration.

IOC status: Banned.

Adverse reactions: Clenbuterol will produce a predictable tremor and tachycardia. There are anecdotal reports of sudden death in two bodybuilders.13

Detection: Clenbuterol can be easily detected in urine by mass spectroscopy.

Erythropoietin Autologous and homologous transfusions, commonly known as blood doping, have been used to enhance performance since the 1970s. This practice received considerable prominence when some members of the 1984 United States Olympic cycling team confessed to receiving transfusions. Endurance athletes experience very complex physiological adaptations such as an increase in red cell mass and a decrease in haemoglobin concentration resulting from a considerable increase in plasma volume. It appears that aerobic performance is improved by blood transfusion in some circumstances.14

The ready availability of synthetic erythropoietin (r-HuEPO) scandalised the 1998 Tour de France.15 This substance has been commercially available since that time and has essentially replaced transfusion as a means of blood doping. There is no doubt that rHuEPO can enhance physical performance in patients with anaemia secondary to renal failure. Both haemoglobin levels and physical performance were shown to have increased in 24 young healthy males who received r-HuEPO for seven weeks.16 As it seems to be widely accepted that r-HuEPO will increase aerobic performance, it is not surprising that it is widely misused in endurance sport. As the haematocrit may be measured to detect misuse, plasma expanders are sometimes used to avoid detection.

Dose: Often three injections per week for six weeks. Vials contain varying concentrations, so doses are likely to vary considerably.

IOC status: Blood transfusions and r-HuEPO are both banned.

Adverse reactions: As dehydration will increase blood viscosity during any endurance event, the most serious adverse reactions to r-HuEPO seem likely to result from vascular events caused by thromboses when blood viscosity is markedly increased. However, there are no reported cases of this in the refereed literature. Sporting magazines and the lay press have reported deaths allegedly caused by r-HuEPO. These deaths have not occurred during exercise, but during periods of physical inactivity or sleep.17

Detection: Difficult because of its short half-life of 5-6 hours and the long duration of action on erythropoiesis. r-HuEPO differs from the endogenous hormone in its carbohydrate moiety, and this confers different physicochemical properties, thus allowing the potential for it to be detected in both blood and urine.18 Alternative methods of detection rely on measurement of various haematological and ferruginous parameters in capillary samples of blood.19,20 At present there are a number of studies under way to ascertain which of these methods would be fair to athletes and also stand up to the rigours of legal argument in the setting of a tribunal. On 1 August 2000, the Scientific Committee of the IOC approved a test based on urine and blood analysis (N Vance, Programme Manager, Doping Control, Sydney 2000 Olympics, personal communication).

Insulin Insulin is an anabolic hormone, so it is not surprising that it has become popular in power sports. There are no studies showing an enhancement of sporting performance and, not surprisingly, there are reports of hypoglycaemia in users.21

Insulin is often used in association with anabolic steroids. Clearly, medical practitioners need to be mindful of this area of misuse should unknown patients request renewal of a prescription for insulin. Insulin is also available in Australia without a prescription if the patient is prepared to pay the over-the-counter price, so this caution also applies to dispensing pharmacists.

Dose: 2-15 U 20-40 minutes after exercise with a carbohydrate load, or as 10 U twice daily.22

IOC status: Allowed for athletes with insulin-dependent diabetes.

Adverse reactions: Hypoglycaemia.

Detection: There are numerous analytical methods of detecting insulin. No criteria have been set for insulin misuse in sport.


Growth hormone
Growth hormone (GH) has become popular since the advent of DNA-derived production removed concerns about human pituitary sources and Creutzfeldt-Jakob disease. Athletes usually take it in association with anabolic steroids. There is no doubt about the anabolic effects of the hormone -- the increase in muscle strength in hypopituitary patients receiving treatment and observations that the hormone is released in response to exercise. There is also no doubt that legitimate sources are being diverted into the sporting area.23 In spite of its widespread use there are no data showing an enhancement of sporting performance. One well conducted investigation in experienced training weightlifters showed that 14 days of growth hormone use did not alter protein synthesis or breakdown.24 Another study of exercising elderly men did not show any increase in strength.25 While muscle protein is probably not altered, a placebo-controlled trial showed that lean body weight increased as a result of decreasing body fat. In that study supraphysiological doses of GH were given thrice weekly for six weeks to eight progressive-resistance weight-trained athletes.26

Dose: 2.1 U 2-4 times per week. Cycle length varies depending on availability, but is usually about six weeks.

IOC status: Banned.

Adverse reactions: Clinical acromegaly would be expected, yet a case has yet to be reported in the refereed literature.

Detection: Difficult to detect in urine. The synthetic form can be detected by measurement of isoform ratios in serum,27 as recombinant GH manufacture produces only one isoform, while the pituitary releases principally the single 191 amino acid polypeptide chain with a molecular mass of 22 kDa, a smaller 20 kDa form and some smaller and larger forms.


Insulin-like growth factors
Insulin-like growth factor (IGF) production is principally regulated by GH. IGF is an important factor for some of the actions of GH, such as its anabolic and growth-promoting effects, but not its effects on carbohydrate and lipid levels, which are a direct action of GH on a GH receptor.28,29 At present there are few established clinical applications for IGF and, in sport, it is probably used less than growth hormone. There are no studies of IGF in sporting performance.

Dose: Unknown.

IOC status: Banned.

Adverse reactions: No data from athletes. High-dose intravenous use causes hypoglycaemia; hypophosphataemia causing hypotension and asystole has been reported. Longer-term effects are parotidomegaly, facial pain, hand oedema, sinus tachycardia, gynaecomastia, Bell's palsy and avascular necrosis of the femoral head.28

Detection: Detecting IGF in urine is difficult and, as for GH, determining compound ratios in serum may be a means of detecting misuse.


beta-Hydroxy-beta-methylbutyrate
Infusions of some branched-chain amino acids will decrease protein breakdown in postoperative patients. This is probably the result of an inhibitory action on protein metabolism by metabolites of leucine such as a-ketoisocaproate.30 More recently, its further metabolite, beta-hydroxy-beta-methylbutyrate (HMB), has been considered to be more active in inhibiting protein breakdown. HMB is available as a food supplement in the US, which means that it avoids many of the regulatory hurdles that are required of a drug. A state of clinical deficiency of HMB is yet to be described. This substance has no approved use in Australia. It is currently widely used by athletes in a variety of sports and has no clinical applications in medicine at present.

A randomised trial of doses of 0 g, 1.5 g and 3 g per day and three levels of protein supplementation in 41 subjects showed increases in strength during resistance training.31 A further study in eight cyclists has shown a small increase in maximal oxygen consumption.32 At present there are too few data to ascertain whether the compound has a positive effect on sporting performance and whether high doses have significant toxicity.

Dose: Up to 15 grams/day are sometimes consumed.

IOC status: Not banned.

Adverse reactions: None have been described to date.

Detection: Can be quantified in urine.

Conclusions
Despite the paucity of data showing that any of these drugs, except probably erythropoietin, have positive effects on sporting performance, they are used increasingly for performance enhancement. As toxicity and adverse reactions do not seem to deter such use, detection and its consequences appear to be the main deterrent in top-level sport. Detection methods therefore need to be constantly updated and enhanced, and possibilities in this area include the introduction of blood sampling, the use of carbon isotope ratios to detect anabolic steroid misuse, and widening the scope of out-of-competition testing. Doctors need to bear in mind that drug misuse is not restricted to elite athletes -- indeed, most drug use in sport occurs at a non-elite level. The possibility that a patient has used unusual drugs to enhance performance, and that this may be either causing or confounding the clinical state, should always be considered in athletes presenting with an unusual illness.

Disclaimer While all efforts have been made to ensure the correct information about the IOC status of the drugs mentioned, this may vary between sports. The IOC status of any drug is subject to frequent revision. Athletes and coaches should check the latest status of any drug mentioned in this article with the relevant sporting body or with the Australian Sports Drug Agency.


Acknowledgements
I thank Ms Dianne James, Librarian, Manly Hospital.

References
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Authors' details
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, NSW.
Michael C Kennedy, MD, FRACP, Physician.

Reprints will not be available from the author.
Correspondence: Dr M C Kennedy, Manly Non Invasive Cardiac Laboratory, 22 Darley Road, Manly, NSW 2095.
drmkennATozemail.com.au

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