October 01, 2006
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The meta-endocrinology of sports: hormones’ role in athletic cheating

Athletes focus on the benefits of performance-enhancing drug use; endocrinologists consider the risks.

L. J. Deftos, MD, JD, LLM [photo]
L. J. Deftos

We should be getting used to the feigned indignation by cheating athletes and their sycophants upon failed drug testing.

The endocrine tests to detect hormone abusers in sports have become very complex, especially the sophisticated testing implemented by the World Anti-Doping Agency (WADA) and similar laboratories. They are technologically well beyond (meta) the tests that endocrinologists rely on to identify abnormal levels of hormones. These “drug” tests have been developed specifically for the purpose of catching the abusing athlete and commonly have to distinguish between exogenous and endogenous hormones.

For example, in the recent case of cyclist Floyd Landis, two complex mass spectrometry procedures for testosterone were used so that the natural hormone could be distinguished from its pharmaceutical counterparts. For sprinter Marion Jones, isoelectric focusing was used in an attempt to distinguish endogenous from exogenous erythropoietin, and two tests gave apparently conflicting results. While Justin Gaitlin accepted an eight-year ban from track competition because of two failed tests for anabolic steroids, his coach blames a testosterone-laden rubdown by a vengeful masseuse.

These are but examples of the meta-endocrinology of sports that pervade contemporary athletics. Beyond (meta) expectation are both the sophistication and naiveté about endocrinology that exist in the enhancement of athletic performance.

Consider the pharmacopoeia of hormones that are used by athletes to gain an unfair advantage. While anabolic steroids are at the fore, the abused agents include many other endocrine actors — thyroid hormones, erythropoietin, growth hormone, insulin (and insulin-like growth factor), gonadotropins, corticotropins, adrenergic agents, beta blockers, antiestrogens, clomiphene and even glucocorticoids.

Legislative and analytical loopholes

Legislation in this area has been full of loopholes. The Anabolic Steroid Control Act of 1990 left many anabolics under the ambit of the permissive features of the Dietary Supplement Health and Education Act of 1994. Written by supplement manufacturers, this law actually facilitated the marketing of “dietary supplements” like androstenedione not only by their dietary classification but also by shifting the safety burden from the manufacturer to the consumer.

The Anabolic Steroid Control Act of 2004 somewhat rectified the situation by also regulating steroid precursors, but the deceit and evasion by athletes continues.

Although testosterone is a mainstay, metaendocrinology in sports has become much more sophisticated through the use of designer anabolics. THG (tetrahydrogestrinone) is such a potent anabolic agent, protestations of alleged users and suppliers like the Bay Area Laboratory Cooperative (BALCO), the distributor of performance-enhancing drugs to sports’ San Francisco Giants. It is one of many compounds that can be “designed” and readily synthesized to act through the unique androgen receptor but to escape detection by standard methods.

THG was originally undetectable by steroid testing until a new method was developed by Don Catlin, MD, a professor of medicine and pharmacology at the David Geffen School of Medicine, UCLA, whose laboratories provide testing for the Olympics and other sports organizations, including WADA.

Endocrine testing

Many steroid tests are done by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). Chromatography separates the analytes, and MS identifies them by fragmentation patterns as compared to known standards.

For proteins and peptides, immunochemically-based methods are required for detection. Even sensitive and specific immunoassays, a mainstay of endocrine testing, are limited in their application to illegitimate use of protein and peptide hormones.

For example, the recombinant growth hormone (rGH) and erythropoietin (rEPO) used to enhance performance cannot be readily distinguished from their natural counterparts by standard immunoassays. A blood immunoassay that can distinguish rGH from endogenous GH, based on the immunochemical signature of non-glycosylated rGH, has been developed by WADA, but its use has been limited by the supply of distinguishing antibody. And although isoelectric focusing can distinguish non-gycosylated rEPO from its glycosylated normal counterpart, detectability exists just a few days in blood but effects can last for weeks.

Complex procedures can also be used to distinguish natural testosterone from its pharmaceutical counterpart: Gas chromatography-combustion-isotope ratio mass spectrometry can detect the 13C difference between the two. Similarly, the ratio of epitesterone to testosterone can be used to detect abuse because the pharmaceutical preparation of testosterone contains none. Although both were used for Floyd Landis, these and corresponding procedures are complex and not widely available.

Abuse of endocrine principles

The basic principles of endocrine regulation can also inform drug testing and deceit. Delayed testing may not be effective for short-acting peptides but may allow detection of longer-acting steroids.

In addition, in an androgen abuser who stops taking the drug before an event to avoid detection, a low (endogenous) serum testosterone may reveal the suppression caused by the exogenous androgen. The psuedo-sophisticated use of clomiphene has been used to try to stimulate such suppressed levels.

Drug abusers learn about the half-lives of the various drugs used and the influence thereon of different routes of administration. In any case, more than simple protocols are needed to detect deception. Moreover, drug testing must also satisfy the requirements for collection and admissibility into legal and quasi-legal proceedings. Furthermore, many monitoring programs do not allow blood testing because of “privacy” concerns.

A role for endocrinologists

Endocrinologists have not recognized the type of risk-benefit analysis that athletes apply in considering the pharmacological use of performance-enhancing drugs. The abusing athletes consider the benefits to their performance while minimizing the risks, and some accept great risk for even the slightest edge. Our profession has focused on the risks, well-known to us.

We need to be more realistic when asked for our expertise, and we should ask our professional societies to enter this fray with more than velleity. But it appears too late to mitigate the irony that will prevail as drug investigations proceed after Barry Bonds has passed the home run record of Babe Ruth and chases Henry Aaron.

For more information:
  • L.J. Deftos, MD, JD, LLM, is a Professor of Medicine at the University of California, San Diego, and a Professor of Law at California School of Law. He is a member of Endocrine Today’s Editorial Board.
  • Deftos, L. Games of Hormones. Endocrine Practice. 2006;12:472-474.
  • Foster JJ and Houstner JA. Androgenic-anabolic steroids and testosterone precursors: Ergogenic aids in sport. Current Sports Medicine Reporter. 2004;3:234-241.
  • Layden, T. Outrunning the past. Sports Illustrated, pp 20-21, March 27, 2006.