Epitestosterone is a naturally occurring steroid compound found within the human body. Structurally, it closely resembles testosterone, a well-known male sex hormone, differing only in the arrangement of atoms at a single position, specifically the C17 carbon atom. This subtle difference means epitestosterone is an epimer of testosterone, a type of isomer where molecules have the same chemical formula but vary in their spatial orientation. Despite its structural similarity, epitestosterone possesses distinct biological properties and is produced naturally within the body.
Epitestosterone’s Biological Profile
Epitestosterone is synthesized within the human body, with about 50% of its production in males originating from the testes. While testosterone is primarily known for its androgenic effects, epitestosterone generally exhibits minimal to no androgenic activity.
For a long time, epitestosterone was considered biologically inactive. However, more recent studies suggest it may act as an antiandrogen by competitively binding to androgen receptors and inhibiting the enzyme 5α-reductase. This inhibitory action helps regulate the effects of testosterone in tissues. Epitestosterone is mainly excreted in urine as a glucuronide conjugate.
The production rate of epitestosterone is significantly lower than that of testosterone. Despite this lower production, its urinary excretion rate is relatively high. This difference contributes to its importance in specific analytical applications.
Its Significance in Anti-Doping
Epitestosterone plays a significant role in anti-doping efforts due to its unique relationship with testosterone. While exogenous administration of testosterone can increase the body’s testosterone levels, it does not typically affect epitestosterone levels. This characteristic makes the ratio of testosterone to epitestosterone (T/E ratio) a valuable marker for detecting performance-enhancing drug use.
The World Anti-Doping Agency (WADA) monitors this T/E ratio in athletes’ urine samples. A normal T/E ratio in healthy adult males is typically around 1:1. Historically, WADA considered a ratio above 6:1 as suspicious, but this threshold was lowered to 4:1 in 2005 to enhance detection sensitivity.
An elevated T/E ratio suggests that an athlete may have administered exogenous testosterone. When a sample exceeds the 4:1 threshold, it triggers further investigation. This often involves more advanced analytical techniques, such as isotope ratio mass spectrometry (IRMS), to confirm whether the testosterone detected is of synthetic, rather than natural, origin. The T/E ratio test is an important initial screening tool.
Factors Affecting Epitestosterone Levels
While the T/E ratio is a robust indicator in doping control, various factors can influence epitestosterone levels and, consequently, the T/E ratio, leading to complexities in interpretation. Genetic variations are a notable factor, particularly polymorphisms in genes encoding enzymes involved in steroid metabolism. One such gene is UGT2B17, which primarily facilitates the glucuronidation of testosterone, aiding its excretion.
Individuals with a deletion polymorphism in the UGT2B17 gene may excrete significantly lower amounts of testosterone glucuronide, impacting their T/E ratio. Importantly, UGT2B17 does not glucuronidate epitestosterone, meaning that a deficiency in this enzyme can lead to a naturally higher T/E ratio even without exogenous testosterone administration. This genetic variation is more prevalent in certain ethnic groups, such as Asian populations, where a higher percentage of individuals may naturally exhibit lower testosterone excretion.
Other genetic factors, like polymorphisms in the CYP17 gene, can also affect epitestosterone levels, influencing its formation and urinary excretion. Beyond genetics, factors such as age, specific medical conditions, and certain medications can also subtly alter epitestosterone levels or the overall T/E ratio. For instance, alcohol consumption has been reported to influence the T/E ratio. These complexities underscore the need for comprehensive analysis and individual athlete biological passports in anti-doping programs.