If it were possible for you to take a pill that would turn you into an Olympic champion but would kill you soon after, would you take it? This question may seem absurd to many people, but when elite athletes were asked a similar question, about 50% responded “yes” [1]. Doping, or the use of banned performance-enhancing drugs, originated in ancient times [2], but the use of these substances has increased in recent decades [3]. Each year, more athletes are added to the list of those disgraced, imprisoned, and even killed due to the use of performance-enhancing drugs. Recently, the world-renowned cyclist Lance Armstrong added his name to the list, after more than a decade of denying allegations of doping.

So what are these substances for which athletes risk both their careers and their lives? How do they work? According to the 2013 Prohibited List published by the World Anti-Doping Agency, there are nine substances, three methods of doping, and two drug classes that are banned either in all or in a subset of professional sports [4]. However, this list is continually expanded as athletes find new ways to augment their performance. Consequently, with each new method of performance enhancement, researchers must search for a way to detect these substances. This article will focus on two methods for manipulating blood or blood components, as well as the use of testosterone and human growth hormone (GH), all of which are commonly-abused substances and among those that Lance Armstrong is accused of using [5].

Manipulation of Blood or Blood Components

The manipulation of blood or blood components is a method of performance enhancement utilized primarily by endurance athletes, such as cyclists, distance runners, and skiers [3]. The goal of this method is to increase the number of red blood cells (RBCs) in an athlete’s blood. Red blood cells are responsible for delivering oxygen to tissues throughout the body, including to the brain and muscles, using an oxygen-binding molecule called hemoglobin [3]. By raising the RBC count of an athlete, it is possible to increase his or her maximal aerobic power and thus, overall performance [6].

The primary methods of increasing an athlete’s RBC count are through the use of blood transfusions (aka “blood doping”) or by injecting the molecule erythropoietin. Erythropoietin signals to the body that oxygen levels are low, causing a cascade of events that results in an increase in RBCs [8]. Both of these methods of performance enhancement are popular among elite athletes since they are difficult to detect [5]. In fact, if athletes use their own blood for transfusions, blood doping is all but undetectable, since the newly transfused blood has no distinguishing characteristics. Red blood cells mature from stem cells, and in humans, the percentage of mature RBCs is normally less than 50%. Thus, in many sports, athletes are not allowed to compete if the percentage of mature RBCs in their blood exceeds 50%, but athletes have learned to outsmart this method of detection by using saline or plasma infusions to dilute the concentration of RBCs [5].

Testosterone

Testosterone is a hormone principally produced by the sex organs of men and women, and it is the primary sex hormone in males. Its use as a performance-enhancing drug is widespread among athletes of all skill levels due to its dramatic effects on appearance, strength and muscle mass [7]. Testosterone achieves these effects in several ways, but it does so most directly by increasing the creation of muscle cells from muscle cell precursors, called satellite cells. Researchers believe that testosterone acts on androgen receptors (ARs) in satellite cells. When testosterone enters the cell, it is converted into a form that allows it to bind to an AR, causing the release of proteins normally associated with the AR. The release of these proteins permits the AR to join with one other bound AR. The two receptors can now enter the cell nucleus and bind to DNA, leading to an increase in the transcription of certain genes involved in differentiation (see fig. 1). Although the process is not entirely understood, the activation of these genes forces satellite cells out of their typical resting state and results in the proliferation of muscle cells [7].

However, testosterone use also comes with many deleterious side effects, including increased risk of cardiovascular disease, changes to liver function and the reproductive system, in addition to potentially dramatic behavioral changes [7]. Testosterone abuse is detected using a urine test that measures the ratio of testosterone to another molecule called epitestosterone (called the T:E ratio for short). For the average person, this ratio is about 1:1, so if an athlete’s T:E ratio exceeds 4:1, there is reason to suspect doping, and the sample is subjected to further testing [7]. However, athletes can mask a high T:E ratio simply by injecting epitestosterone, which has no harmful effects [3].

Figure 1. Molecular mechanism of testosterone. After entering the cell, testosterone is altered such that it can bind the androgen receptor (AR). Binding to the AR displaces proteins normally associated with the receptor and allows the AR to come together with another bound receptor. When two ARs have come together, they can enter the nucleus and bind to DNA to initiate gene transcription of specific genes involved in changing the satellite cell into a muscle cell. Image based on [9]

Growth Hormone

Growth hormone is produced in the pituitary gland and normally stimulates growth and cell proliferation in humans. In patients with hypopituitarism, a condition resulting in decreased levels of GH, the administration of GH causes an increase in skeletal muscle and a decrease in body fat [8]. However, there is little evidence that the use of GH by healthy adults improves athletic performance [8]. Nonetheless, GH may be widely used for performance enhancement [8]. Growth hormone works by binding GH receptors on cells, causing the activation of many cellular signaling pathways, which can lead to cellular proliferation, prevention of cell death, and changes in the regulation of metabolic pathways. Side effects caused by the use of GH may include serious conditions such as acromegaly (which results in soft tissue swelling leading to enlarged appendages and internal organs), diabetes, osteoporosis, and carpal tunnel [8].

GH use in athletes is particularly difficult to detect because GH exists in many different forms (called isoforms). Moreover, because GH is also produced in cells of people who are NOT doping, and because it is secreted in pulses, it is not possible to rely on testing for concentrations that exceed normal levels [8]. Currently, the most common method of detection involves using antibodies to determine the ratio of the different isoforms in an athlete’s blood, since the proportion of different isoforms should remain constant in an individual who is not abusing GH [8]. This method of testing is often used in conjunction with what is known as the “GH-dependent marker method,” which exploits the fact that concentrations of some serum proteins are changed by the administration of GH [8].

Arms Race

Elite athletes experience a tremendous amount of pressure to perform from fans, sponsors, teammates, agents, and coaches, in addition to the extraordinary pressure they put on themselves. The drive to win can be so great that many of these athletes would give up their health or even their lives for a few years of success. Indeed, athletes have been taking that risk since the dawn of sports, and they will probably continue to do so, in spite of the threat of side effects, disgrace, and punishment. Thus, we have a veritable arms race between the athlete’s quest for the perfect performance-enhancing drug and the development of new technologies capable of detecting these new drugs.

Hannah R. Foster is a Ph.D. student in Molecular and Cellular Biology at Harvard University.

References

1) Bamberger M, Yaeger D: Over the edge: special report. Sports Illustrated 1997;86:64.

2) Grucza, Ryszard (2006, May). HISTORY OF DOPING. <http://www.wada-ama.org/rtecontent/document/Athens_Grucza.pdf> [20 January 2013]

3) Freudinrich, PhD. C. & Allen, K. (2000). How performance-enhancing drugs work. http://entertainment.howstuffworks.com/athletic-drug-test.htm# [11 January 2013]

4) World Anti-Doping Agency. The 2013 Prohibited List. Available at: <www.wada-ama.org> [13 January 2013]

5) Park, Alice. (2012). Which Drugs Is Lance Armstrong Accused of Taking? Time Magazine.<http://healthland.time.com/2012/08/24/which-drugs-is-lance-armstrong-accused-of-taking/> [13 January 2013]

6) Robinson, N., S. Giraud, C. Saudan, N. Baume, L. Avois, P. Mangin, & M. Saugy. 2006. Erythropoietin and blood doping. British Journal of Sports Medicine. 40:i30-i34.

7) Kadi, F. 2008. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. British Journal of Pharmacology. 154:522—528.

8) Holt, R.I.G. & P.H. Sönksen. 2008. Growth hormone, IGF-I and insulin and their abuse in sport. British Journal of Pharmacology. 154:542-556.

9) Gardner, D.G. & D. Shoback. Greenspan’s Basic and Clinical Endocrinology, eighth edition. New York: McGraw Hill. 2007.

Links of Interest

Lance Armstrong BIGGEST CHEATER In Sports History, Stored His Blood in Fridge <https://www.youtube.com/watch?v=t5_r7EX0Fy4>

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