Use of performance-enhancing drugs challenges experts, remains a moving target

Many tuned in to the 2012 London Olympic Games in July and August to see who would take home the most medals or who would set world records, but some in the scientific and medical communities had their eyes on doping — the use of performance-enhancing substances — and the lengths to which athletes would go to hide it.

“What is disturbing to me is how much effort that athletes now put into doping,” Richard J. Auchus, MD, PhD, professor of internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan Health System, told Endocrine Today. “In some cases, [athletes] spend more time trying to figure out how to dope and get away with it than they spend training. It’s sad because it’s just not what sports are all about.”

The problem of doping, however, extends far beyond one major athletic competition. The use of various hormones, such as testosterone and growth hormone, is widespread in some professional sports and, during the past 3 decades, has even spawned a subculture among non-athletes.

“We don’t know the exact numbers because, as is true of all drugs of abuse and other illicit behaviors, people are not necessarily forthcoming,” Shalender Bhasin, MD, section chief of the division of endocrinology, diabetes and nutrition at Boston University School of Medicine, said in an interview. “But experts who have watched this field evolve during the last 30 years feel that as many as 2 million Americans may have used anabolic steroids.”

Unfortunately, Auchus said, steroid use is a complex problem for which there is no easy solution. For instance, physicians and researchers often find themselves operating in the dark, with patients using multiple drugs at different doses in hopes of seeing a greater benefit or eluding detection. Moreover, there is no concrete way to identify those who will be affected most by the significant physical and psychological harms associated with steroids, including stroke, heart attack and liver damage, to name a few. Add in that these drugs are easily obtainable and the problem grows exponentially.

To further explore this complicated matter, Endocrine Today spoke with experts about current issues and misconceptions surrounding steroid use, as well as how athletic organizations, researchers and physicians are working to stay ahead of the dopers in this rapidly evolving field.

Questionable benefits

Although use varies by sport, androgens, such as testosterone and its synthetic forms, top the list of the most commonly used performance-enhancing substances among athletes, according to Auchus. Also popular are the two protein hormones GH and erythropoietin. However, questions persist as to whether some of these drugs actually improve athletic performance.

In a landmark study published in The New England Journal of Medicine in 1996, Bhasin and colleagues conducted a trial in which they randomly assigned 43 men to one of four groups: placebo with no exercise, testosterone with no exercise, placebo plus exercise and testosterone plus exercise.

Results revealed greater increases in muscle size in the arms and legs, and greater increases in strength in both bench-press and squatting exercises among men who received testosterone vs. placebo in the no-exercise groups. Further, those in the testosterone plus exercise group experienced greater increases in fat-free mass, muscle size and muscle strength when compared with either no-exercise group.

“We don’t have clear evidence that androgens enhance performance,” Bhasin said. “But they clearly increase muscle mass and strength, so in some types of athletic events, such as power lifting or shot putting, where you need greater strength, you can imagine that it would be beneficial. They have also been associated with quicker recovery time, which allows athletes to train harder.”

Similarly, the science suggests that erythropoietin provides an advantage in endurance sports, such as cycling or long-distance running, because it builds red blood cells and, therefore, increases oxygen consumption, according to Alan D. Rogol, MD, PhD, professor emeritus at the University of Virginia.

In contrast, evidence on GH is less definitive.

“In terms of athletics, the most interesting thing about GH is that there are real, known effects on the body,” Tamara L. Wexler, MD, PhD, of Massachusetts General Hospital, told Endocrine Today. “It does promote lean body mass and it does decrease fat mass and visceral adiposity, but does that change in body composition actually improve your performance? I haven’t seen anything to prove that at all.”

For example, Wexler cited a meta-analysis of 44 trials published in the Annals of Internal Medicine in 2008 indicating that GH increased lean body mass but had no effect on strength or exercise capacity. Moreover, the researchers found that participants treated with GH had significantly higher lactate levels during exercise in two of three studies evaluating that outcome. These participants also appeared to experience more soft tissue edema and fatigue when compared with those not treated with GH.

Even so, Bradley Anawalt, MD, professor and vice chair of the department of medicine at the University of Washington, said anecdotal and experiential evidence have perpetuated its use.

“Most scientists don’t believe it does much for performance,” he said. “But if you watch the Olympics and see an athlete lose a track and field event by one one-hundredth of a second, you can imagine that some people may consider the very small, potential advantage that might be conferred by GH as worth the risk.”

‘One step ahead’

Keeping pace with determined dopers is a difficult task, according to Anawalt, but researchers are making progress. Armed with new detection methods, officials are now able to identify those using certain performance-enhancing substances with more accuracy.

“Certainly, there are much better assays for compounds that are being used by athletes, and they’re used much more commonly,” he said, highlighting the fact that significant strides have been made with the use of liquid chromatography and mass spectrometry.

The use of carbon isotope ratio mass spectrometry, for example, offers a way to distinguish endogenous testosterone from exogenous testosterone. Currently, when screening for testosterone doping, sporting authorities measure the ratio of testosterone to epitestosterone and set a cutoff value of 4:1. Any higher, Anawalt said, is considered a failed test. However, before screening, some athletes co-administer testosterone and epitestosterone to avoid detection. A carbon isotope ratio would help settle any lingering suspicions regarding an abnormal test result.

Many challenges, however, still remain, according to Auchus. For instance, deletion of the UGT2B17 allele, which is common in Asians, lowers the testosterone-to-epitestosterone ratio and may allow people with this deletion to escape detection when doping. However, the potential for false positives also exists, with one study from the British Journal of Sports Medicine suggesting that a person may test positive for the banned substance nandrolone without having ingested any.

Screening for GH also is problematic, as the current test is limited by its short window of opportunity for detection — approximately 12 to 24 hours after the last GH dose — and a second biomarker test based on stimulation of insulin-like growth factor I and collagen III synthesis has a longer detection window but lower specificity, Gerhard P. Baumann, MD, of the Northwestern University Feinberg School of Medicine, wrote in Endocrine Reviews in 2012.

Nevertheless, researchers continue to develop ways to improve detection. One concept that harbors significant potential to improve screening is the athlete biological passport — an idea that the World Anti-Doping Agency has embraced.

“When an athlete gets tested, whether it’s their hematocrit to detect erythropoietin or the testosterone-to-epitestosterone ratio to detect synthetic androgens, those values are recorded, and deviations over time trigger a second, more sophisticated test,” Auchus said. “Athletes and chemists are always experimenting. We always have to stay one step ahead.”

In the works

Experts have been monitoring trends and potential new performance-enhancing drugs as they begin to appear to keep up with the criminals.

“On the horizon is gene doping,” Rogol said. “There’s no question that you can transfer genes into muscles and make the muscle hypertrophy in animals, and it likely will occur in humans. It should be virtually untraceable except for bits and pieces of the vectors that are used to transfer the DNA.”

Anawalt said gene doping would also work with erythropoietin. “Basically, you stick an altered erythropoietin gene from a human onto a virus and inject it into the arm, and the gene will work with the DNA of the human and increase red blood cell production,” he said. “This has been done in the context of clinical trials in patients with kidney diseases and cancers, but it raises the prospect of the possibility that athletes are going to do something similar themselves to basically increase their own production of red blood cells.”

Additionally, erythropoietin mimetics — small molecule compounds that act as agonists of the erythropoietin receptor — are concerning, as are selective androgen receptor modulators, which would provide the benefits of androgenic anabolic steroids without some of the adverse effects, such as virilization or feedback inhibition on the pituitary, according to Auchus.

Myostatin antagonists are also drawing attention, he said. Similar to androgens, these drugs may trigger muscle growth, but those gains will not necessarily translate into better athletic performance. Further, the possible adverse effects could be severe, including cardiac hypertrophy that can lead to diastolic dysfunction, heart failure and arrhythmias.

Significant risks

One of the primary problems encountered when trying to curb steroid use is that many people do not view these drugs as dangerous, according to Bhasin.

“There is a great misperception that anabolic steroids are safe,” he said. “Most of the published literature on androgen use comes from clinical trials of physiologic replacement testosterone doses in hypogonadal men. People then extend those observations to imply that large doses of androgens are safe as well, but the studies we have done were in healthy volunteers under pristine clinical research conditions with appropriate dosing.”

The reality, Auchus said, is that these drugs are linked to a whole host of adverse effects. Androgens, in particular, may cause irreversible voice deepening, breast atrophy, amenorrhea and virilization in women, even at very small doses, whereas men may experience infertility and testicular shrinkage. They can also cause polycythemia; LDL elevations and HDL suppressions; elevated liver enzymes; and liver failure.

Anawalt also said the issue of sexual dysfunction in androgen users is likely underappreciated. Designer androgenic steroids tend to have adverse effects on sexual function, potentially because the modification to the drug adversely affects the brain.

Furthermore, athletes tend to “cycle” and “stack” when doping, which further compounds these risks, according to Anawalt.

“Cycling means that you’re using different kinds of compounds in an alternating fashion. The rationale is twofold — one, that it may make it safer to take erythropoietin, for example, for a period of time and then switch to something else because they feel they will experience fewer side effects with drug holidays. Two, they think perhaps they’re less likely to be detected in cheating, which is inaccurate, but that’s the reasoning,” he said.

Stacking, however, involves taking more than one compound in a class at the same time. “If you’re taking anabolic androgenic steroids, you might take four different kinds, with the rationale being that there may be additive effects of these different steroids and maybe it’ll lessen the side effects of any one specific one,” Anawalt said.

Despite these significant physical risks, the psychological effects of androgens frequently receive the most attention. Often, though, people misunderstand this connection.

“Many people will take androgens and be able to maintain their same psyche, but with others, they become aggressive to the point where they can commit acts of violence, such as rapes or assaults,” Auchus said. “But only a minority of people experience this, and we have no way to predict who it’s going to happen to. It is also impossible to know which drug caused what, because they are using multiple androgenic steroids at very high doses.”

Additionally, performance-enhancing drugs, especially androgenic anabolic steroids, may be somewhat addictive, according to Anawalt. Because they allow people to recover more quickly, discontinuing use may cause discomfort.

“You feel crummy because you’ve turned off your own body’s production when using these very high dosages so that you get into a high feedback cycle where, in order to continue to feel good, you have to keep taking them,” he said. “It can be very difficult for people to stop.”

Beyond androgens

GH and erythropoietin also pose significant health risks, according to experts interviewed by Endocrine Today.

Abusing GH, for instance, can lead to many of the same negative effects that are seen with diseases of too much GH production, Wexler said. Fluid retention, joint ache and overall fatigue are perhaps the most recognizable symptoms, but the potential for more dangerous and lesser known side effects exists.

“Adults may start to develop an insulin antagonism that is similar to the type of insulin resistance that patients with diabetes experience,” she said. “People with excess endogenous GH (acromegaly) may develop a specific acromegaly-related cardiomyopathy with increased left ventricular mass, and have a 2- to 3.5-fold increased relative mortality risk. This hasn’t been studied in people who dope, but one can imagine that it may have negative sequelae along that spectrum.”

There are also concerns that GH may promote growth of existing cancers (though no evidence that GH causes cancer). Moreover, if an adolescent who has not yet completed puberty is abusing GH, he or she will experience changes in the bones because they have not completed fusing, leading to abnormal enhanced growth.

Erythropoietin is also dangerous when abused, Rogol said, noting that it can lead to strokes, as well as other conditions.

“As [people using erythropoietin] increase their hematocrit, blood has a greater resistance to flow, so they become phenomenally more prone to developing blood clots in the lungs,” he said. “People have died that way. It’s a dangerous drug.”

Hidden harms

Aside from the direct adverse physical and psychological effects, the culture surrounding steroid use, especially among non-athletes, presents its own dangers, according to Bhasin.

“People who use anabolic steroids also abuse other drugs; they share needles and can develop infections,” he said. “Also, there are personality types that are probably more susceptible to anabolic steroid use, and these personality types are also often prone to both homicidal and suicidal behaviors, as well as other risk-taking behaviors.”

Further, Bhasin said many of these people may end up in prison, placing them at high risk for contracting certain diseases, including HIV and hepatitis C.

Another point of consideration regarding steroid use among non-athletes, Bhasin said, revolves around duration of use. With an average career span of 3 years, many professional football players, for example, are unlikely to use performance-enhancing drugs outside of that length of time. Non-athletes who initiated use during the 1980s when steroids became more easily available and popular, however, have likely continued to use them and have, by now, accumulated 30 years of high-dose steroid use.

“Most of these people are entering their fifth or sixth decade of life,” Bhasin said. “One of the great concerns that we have is that we’re going to see a tsunami of health conditions as a result of long-term steroid use interacting with age-related comorbid conditions.”

Deeper concerns

Although the problem of doping in athletic competition usually takes center stage, putting an end to use of these drugs overall requires careful consideration of several issues, according to Auchus.

Easy access to steroids, for instance, is a major problem. Most people, he said, can simply turn to the Internet and order these drugs outside the country, and others can buy certain nutritional supplements that have similar properties at the local drugstore.

Another problem is the use of steroids to enhance athletic performance or, just as often, to enhance appearance, among adolescents. Auchus said, depending on what population is being examined, between 1% and 5% of adolescents have reported using these drugs, which is potentially representative of a larger problem that needs to be addressed as much as research and testing.

Bottom line, Auchus said, better efforts are needed to both stop and prevent the use of performance-enhancing drugs from growing.

“This is sort of one of those publicly acceptable forms of cheating because we’ve become somewhat numb to it,” he said. “It’s going to be hard to stop this, but the important thing is to try to prevent young people from starting to use these drugs. We want kids to participate in sports, to be healthy and to teach them teamwork and goal-setting and accomplishment, not how to get around the system.” – by Melissa Foster

How would you treat a patient who has admitted to using anabolic androgenic steroids and would like to discontinue use?

Watchful waiting is key

Generally, men using anabolic steroids are young, healthy and are very likely to recover without intervention, if indeed steroids are stopped.

I prefer to completely discontinue the steroid use and re-evaluate the patient after a predetermined period of time. Testosterone levels and sperm counts usually recover within 3 and 6 months, respectively. If the patient continues to experience problems, I would look for a pathologic cause like hypgonadism which I would treat appropriately with testosterone or gonadotropins.

Recovery after anabolic steroid use is dependent on a number of factors, including baseline hypothalamic-pituitary-testicular (HPT) function; dosage and duration of administration; coadministration of other substances or potential contaminants; co-existing illness and medication use; nutrition; and training intensity. Therefore, I would encourage the patient to reduce or manage these coexisting factors that might affect the testis function, in particular to stop or reduce training for a while and ensure proper nutrition.

An advantage of waiting and not treating immediately is that it allows the physician to uncover a possible underlying (albeit rare) defect in the HPT axis, such as an undiagnosed pituitary tumor that is causing the hypogonadism.

I probably wait a little longer than other physicians, but recovery of testosterone and sperm production is not generally a life-threatening problem. However, I do warn patients that a period of androgen deficiency following discontinuation of steroids may be associated with unpleasant symptoms. Waiting also gives me some time to ensure that the patient has completely discontinued steroid use and whether, for example, the patient is overtraining or nutritionally deficient.

Alvin M. Matsumoto, MD, is Professor in the Department of Medicine at the University of Washington School of Medicine, and Associate Director of the Geriatric Research, Education and Clinical Center at the VA Puget Sound Health Care System. Disclosure: Matsumoto is a consultant to the US Anti-Doping Agency and serves on the Scientific Advisory Board of the Partnership for Clean Competition.

Consider tapering testosterone replacement in certain patients

Whether the patient is asking to discontinue or I am recommending discontinuation, I present the patient with two options assuming that the patient did not have pre-existing hypogonadism.

The first option is discontinuation of the anabolic steroids and their related preparations, such as human chorionic gonadotropin, and allowing the patient’s hypothalamic-pituitary axis to recover. The second option is substitution of the anabolic steroids with a standard dose and preparation of testosterone followed by a guided taper. Neither of these options presents any significant medical risks. I also am very clear about my approach and clearly define the patient’s goals and concerns to ensure that we can work together.

Most patients opt for the guided taper because they want to avoid hypogonadal symptoms for a variety of reasons, including the fact that they may still be body building or sculpting or participating in similar activities. Essentially, they want to avoid the low testosterone levels that will occur during the interval between when they discontinue the steroid use and their own system recovers. I would use a dose that is not going to produce a high hematocrit or cause aggressive or unstable behavior. I do not, however, use hCG because it is not required for recovery of the patient’s own system.

I offer two options to increase the odds of accomplishing my primary goal of increasing the patient’s safety. This is accomplished by discontinuing anabolic steroids that are usually obtained as street or Internet drugs or with questionable content and avoiding the risks of high doses of anabolic steroids. My ultimate goal is to restore normal testicular function and avoid the risks of uncontrolled substances as well as unnecessary therapy with testosterone. If offering the patient a steroid taper will help them stop abusing anabolic steroids more quickly, then I think that is a benefit.

Daniel Spratt, MD, is director of reproductive endocrinology and infertility at the Maine Medical Center and Tufts University School of Medicine. Disclosure: Spratt reports no relevant financial disclosures.