The development of a methodology for detecting abuse with IGF-I in sport
Growth hormone (GH) is a naturally occurring endogenous peptide hormone produced by the pituitary gland. Although banned under the International Olympic Committee (IOC) and World Anti Doping Agency (WADA) list of prohibited substances, the detection of exogenously administered GH poses a formidable challenge. Two approaches for the detection of GH have been developed in collaboration with WADA and USADA. The first approach is based on the measurement of different GH isoforms. This method is able to detect recombinant human GH (rhGH) within a short ‘window of opportunity’ of <36 hours after the last injection of rhGH but will not detect any injection of pituitary-derived GH (that is readily available).The second approach is based on the measurement of GH-sensitive markers. The GH-2000 group showed that the administration of rhGH caused a significant rise in GH-sensitive markers. The magnitude and duration of the elevation was dependent on the dose of rhGH given, gender and the individual marker. Men were more sensitive to the effects of rhGH than women. Although IGF-I and P-III-P were the best of the markers of GH action and were selected to construct formulae that gave good discrimination between those taking GH and those taking placebo, adjustments have to be made to account for the fall in IGF-I and P-III-P that occurs with age.The results of GH-2000 were reviewed by a panel of international experts (including a representative of the Court of Arbitration in Sport – CAS) at an IOC-organised Workshop in Rome in March 1999. This review produced a number of key issues that needed addressing before the experts felt that there would be a viable test suitable for implementation at an Olympic Games. The main issue raised concerned possible ethnic effects on the GH-sensitive markers proposed, since the large majority of volunteers in GH-2000 were white Caucasians. The GH-2004 project, funded by WADA and USADA, is now currently addressing these issues as well as the effect of injury on GH-sensitive markers. In April 2004, the results of the GH-2000 and preliminary results of the GH-2004 project were presented and reviewed at the “USADA symposium on the detection of hGH abuse in Sport”. Although both WADA and USADA strongly support the marker approach, it was felt that further complementary work remains to be done before such a test can be fully implemented.The major issues relating to the “marker” approach were:
1. The effect of adolescence and puberty on the GH sensitive markers.
2. The need for independent confirmation of the algorithm.
3. Assay calibration
4. The use of other GH sensitive markers
5. Clarification of the collection and storage procedures.
The major issue relating to the “isoform” approach was the need to establish the method in an independent IOC accredited laboratory and validate the method against further sample sets.In this proposal, we plan to address each of these issues.
• It is believed that growth hormone (GH) is abused by athletes and other professional sports men and women.
• The use of GH is banned under the World Anti-Doping Agency (WADA) list of prohibited substances.
• The detection of abuse with GH by poses several challenges because injectable GH is identical to naturally produced GH.
• The GH-2000 study based at St Thomas’ Hospital, London and led by Professor Peter Sönksen showed that it is possible to detect GH abuse by measuring insulin like growth factor –I (IGF-I) and type 3 procollagen (P-III-P) whose concentrations increase in response to injections of GH and the application of discriminant function analysis.
• The results of GH-2000 were presented to a panel of international experts at an IOC-organised Workshop in Rome in April 1999. This review raised a number of key issues that needed addressing before any test could be implemented. The main issue concerned possible ethnic effects on the proposed markers, since the majority of volunteers in GH-2000 were white European.• The GH-2004 project, which is a 3-year project based at the University of Southampton, is funded by WADA and the US Anti-Doping Agency and aims to address these concerns.
• The first part of the project, which was funded by WADA, measured serum IGF-I and P-III-P in blood samples obtained from 242 male and 62 female elite athletes from different ethnic backgrounds within 2 hours of the end of competition at 9 international sporting events in 13 disciplines.
• The study showed that although there are small differences (<20%) in the concentrations of IGF-I and P-III-P between different ethnic groups, the majority of values for individuals of non-white European background lie within the normal range for the white European subjects.
• Application of the GH-2000 discriminant function analysis formulae to the GH-2004 subjects showed that no individual would have been falsely accused of doping.
• The significance of these results means that the test can be applied across different ethnicities. As it is extraordinarily difficult to define ethnicity, if there had been major differences between ethnic groups, it would have been impossible to apply the test.