Baseball's hGH Testing: An Imperfect, But Effective, Solution

As a condition of Major League Baseball's new collective bargaining agreement, the league will begin testing for human growth hormone, or hGH. But how effective will the testing be? Our medical expert, Dr. Ali Mohamadi, explains.

With Monday’s announcement that Major League Baseball will begin testing players for illegal use of recombinant human growth hormone (hGH) under its new collective bargaining agreement, a sport that was once ridiculed for its lax drug policy now finds itself with the most comprehensive testing program in North American professional athletics.

Over the past decade, dozens of major leaguers have been linked to use of recombinant hGH, a synthetic version of the naturally-occurring growth hormone banned by MLB since 2005, as a performance-enhancing supplement. Under yesterday’s agreement, players testing positive would face a 50-game suspension for their first offense, 100 games for their second, and a lifetime ban for their third, with the program initially limited to Spring Training and the offseason before potentially being expanded to include the regular season in later years. 

Despite the praise Commissioner Bud Selig and the MLB Players Association have received for this unprecedented step, however, for years scientists have questioned whether this particular hGH test, known in some circles as the "Isoform Test," is accurate enough to warrant being used in a widespread fashion. While these questions are legitimate, the mere possibility that the threat of being caught might deter players from using a drug with hazardous side effects is reason enough to believe the decision to test for hGH is the right one.

Human Growth Hormone: A Natural Performance Enhancer

Naturally-produced hGH is made in the pituitary gland, a pea-sized structure at the base of the brain that is responsible for releasing various hormones into the bloodstream. When hGH enters the bloodstream, it has three main targets: the bones and muscles, which enlarge and strengthen due to its effect, and the liver, which it instructs to produce additional hormones that themselves have anabolic (growth/body building) properties.

In childhood, hGH is vital to achieving normal height gain, and in adulthood it is critical for maintenance of muscle mass, bone density, and normal healing and recovery processes. Because of these effects, at face value the temptation for baseball players to use hGH is not surprising: in theory, it allows batters to hit farther, pitchers to throw harder, and injured players to return to action faster than normally.

In the United States, recombinant hGH has been approved by the FDA since 1985 for the treatment of adults with the inability to produce natural growth hormone, and more commonly for children with short stature due to a number of medical conditions. Recombinant hGH is administered as an injection that must be given 5-7 days per week in order to maintain effectiveness. This high frequency of injections is due to the fact that the drug has a short half-life, meaning that it is removed from the body in a matter of hours after it is given. This short half-life is what makes recombinant hGH so difficult to detect, and in combination with its effects on strength and endurance is what makes it an enticing – albeit illegal – performance enhancing drug for athletes.

The Challenges Of Developing An Ideal hGH Test

Creating a test to detect synthetic hGH in the blood or urine has been a struggle for scientists since the drug was first engineered in the early 1980s. MLB is proposing to implement the Isoform Test, which is endorsed by the World Anti-Doping Agency (WADA) and has been used in minor league baseball since 2010.

Until the 2004 Summer Olympics in Athens , hGH doping was considered undetectable. For starters, this was due to its short half-life in blood, which meant if the sample was not taken within several hours of administration, it would go unnoticed.

To make matters more difficult, natural hGH is released by the pituitary gland in waves over the course of a day, leading to highly fluctuating levels in the blood that are nearly impossible to predict. In fact, at any given time, normal individuals can have levels that run the spectrum from extremely high to undetectable.

Finally, hGH levels are affected by factors such as sleep, nutritional status, and exercise, with levels rising sometimes above the range of normal after strenuous activity. Therefore, in the case of athletes, it could be difficult to determine whether a high value is due to recombinant hGH administration or merely coming off a tough workout.

The hGH Isoform Test: Ideal, in Theory

These factors led researchers to turn their attention to analyzing the structure of hGH rather than the actual levels in the bloodstream. Natural hGH made in the pituitary gland comes in several sizes, known as isoforms. It is known that in a normal individual about half of the hGH molecules in the bloodstream are 22 kilodaltons in weight (known as the 22 kilodalton isoform), but the remainder is made up of isoforms of many different sizes. In comparison, the recombinant hGH that can be purchased on the market is 100% comprised of the 22 kilodalton isoform.

Researchers learned that they could use this key difference between naturally-produced hGH and recombinant hGH to their advantage. When recombinant hGH is injected into the body, this increases the proportion of the 22 kilodalton isoform in comparison with all other isoforms. Moreover, with long-term use, the pituitary slows down its production of natural hGH, which also favors the proportion of the 22 kilodalton isoform.

Therefore, the Isoform Test that has been endorsed by WADA and will be used in MLB is a measurement of the proportion of the 22 kilodalton isoform in the blood. Researchers have established a threshold for what is considered a "normal" abundance of that isoform in a healthy individual. Players whose results exceed the threshold (and then are backed up by a confirmatory, repeat test) will fail the test and be notified by MLB.

An Imperfect Solution…

That said, despite widespread use of the test (especially in Europe) since WADA’s endorsement, only eight athletes across the globe have tested positive since it was unveiled during the 2004 Summer Olympics, leading many to believe it lacks the accuracy to be considered credible. Despite the sound science behind the hGH isoform test, there is a reason so few athletes have tested positive so far: it has a high false negative rate, meaning that it fails to detect users rather frequently. This is due to a number of factors, but two are of particular importance.

First, the accuracy of the test is limited to approximately 20-30 hours after administration of recombinant hGH. As previously mentioned, for maximum effectiveness, the drug must be administered 6-7 days per week, but it is possible if testing is done on an "off day," or if an individual knows in advance when he will be tested and holds off on taking it for long enough, the test may turn out negative.

Second, active exercise not only increases the amount of hGH in the bloodstream, but in normal individuals it preferentially increases the proportion of 22 kilodalton hGH for a short period of time compared to the other isoforms. Therefore, a borderline positive result could theoretically be explained as being due to a recent period of strenuous activity.

…But a Solution That Deserves Implementation

Despite these limitations, which are noteworthy, there is evidence to indicate that with experience, the accuracy of the Isoform Test has improved. To this point, all eight athletes who have tested positive – including Mike Jacobs, a minor leaguer in the Colorado Rockies’ organization who was caught in August, 2011 – were screened over the past two years. And despite the relative paucity of positive tests as a whole, it stands to believe that having a test in place would deter some players from continuing to seek the drug illegally due to the implications of a positive test.

When hGH testing has been discussed in the past, some athletes have expressed concern that the volume of blood required could impact their ability to perform at a high level on the day of the test. However, the Isoform Test only requires about a teaspoon of blood to be drawn, on par with most other routine lab tests, and therefore should be quite safe.

Which segues to a final point, and the most important one: safety. In order to achieve increases in muscle strength, endurance, and function, recombinant hGH must be given in higher-than-normal doses that carry innumerable risks, including but not limited to diabetes, high blood pressure, heart disease, osteoporosis, and abnormal bone growth. With the decision to institute hGH testing starting this Spring, MLB and the MLB Players’ Association have made a pledge to put player safety first.

And this is reason enough to support this bold show of leadership, whether or not the test is perfect.

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