British Journal of Pharmacology (2008) 154, 542–556 & 2008 Nature Publishing Group All rights reserved 0007– 1188/08 $30.00 www.brjpharmacol.org REVIEW Growth hormone, IGF-I and insulin and their abuse in sport RIG Holt and PH So¨nksen Principal Investigators GH-2004 Project, Endocrinology and Metabolism Sub-Division, Developmental Origins of Adult Health and Disease Division, School of Medicine, University of Southampton, Southampton, UK There is widespread anecdotal evidence that growth hormone (GH) is used by athletes for its anabolic and lipolytic properties. Although there is little evidence that GH improves performance in young healthy adults, randomized controlled studies carried out so far are inadequately designed to demonstrate this, not least because GH is often abused in combination with anabolic steroids and insulin. Some of the anabolic actions of GH are mediated through the generation of insulin-like growth factor-I (IGF-I), and it is believed that this is also being abused. Athletes are exposing themselves to potential harm by self- administering large doses of GH, IGF-I and insulin. The effects of excess GH are exemplified by acromegaly. IGF-I may mediate and cause some of these changes, but in addition, IGF-I may lead to profound hypoglycaemia, as indeed can insulin. Although GH is on the World Anti-doping Agency list of banned substances, the detection of abuse with GH is challenging. Two approaches have been developed to detect GH abuse. The first is based on an assessment of the effect of exogenous recombinant human GH on pituitary GH isoforms and the second is based on the measurement of markers of GH action. As a result, GH abuse can be detected with reasonable sensitivity and specificity. Testing for IGF-I and insulin is in its infancy, but the measurement of markers of GH action may also detect IGF-I usage, while urine mass spectroscopy has begun to identify the use of insulin analogues. British Journal of Pharmacology (2008) 154, 542–556; doi:10.1038/bjp.2008.99; published online 31 March 2008 Keywords: GH; IGF-I; insulin; sport; abuse Abbreviations: FFA, free fatty acid; GH, growth hormone; IGF-I, insulin-like growth factor-I; IGFBP, IGF binding protein; P-III-P, type 3 pro-collagen; rhGH, recombinant human growth hormone Introduction It is widely believed that growth hormone (GH) has been from anabolic steroids and therefore it seems likely that their used by sportsmen and women since the 1980s to improve effects will be additive. This has led many athletes to their athletic performance (McHugh et al., 2005) despite combine GH with insulin and anabolic steroids (So¨nksen, being banned for many years and appearing on the World 2001). Anti-Doping Agency list of banned substances. The GH doses used by athletes are thought to be up to 10 The actions of GH that interest athletes are anabolic and times higher than those used by endocrinologists, and as lipolytic, leading to an increase in lean body mass and such athletes are putting themselves at risk of harmful effects reduction in fat mass. Some of the anabolic GH actions are such as hypertension, diabetes and Creutzfeld–Jakob disease. mediated through the generation of insulin-like growth The detection of GH poses the greatest contemporary factor-I (IGF-I), and there is anecdotal evidence that this too challenge to the anti-doping community. The detection of is being abused by athletes either alone or in combination GH abuse has proved difficult for several reasons. Unlike with GH. The regulation of protein synthesis involves the many substances of abuse, such as synthetic anabolic synergistic actions of GH and IGF-I stimulating protein steroids, GH is a naturally occurring substance. The demon- synthesis, while insulin simultaneously inhibits protein stration of exogenous administration must therefore rely on breakdown (Russell Jones et al., 1993). GH stimulates protein finding concentrations exceeding normal physiological synthesis through a mechanism that is separate and distinct levels while excluding pathological causes such as acrome- galy. This is made harder because GH is secreted in a pulsatile manner with exercise and stress being major stimulators of Correspondence: Dr RIG Holt, IDS Building (MP887), Centre Block, GH secretion (Prinz et al., 1983; Savine and So¨nksen, 2000). Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. Consequently, GH concentrations are often at their highest E-mail: [email protected] Received 25 July 2007; revised 14 November 2007; accepted 3 March 2008; in the immediate post-competition setting when most dope published online 31 March 2008 testing occurs. Recombinant human GH is almost identical GH abuse in sport RIG Holt and PH So¨nksen 543 to pituitary GH, whereas cadaveric GH, which is in plentiful In 2000, Australian discus champion Walter Reiterer claimed supply on the Internet, is indistinguishable from endogenously institutional and supervised usage of GH. With this in mind, produced GH. Blood testing is needed for GH and IGF-I it is interesting to note that 6 months before the Sydney because less than 0.1% is excreted unchanged and even that Olympic Games, 1575 vials of GH were stolen from an is erratic, rendering urine testing unfeasible (Moreira-Andres importer’s warehouse in Sydney. et al., 1993). More recently, Victor Conte, the owner of the Bay Area The review will explore why athletes abuse GH, IGF-I and Laboratory Co-Operative, claimed that he had supplied GH insulin and also the methodology that has been developed to many high-profile American athletes including Tim to catch the cheats. Montgomery and Marion Jones. This admission came after the raid on the Bay Area Laboratory Co-Operative’s head- quarters on 3 September 2003, when evidence of systematic GH abuse in sport doping was found and many of the top names in athletics, baseball and American football were implicated in the Growth hormone was first extracted from human pituitary scandal. Although many have denied taking GH, Tim glands in 1945 (Li et al., 1945). It was shown to promote Montgomery allegedly admitted to taking GH before a US growth in hypopituitary animals and was soon used to Federal grand jury and later faced a 2-year ban for doping restore growth in children with hypopituitarism. How and offences. Conte was imprisoned for 4 months for his role in where GH was first used as a doping agent is unknown, but the scandal (Fainaru-Wada and Williams, 2006). the earliest publication to draw attention to it was Dan The recent conviction of Sylvester Stallone, who was Duchaine’s ‘Underground Steroid handbook’, which caught with GH in his possession on entering Australia, emerged from California in 1982 (Duchaine, 1982). suggests that GH is readily available in athletic and body- Although it contains some fundamental errors, such as the building circles. recommendation and advertisement of animal GH for use in humans, the description of the actions of GH in this article was remarkably accurate and pre-dated adult endocrinology IGF-I abuse in sport experience by about a decade. GH was described as the ‘most expensive, most fashionable and least understood of the new The prevalence of IGF-I abuse is probably much lower than athletic drugs. It has firmly established itself in power-lifting for GH because, unlike GH, there is no readily available and within a few years will be a commonly used drug in all natural source, and therefore all IGF-I is obtained through strength athletics.’ recombinant DNA technology. Two companies currently The most famous case of GH abuse in professional athletics market IGF-I, and these preparations have only recently came to light in 1988 after Ben Johnson won the 100 m gold received approval for use in humans to treat growth failure medal at the Olympic Games in Seoul. He was subsequently in children with severe primary IGF-I deficiency or with GH disqualified after stanazolol was detected in his urine, but at gene deletion who have developed neutralizing GH anti- a later hearing, both he and his coach Charley Francis bodies. The first product is Increlex or recombinant human admitted under oath that he had taken human GH in IGF-I, manufactured by Tercica, and the second product addition to anabolic steroids. manufactured by Insmed is Iplex, which differs from Increlex It is impossible to determine the precise prevalence of GH in that the recombinant human IGF-I is supplied bound to abuse among sportsmen and women, as much of our its major binding protein, IGFBP-3 (Kemp et al., 2006; Kemp, evidence comes from anecdotal reports (McHugh et al., 2007). 2005). Although initially advocated for strength disciplines, Although in relatively short supply, other companies endurance athletes are also attracted to GH’s lipolytic actions make IGF-I for cell culture and other uses, and this material and reduced fat mass; in 1988, a large quantity of GH was could also become available to athletes. The wider avail- found in a team car at the Tour de France. ability of IGF-I, together with an appreciation of the efforts There is evidence that adolescents are using GH. In a to detect GH abuse, is likely to increase its illicit use by survey of two US high schools, 5% of male students admitted athletes, despite being prohibited by the World Anti-Doping to having taken GH and nearly one-third knew someone Agency. who had taken GH (Rickert et al., 1992). Most GH users were unaware of its side effects and reported their first use between 14–15 years of age. Abuse of insulin in sport Growth hormone is an expensive drug and this has led some parents to sell GH prescribed to treat their child’s GH We have only sketchy details about the use of insulin by deficiency on the black market.