Testosterone..loopholes?

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April 30, 2008

Some Athletes’ Genes Help Outwit Doping Test

By GINA KOLATA

The 55 men in a drug doping study in Sweden were normal and healthy. And all

agreed, for the sake of science, to be injected with testosterone and then

undergo the standard urine test to screen for doping with the hormone.

The results were unambiguous: the test worked for most of the men, showing that

they had taken the drug. But 17 of the men tested negative. Their urine seemed

fine, with no excess testosterone even though the men clearly had taken the

drug.

It was, researchers say, a striking demonstration of a newly discovered genetic

peculiarity. Those 17 men can build muscles with testosterone, they respond

normally to the hormone, but they are missing both copies of a gene used to

convert the testosterone into a form that dissolves in urine. The result is that

they may be able to take testosterone with impunity.

The gene deletion is especially common in Asian men, notes Jakobsson

Schulze, a molecular geneticist at the Karolinska University Hospital in

Stockholm. Dr. Schulze is the first author of the testosterone study, published

recently in The Journal of Clinical Endocrinology and Metabolism.

Dr. Schulze learned from an earlier study that about two-thirds of Asian men are

missing both copies of the gene, as are nearly 10 percent of Caucasians. The

prevalence in other groups is not known.

Doping researchers said the study raised questions about what to do next.

“It’s disturbing,” said Dr. Don Catlin, the chief executive of Anti-Doping

Research, a nonprofit group in Los Angeles. “Basically, you have a license to

cheat.”

Should athletes give DNA samples for scientists to analyze as genes like the

testosterone-metabolizing one are found to be important? Or would another

approach, the so-called athlete’s passport, be sufficient? The passport, favored

by the World Anti-Doping Agency, is a record of all of an athlete’s screening

tests and would detect results that vary from the athlete’s baseline values —

but it would not include gene testing and therefore may not detect those

athletes lacking this gene.

But nothing will happen soon, and certainly not in time for the Beijing Olympics

in August.

Testosterone and substances that act like it are the most frequently detected

drugs in screening tests of athletes. The anti-doping agency reported that these

drugs have been implicated in 43 percent of its positive doping tests.

Researchers have long known that some men, Asians in particular, seemed to be

able to take the drugs without getting caught, although no one had identified

the cause of the phenomenon. Without gene testing, there is no way to know

whether any athletes have exploited this doping loophole, but Dr. Catlin says he

suspects some athletes discovered their invulnerability by accident and took

advantage of it.

Men with the gene deletion still metabolize testosterone, Dr. Schulze says. But,

she adds, she does not know where the hormone goes. “We have no idea,” she said.

“That’s what we’re trying to find out.”

The gene in question adds a chemical, glucuronide, to testosterone. That

converts it from a substance that dissolves in oil into one that dissolves in

water and urine.

The testosterone screening test looks for testosterone and another substance,

epitestosterone, that is produced in parallel to testosterone but does not have

testosterone’s effects. The anti-doping agency considers a testosterone to

epitestosterone, or T to E, ratio of four or greater a positive test and follows

it with a more expensive and definitive test that asks whether the excess

testosterone is of human origin or whether it is from plants. The testosterone

used in doping usually comes from plants.

When they conceived of their study, Dr. Anders Rhane and Dr. Mats Garle, head of

the Doping Control Laboratory at the Karolinska University Hospital, applied for

and received a grant from the anti-doping agency. Then, to test their

hypothesis, the Karolinska scientists injected the men with 500 milligrams of

testosterone and looked at T to E ratios over the next 15 days as the

testosterone was metabolized.

The men with two normal copies of the gene had T to E ratios that soared to 100;

those with one copy of the gene had ratios that reached 50; those with no copies

had almost no rise in their ratios and 40 percent of them had a ratio that never

reached 4.

Dr. Schulze and her colleagues suggest that athletes be tested to see if they

have the testosterone-metabolizing gene. Others said the testing of athletes for

this and other genes may be coming soon.

“The specter of doing this is out there,” says Dr. Alvin Matsumoto, a

testosterone expert at the University of Washington in Seattle and the Veterans

Affairs Puget Sound Health Care System.

The World Anti-Doping Agency is studying instead the athlete’s passport. It

hopes to keep track of each athlete’s drug tests to see if any results suddenly

change compared to before.

“You are in a situation where you monitor the athlete and you can see right away

if there are modifications” in test results, said Olivier Rabin, the science

director of the agency.

Dr. Rabin is less enthusiastic about genetic testing because, he said, it raises

ethical questions.

But in either case, it is not clear what to do if an athlete has a genetic

feature that makes doping tests turn out negative when the athlete is using

drugs. The testosterone follow-up test is technically complex and expensive,

raising questions about whether it is feasible to use it for as many as

two-thirds of Asians and 10 percent of Caucasians.

“The analytical facilities and costs required preclude any routine use of this

methodology for screening in anti-doping testing,” Dr. Schulze and her

colleagues wrote.

And the newly discovered gene deletion may be just one reason the T to E ratio

test may fail in some men.

There may be more than a dozen testosterone-metabolizing enzymes, said Dr.

Shalender Bhasin, a testosterone researcher at Boston University School of

Medicine, and it may be necessary to examine all of them to see if gene

variations affect test results. He added that there may be differences in the

way men and women metabolize testosterone, so a separate study on women would be

necessary to determine whether the gene deletion affects their testosterone

tests the same way.

Still Dr. Catlin said, the work by the Karolinska scientists offers hope for the

future, showing that the doping world is entering a new era.

“To me it’s inevitable that we are going to learn more and more about how genes

are influencing the outcome of tests,” he said. “It’s here,” he added. “We might

as well get used to it.”

S. Kalman PhD, RD, CCRC, FACN

Director, Nutrition & Applied Clinical Research

Miami Research Associates

6141 Sunset Drive #301

Miami, FL. 33143

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