Olivier Rabin

Hormone abuse in sports: the antidoping perspective.

Since ancient times, unethical athletes have attempted to gain an unfair competitive advantage through the use of doping substances. A list of doping substances and methods banned in sports is published yearly by the World Anti-Doping Agency (WADA). A substance or method might be included in the List if it fulfills at least two of the following criteria: enhances sports performance; represents a risk to the athletes health; or violates the spirit of sports. This list, constantly updated to reflect new developments in the pharmaceutical industry as well as doping trends, enumerates the drug types and methods prohibited in and out of competition. Among the substances included are steroidal and peptide hormones and their modulators, stimulants, glucocorticosteroids, beta2-agonists, diuretics and masking agents, narcotics, and cannabinoids. Blood doping, tampering, infusions, and gene doping are examples of prohibited methods indicated on the List. From all these, hormones constitute by far the highest number of adverse analytical findings reported by antidoping laboratories. Although to date most are due to anabolic steroids, the advent of molecular biology techniques has made recombinant peptide hormones readily available. These substances are gradually changing the landscape of doping trends. Peptide hormones like erythropoietin (EPO), human growth hormone (hGH), insulin, and insulin-like growth factor I (IGF-I) are presumed to be widely abused for performance enhancement. Furthermore, as there is a paucity of techniques suitable for their detection, peptide hormones are all the more attractive to dishonest athletes. This article will overview the use of hormones as doping substances in sports, focusing mainly on peptide hormones as they represent a pressing challenge to the current fight against doping. Hormones and hormones modulators being developed by the pharmaceutical industry, which could emerge as new doping substances, are also discussed.

Detection of GH abuse in sport: Past, present and future

Due to its considered performance enhancing effects, human growth hormone (hGH) is abused as a doping agent in sport. Its misuse also carries potentially serious side effects to a persons health. Consequently, hGH and its releasing factors are prohibited in sport, as established in the Prohibited List which is updated and published yearly by the World Anti-Doping Agency (WADA). In order to fight the menace that hGH doping poses to the spirit of sport and to the health of athletes, the sport movement and the anti-doping authorities, initially led by the International Olympic Committee (IOC) and later by WADA, have put substantial efforts into developing tests for its detection. Currently, a primary analytical approach, the isoform differential immunoassay, has been implemented in WADA-accredited laboratories. In parallel, a second, indirect approach for the detection of hGH abuse, based on the quantification of hGH-associated biological markers, has been developed. The final aim is to combine both methodologies to improve the sensitivity and expand the time window to detect doping with hGH. In addition, novel analytical procedures, based on proteomic and genomic technologies as well as the use of mass spectrometry-based methods of detection, are being investigated for future application in hGH anti-doping tests.

An integrative ‘Omics’ solution to the detection of recombinant human erythropoietin and blood doping

Administration of recombinant human erythropoietin (rHumanEPO) improves sporting performance and hence is frequently subject to abuse by athletes, although rHumanEPO is prohibited by the WADA. Approaches to detect rHumanEPO doping have improved significantly in recent years but remain imperfect. A new transcriptomic-based longitudinal screening approach is being developed that has the potential to improve the analytical performance of current detection methods. In particular, studies are being funded by WADA to identify a ‘molecular signature’ of rHumanEPO doping and preliminary results are promising. In the first systematic study to be conducted, the expression of hundreds of genes were found to be altered by rHumanEPO with numerous gene transcripts being differentially expressed after the first injection and further transcripts profoundly upregulated during and subsequently downregulated up to 4 weeks postadministration of the drug; with the same transcriptomic pattern observed in all participants. The identification of a blood ‘molecular signature’ of rHumanEPO administration is the strongest evidence to date that gene biomarkers have the potential to substantially improve the analytical performance of current antidoping methods such as the Athlete Biological Passport for rHumanEPO detection. Given the early promise of transcriptomics, research using an ‘omics’-based approach involving genomics, transcriptomics, proteomics and metabolomics should be intensified in order to achieve improved detection of rHumanEPO and other doping substances and methods difficult to detect such a recombinant human growth hormone and blood transfusions.

Determination of urinary concentrations of pseudoephedrine and cathine after therapeutic administration of pseudoephedrine-containing medications to healthy subjects: implications for doping control analysis of these stimulants banned in sport.

Due to its stimulatory effects on the central nervous system, and its structural similarity to banned stimulants such as ephedrine and methamphetamine, pseudoephedrine (PSE) at high doses is considered as an ergogenic aid for boosting athletic performance. However, the status of PSE in the International Standard of the Prohibited List as established under the World Anti-Doping Code has changed over the years, being prohibited until 2003 at a urinary cut-off value of 25 µg/ml, and then subsequently removed from the Prohibited List during the period 2004-2009. The re-consideration of this position by the World Anti-Doping Agency (WADA) List Expert Group has led to the reintroduction of PSE in the Prohibited List in 2010. In this manuscript, we present the results of two WADA-sponsored clinical studies on the urinary excretion of PSE and its metabolite cathine (CATH) following the oral administration of different PSE formulations to healthy individuals at therapeutic regimes. On this basis, the current analytical urinary threshold for the detection of PSE as a doping agent in sport has been conservatively established at 150 µg/ml

Involvement of the health industry in the fight against doping in sport

Most substances used for doping in sport are legitimate pharmaceutical products deviated from their intended therapeutic applications. One of the major challenges for anti-doping authorities, in anticipation of future doping trends, is to assess the doping potential of drugs in development by the health industry and to timely develop anti-doping analytical methods to detect their abuse before such drugs become available to athletes intending to use them as doping agents. In this regard, the World Anti-Doping Agency (WADA) has recently consolidated several agreements with representatives from the pharmaceutical sector in order to establish a framework of collaboration and to facilitate the identification and transfer of information on drugs in development. The context of the collaborative effort between WADA and the pharmaceutical and biotechnology industries, as well as the role of drug regulatory agencies in an integrated process in support of the fight against doping in sport are described in this article.

Challenges and perspectives in anti-doping testing.

In less than 10 years after the implementation of the World Anti-Doping Code and of the International Standard for Laboratories and its related Technical Documents, the analysis of human samples for the purpose of anti-doping testing has undergone a noticeable evolution. The research programs developed by the anti-doping organizations, and in particular the World Anti-Doping Agency (WADA), have created an unprecedented momentum in anti-doping science to strengthen the existing analytical methods, as well as to support the development and implementation of new and more sophisticated methodologies by the WADA-accredited laboratories. The integration of technical novelties into the analytical menus has been stimulated by the never-ending challenges posed by the adoption of more complex doping regimens by some athletes and their entourage. This increased sophistication of doping practices has also been reflected in the addition of new doping substances or methods on the WADA Prohibited Substances and Methods List. The integration of new anti-doping scientific paradigms with the development of the Athlete Biological Passport or the foreseen implementation of genomic- and proteomic-based tests constantly reshapes the environment of anti-doping analysis. This article provides a multiangle perspective on some of the key analytical challenges that anti-doping analytical science will face in 2012 and beyond.

Ensuring high quality in anti-doping laboratories.

The worldwide network of World Anti-Doping Agency (WADA)-accredited anti-doping laboratories plays a fundamental role in supporting the global fight against doping in sport. This role is dependent on the ability to provide accurate, reliable and comparable data in identifying and measuring the presence of prohibited substances and methods. The accredited laboratories participate in WADAs External Quality Assessment Scheme (EQAS) program, which provides the structure to continuously assess and improve laboratory performance in compliance to the requirements of the International Standard for Laboratories and related Technical Documents. The WADA EQAS is comprised of various programs, including a blind EQAS, a double-blind EQAS and an educational EQAS, each with specific goals with regard to monitoring and improving laboratory competence. In this article, the anti-doping rules and processes that govern granting and maintenance of WADA laboratory accreditation, aimed at ensuring a high-quality of laboratory operations within the framework of the global fight against doping in sport, are reviewed.

Anti-doping Challenges with Novel Psychoactive Substances in Sport

Psychoactive substances have a long history of use as doping substances in sport, usually constituting the second most used drug class behind anabolic steroids. In addition to classic stimulants, a more disturbing problem is the increasing availability of novel psychoactive substances (NPS). The challenges faced by anti-doping authorities regarding these NPS are of the same kind as those experienced by public health authorities and law enforcement agencies. These include easy access to raw material for synthesis, rapid and worldwide dissemination of the products and difficulty to analytically characterize these unknown chemical entities and their metabolites. Information and resource sharing between the different parties concerned in detecting and curtailing the production, distribution and use of NPS, either from a health or anti-doping fields, should be encouraged to effectively counteract the use of NPS in society and sports.

Harmonization of anti-doping rules in a global context (World Anti-Doping Agency-laboratory accreditation perspective)

This article provides a review of the leading role of the World Anti-Doping Agency (WADA) in the context of the global fight against doping in sport and the harmonization of anti-doping rules worldwide through the implementation of the World Anti-Doping Program. Particular emphasis is given to the WADA-laboratory accreditation program, which is coordinated by the Science Department of WADA in conjunction with the Laboratory Expert Group, and the cooperation with the international accreditation community through International Laboratory Accreditation Cooperation and other organizations, all of which contribute to constant improvement of laboratory performance in the global fight against doping in sport. A perspective is provided of the means to refine the existing anti-doping rules and programs to ensure continuous improvement in order to face growing sophisticated challenges. A viewpoint on WADAs desire to embrace cooperation with other international organizations whose knowledge can contribute to the fight against doping in sport is acknowledged.