testosterone: Some Athletes’ Genes Help Outwit Doping Test

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*Doping Test Results Dependent on Genotype of UGT2B17, the Major Enzyme

for Testosterone Glucuronidation

*Schulze JJ et al.

J Clin Endocrinol Metab. 2008 Mar 11 [Epub ahead of print]

http://jcem.endojournals.org/cgi/rapidpdf/jc.2008-0218v1

Context: Testosterone abuse is conventionally assessed by the urinary

testosterone/ epitestosterone (T/E) ratio, levels above 4.0 being

considered suspicious. The large variation in testosterone glucuronide

(TG) excretion and its strong association with a deletion polymorphism

in the UGT2B17 gene challenge the accuracy of the T/E ratio test.

Objective: To investigate whether genotype based cut-off values will

improve the sensitivity and specificity of the test. Design: Open

3-armed comparative study. Participants: 55 healthy male volunteers with

either two, one or no allele (ins/ins, ins/del or del/del) of the

UGT2B17 gene. Intervention: A single intramuscular dose of 500 mg

testosterone enanthate. Main outcome measures: Urinary excretion of TG

after dose and the T/E ratio during 15 days. Results: The degree and

rate of increase in TG excretion rate was highly dependent on the

UGT2B17 genotype with a 20-fold higher average maximum increase in the

ins/ins group compared to the del/del group. Forty percent of the

del/del subjects never reached the T/E ratio of 4.0 on any of the 15

days after the dose. When differentiated cut-off levels for the del/del

(1.0) and the other genotypes (6.0) were applied, the sensitivity

increased substantially for the del/del group and false positives in the

other genotypes were eliminated. Conclusion: Consideration of the

genetic variation in disposition of androgens will improve the

sensitivity and specificity of the testosterone doping test. This is of

interest not only for combatting androgen doping in sports, but also for

detecting and preventing androgen abuse in the society.

PMID: 18334593

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Hormones in autism

<http://www.autism.com/medical/research/advances/autism-hormones.htm>:

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*Some Athletes’ Genes Help Outwit Doping Test*

By GINA KOLATA

April 30, 2008

http://www.nytimes.com/2008/04/30/sports/30doping.html?_r=1 & hp & oref=slogin

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 genetic

discovery. 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 antidoping 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 antidoping 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 antidoping 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 antidoping 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.”

*

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