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For a Few Atoms More

When the game becomes less of a game

Roald Hoffmann

Chemical Detective Work

It's fun to figure out this exquisite biological diversity, but why should a biker take testosterone? And how did the testers find out that Landis did?

Testing for abuse is not simple. Blood concentrations of testosterone vary widely between individuals and within one individual over time. So one cannot conclude from just an elevated level of testosterone that the molecule has been supplemented!

Chemical reactions that make testosteroneClick to Enlarge ImageEnter epitestosterone, a stereoisomer of testosterone. In other words, it contains all the same atoms as testosterone, attached to each other in similar ways, but with a different disposition in space. In particular, the OH group of epitestosterone points "down" in the picture shown, instead of "up" toward us, as it does in testosterone. It turns out that epitestosterone has no apparent physiological effect (the same and not the same redux). Both testosterone and epitestosterone are produced in the body in similar amounts, by distinct biochemical pathways. So whereas there may be a higher absolute concentration of testosterone (and epitestosterone) in one person compared with another, the ratio of testosterone to epitestosterone is close to 1 for both of them.

This is the clue to detecting abuse. Supplementing testosterone, the only isomer that has the desired physiological effects, doesn't change the biological production of epitestosterone. So the sports-medical bodies settle on the testosterone:epitestosterone ratio as an indicator of foul play. Ideally, one should have a profile of that ratio for every individual. In the absence of this profile, one makes liberal assumptions for the entire population: near 1:1 is normal, 4:1 is when the red card is shown. Landis's samples apparently had an 11:1 ratio.

I know, I know—you will tell me that the dopers, making big bucks, are not stupid. They'll give not only testosterone, but also some epitestosterone, so as to keep the ratio of testosterone:epitestosterone under 4:1. The sports "doctors" in the GDR did this 25 years ago.

With good science, this strategy too can be countered. Natural testosterone differs from the synthetic material in its ratio of carbon-12 to carbon-13 isotopes. The synthetic molecules are made from precursors derived from steroids found in certain plant oils, such as soybean. These plants biosynthesize their steroids from smaller building blocks of three carbons, somewhat different from those found in many of the plants we consume (and which then go into our testosterone), which form C4 molecules. A consequence of the different biochemical mechanisms is an isotope effect, a slight difference in the way 12C and 13C (present naturally in small amounts) are incorporated. The net result is that our testosterone is ever so slightly (and detectably) richer in 13C than synthetically derived steroids.

What is puzzling in this story is why any bicyclist would take testosterone on one isolated occasion (Landis was tested at other stages of the race, and nothing showed up in those samples). Anabolic, muscle-mass-building processes require the prolonged use of testosterone. Perhaps its use was an act of desperation by a superb cyclist who was behind. The irony is that it may have functioned not because of what it was, but as a placebo.

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