T/E RATIO TEST IS GENETICALLY BIASED SOME INDIVIDUALS WILL NOT TEST POSITIVE DESPITE USING TESTOSTERONE

Schulze, J. J., Lundmark, J., Garle, M., Skilving, I., Ekstrom, L., & Rane, A. (2008). Doping test results dependent on genotype of UGT2B17, the major enzyme for testosterone glucuronidation. Journal of Clinical Endocrinology and Metabolism, [http://jcem.endojournals.org/cgi/content/abstract/jc.2008-0218v1]

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"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."

This study investigated whether genotype based cut-off values will improve the sensitivity and specificity of the test. Healthy male volunteers (N = 55) with either two (INS/INS), one (INS/DEL), or no allele (DEL/DEL) of the UGT2B17 gene served as Ss. A single intramuscular dose of 500 mg testosterone enanthate was administered. Urinary excretion of testosterone glucuronide after the dose and the T/E ratio during the ensuing 15 days were measured.

The degree and rate of increase in testosterone glucuronide 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 Ss 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.

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 combating androgen doping in sports, but also for detecting and preventing androgen abuse in the society.

Implication. Positive test results for T/E ratio are dependent upon the genetic structure of the individual. Those who have no allele of UGT2B17 are virtually immune from testing positive if the current 4:1 ratio is employed. On the other hand, individuals with two alleles are very likely to test positive no matter how much testosterone (including very small amounts introduced from unknown sources) will test positive. As it stands, the T/E ratio test is genertically biased against a subset of athletes.

This is yet another instance of drugs being banned without knowing all the parameters and dynamics surrounding their possible presence in a sample. This natural occurrence of elevated testosterone levels joins substances such as EPO, Nandrolone metabolites, probenecid, etc. all of which have been shown to require different consideration than a simple interpretation of "if it is there, it is proof of cheating."

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