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.
Richard J. Auchus, MD, PhD, said these drugs are linked to a variety of adverse effects, and it’s important for researchers to stay one step ahead.
Source: Hwei-Ming Peng, PhD, reprinted with permission.
“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
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.
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
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
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
“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.”
Alan D. Rogol
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.
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
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
“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
“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.”
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.”
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
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
For more information:
- Baumann G. Endocr Rev. 2012;33:155-186.
- Bhasin S. N Engl J Med. 1996;335:1-7.
- Kohler RM. Br J Sports Med. 2002;36:325-329.
- Liu H. Ann Intern Med. 2008;148:747-758.
- Anawalt is a consultant for the United States Anti-Doping Agency. Auchus is a co-investigator on grant from the Partnership for Clean Competition to study androgen detection methods and is a consultant for the US Anti-Doping Agency. Bhasin reported no relevant disclosures before the press date. Rogol is a consultant for Abbott, Novo Nordisk and Pfizer. Wexler is a neuroendocrinologist and expert in growth and sex hormones, who conducted clinical GH research at MGH.
How would you treat a patient who has admitted to using anabolic
androgenic steroids and would like to discontinue use?
Watchful waiting is key
Alvin M. Matsumoto
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
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
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
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