How Does an Anabolic/Androgenic Steroid Get Banned from Sport Competition?

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What is an androgen (anabolic-androgenic steroid)? Most would state that it is a derivative of the major sex steroid in men and most mammals, testosterone (T). Others might answer in the more generic sense: any compound that is an agonist (or partial agonist) at the androgen receptor (AR). There are seemingly enough forms of T activity available to satisfy the needs of the medical population with oral, buccal, cutaneous patches (really, drug delivery devices) and gels, injectables of various durations (days to months), and implantable forms with a duration of action of 6 months or more. Why then are some arcane designer steroids produced? It seems that performance enhancement for human (and at least equine) athletes provides the backbone for the design of new anabolic steroids to circumvent the sophisticated testing procedures that surround major national and international competitions [World Anti-Doping Agency (WADA), www.wada.ama.org]. In the 1940s and 1950s, many pharmaceutical companies evaluated a myriad of compounds with purported anabolic activity searching for those that had anabolic (at muscle) activity without the more androgenic activities. It was to little avail given that there is but one AR, albeit with a greater affinity for dihydrotestosterone than for T itself (1). Arcane T chemistry produced many compounds that had sat on shelves for years without any clinical trials for evaluation for human or veterinary use or commercial promotion. In the future, the concept of selective AR agonists may come to play a much more prominent role. Such compounds may selectively produce the beneficial effects of androgens on musculoskeletal mass and strength without the androgenic adverse events (2). Clandestine laboratories seeking to make a product to give an edge to athletes began to screen compounds for their anabolic/androgenic activities with the proviso that the compound and its metabolites be invisible to the WADA screening protocol, www.wada-ama.org. It appeared quite straightforward to begin with the steroid structure of testosterone, add multiple decorations to the various carbon atoms, test in vitro with various cell lines that contain the AR linked to an objective outcome, for example, AR nuclear translocation or myogenic activity (2). Then comes the nefarious part: all certified antidoping laboratories have libraries of chromatography/mass spectroscopy (MS)/MSfragments, andeachanabolic/androgenic steroid has its own unique signature. The skill is to find a compound active at the AR, but that is not yet in the library. Is this just an academic exercise in steroid biochemistry? I think not, given the example of tetrahydrogestrinone (THG). THG had been invisible to the antidoping laboratories until a sample of pure THG was presented to an antidoping lab. It had been synthesized by an underground laboratory and likely underwent enough testing (in vitro and in vivo) to determine its anabolic/androgenic activity and that it could not be detected by the then extant WADA testing procedure. However, within a week of obtaining that pure sample of THG, the University of California at Los Angeles (UCLA) Olympic Analytic Laboratory was able to devise a test for this compound and its metabolic products (3). This task was later verified by the synthesis of THG and characterized by MS and nuclear magnetic resonance spectroscopy. The UCLA laboratory developed and verified sensitive and specific methods for the rapid screening of urine samples by liquid chromatography/tandem MS, both in the natural state and with trimethylsilyl ether-oxime derivatives (as is done in the standard anti-