WADA

Triathletes and Doping

January 29, 2014 By Larry Creswell, MD Leave a Comment

At my column this month at Endurance Corner, I wrote about age group triathletes and doping. Based on athlete questionnaires, a recent study found that about 15% of age group triathletes at three long course events in 2013 reported some form of doping in the preceeding year. I shared some information about the study and its findings as well as some of the cardiovascular concerns with the common doping agents.

Looking at the Tweets and comments today, some are surprised the rate is so high….and others are surprised it’s so low. I’m not surprised.

Anabolic Steroids and the Heart

June 12, 2013 By Larry Creswell, MD 8 Comments

I had a chance earlier today to visit with the production crew from Mississippi Public Broadcasting. They’re working on an upcoming television program on body building and were looking for information about the cardiovascular effects of anabolic steroids.

Also today, I came across a new study published this week (online, ahead of print) in the medical journal, JAMA Internal Medicine, that reported on a 40% increase in testosterone replacement therapy in middle-aged men during the time period from 2001-2011. The authors noted that testosterone replacement therapy was often prescribed without an established diagnosis of low testosterone levels (hypogonadism).

So….with steroids on my mind, I thought I’d share some information about these drugs, particularly as they relate to athletes.

What are Anabolic Steroids?

The history of anabolic steroids dates to the mid-1930s when the chemical structure of the male sex hormone testosterone was elucidated. Soon afterward, chemical synthesis of testosterone was possible in the laboratory.

The group of medications that we call anabolic steroids are synthetic derivatives of testosterone. These medications have a variety of arcane names including: nandrolone, methandienone, stanozolol, androsterone, and androstane, among others.

The anabolic steroids have 2 major groups of effects: androgenic effects and anabolic effects. The various available steroids differ from one another in the relative potency of these 2 sets of effects. Each manufacturer’s drug might then be targeted toward a specific use that focuses to a greater extent on one or the other of these sets of effects.

Clinically, the U.S. Food and Drug Administration has approved the use of anabolic steroids for: hypogonadism (eg, low testosterone level); generalized wasting in conditions such as human immunodeficiency virus infection (HIV), acquired immunodeficiency syndrome (AIDS), or cancer; hypoplastic anemias that accompany bone marrow failure or renal failure; growth stimulation in children with growth failure; male contraception; induction of male puberty; and gender identity disorder.

These medications can be delivered orally, intravenously, by intramuscular injection, or by transdermal patch.

The anabolic steroids should not be confused with the corticosteroids that are much more commonly used in clinical practice.

In 1990 the anabolic steroids were added to Schedule 3 of the Controlled Substance Act, making it a federal crime to possess these drugs in the United States without a prescription. For context, other drugs in Schedule 3 include the barbiturates, LSD precursors, ketamine, and some narcotic analgesics. The laws regarding the prescription and possesion of anabolic steroids vary from country to country.

Anabolic Steroids and Sports

The anabolic steroids have been used for decades by athletes of many different sports to gain competitive advantage. Used for this purpose, these drugs are often taken at many times the conventional prescription dosage. At these dosages, the anabolic steroids lead to an increase in muscle mass and likely potentiate the effects of exercise on gaining additional muscle mass and strength.

The first reliable tests for the detection of steroids (or their metabolites) became available in 1974 and anabolic steroids were added to the International Olympic Committee’s (IOC) banned substance list in 1976 and have been on the World Anti-Doping Agency (WADA) banned substance list since its inception in 1999. As such, these drugs are banned by the entire Olympic movement and by all sports organizations that adhere to the WADA code. In addition, these drugs are prohibited by the majority of professional sports organizations in the United States, including the National Football League, National Hockey League, National Basketball Association, and Major League Baseball.

How Many People are Using Anabolic Steroids?

The number of Americans currently using anabolic steroids is unknown, but some estimates have placed that number at more than 3 million. In surveys of steroid usage among body-building or power athletes, rates of up to nearly 70% have been reported, with considerably greater usage among male athletes.

What are the General Side Effects?

Many unwanted side effects have been attributed to anabolic steroids. Some are drug-specific and dose-dependent. The list of adverse effects of anabolic steroids includes: in men, enlargement of the breasts (gynecomastia), suppression of naturally-produced testosterone, decreased sperm production, and testicular atrophy; in women, increases in body hair, decreases in menstrual cycles, and lowering of the voice; development or worsening of acne; and alterations in the mood, with increased aggression. In order to avoid the unwanted side effects of gynecomastia and weight retention, men who use steroids sometimes also take drugs (eg, Arimidex) that limit conversion of the steroids to estrogen.

What are the Adverse Cardiovascular Effects?

Our understanding of the cardiovascular effects of the anabolic steroids comes from a relatively small set of observations made in athletes taking these medications and from a small number of animal studies. Retrospective human studies in this area suffer from important methodologic problems such as: incomplete or inaccurate reporting on drug dosages by athletes; confounding influences of other supplements or medications that athletes may be taking; and the cardiovascular effects of an athlete’s training routine that may mimic some of the effects of steroids.

Some, but certainly not all studies, have shown an increase in blood pressure attributed to anabolic steroids. This issue has been difficult to study in power athletes because of the myriad of factors that influence the blood pressure, including weight-lifting itself. There are certainly anecdotes of finding cases of severe hypertension in athletes who have no other obvious cause than steroids. The amount of blood pressure elevation associated with long-term use of steroids appears to be mild to moderate and the effect may subside if the steroids are stopped.

The majority of studies show that anabolic steroids have an unfavorable effect on the serum lipid profile. These medications can lead to a 20% increase in the unhealthy, “bad” cholesterol (LDL) and also a 20% decrease in the healthy, “good” cholesterol (HDL). The exact mechanism for these changes has not been established. These changes are thought to develop within weeks of starting steroids and can linger for months after these medications are stopped, despite a relatively short pharmacologic half-life measured in days. Some studies have suggested that the oral route of administration may be worse in this regard than the injectable route. These unfavorable changes in the serum lipid profile are noteworthy because there is considerable evidence that high LDL and low HDL levels are associated with increased risk for coronary artery disease, heart attack, and stroke.

Athletes who use anabolic steroids are often found to have thickening of the muscular walls of the left ventricle that we call left ventricular hypertrophy (LVH). The degree of hypertrophy can range from mild to severe. But to date, there has not been a long-term, carefully controlled, prospective study to help sort out the precise effects of steroids. The data regarding which portions of the left ventricle become hypertrophied have been inconsistent, but it appears that the resulting LVH may not be uniform throughout the chamber. It’s important to remember, though, that power exercise alone can produce LVH and that elevated blood pressure alone can produce LVH, and both of these influences will be in play in power athletes.

Sudden cardiac death (SCD) may occur in athletes who are taking anabolic steroids. This appears to be a rare event. In the absence of any other explanation, it might be easy to ascribe such deaths in otherwise healthy athletes to the steroids. But we can only speculate now about the mechanism by which steroid use might predispose the athlete to SCD. Nonetheless, there have certainly been athletes with SCD where autopsy findings have shown severe LVH or cardiac fibrosis (which might predispose to arrhythmias) where no potential cause except the steroids was obvious.

Acute myocardial infarction (MI), or “heart attack” may occur in young athletes who are taking anabolic steroids, often without any prior indication of heart disease. The cause-and-effect relationship between steroids and MI is not completely understood, but we know from animal studies that the steroids may increase platelet aggregation–a step that occurs clinically during sudden blockage of one of the coronary arteries during acute MI. We also know from animal studies that the steroids may increase oxygen demand of the cardiac muscle, potentially leading to a mismatch in blood/oxygen supply and demand during exercise. This may also play a role.

The precise epidemiologic link between steroid use and mortality is yet to be established. Small studies have shown that among users of anabolic steroids, the cause of death, perhaps not surprisingly, is cardiac in up to two thirds. One interesting recent study from Sweden identified users of anabolic steroids by blood tests (toxicology screen) that were administered during evaluations for some other medical problem. The investigators found that, over a several-year period, the mortality rate for users was 2-5 times that for non-users. The study was not controlled, though for many other, potentially important, factors that influence mortality.

Some Thoughts

To reiterate, our current understanding of the adverse cardiovascular effects of anabolic steroids is based on rather limited information gathered from a small number of research studies. The available reports, though, certainly give a glimpse of unwanted cardiovascular effects that may occur, even if the causal mechanisms are not yet understood. Going forward, we are unlikely to have large-scale prospective studies to gather more information and additional retrospective studies are likely to have the methodologic pitfalls I mentioned above. Given our current understanding, athletes who choose to use anabolic steroids should be aware of the possibilities of high blood pressure, unfavorable lipid profile, structural changes in the heart, and even heart attack or SCD.

A Primer on EPO

December 28, 2012 By Larry Creswell, MD 2 Comments

Lance Armstrong was certainly in the news this year, with the ongoing–and seemingly endless–saga of the USADA investigation into the use of performance enhancing drugs (PED) in professional cycling. I’ve gotten several inquiries about erythropoeitin (EPO) and thought that I’d write a short piece about the agent, its effects on the heart and vascular system, its use as a PED, and a little about the detection of its use.

The Hormone

The first thing to understand is that erythropoetin is a naturally occurring glycoprotein hormone. The existence of this hormone was theorized as early as the 1950’s and the hormone was given the name erythropoeitin, but its isolation proved to be very difficult. The human body produces more than a half ton of blood in a lifetime, but only enough EPO to make a tiny pill. Early efforts sought to isolate the hormone from patients who were thought to have increased levels of EPO–those with anemia of various sorts. It was the serendipitous observation that excess erythropoeitin was excreted in the urine that eventually led to the isolation of the hormone. In 1977, Eugene Goldwasser from the University of Chicago isolated 8 mg of erythropoeitin from the dried concentrate of 2,550 liters of urine colleted from a group of aplastic anemia patients in Japan.

We know today that EPO is produced primarily in the kidney, and less so in the liver, and acts to stimulate production of red blood cells (RBCs) in the bone marrow.

The Blood

It helps with this discussion to have an understanding about blood itself. We often take for granted this liquid that courses through the body’s arteries and veins. There is a cellular component to blood–cells that we typically call red or white. The RBCs far outnumber the white blood cells (WBCs), and it is the RBCs that are important for today’s discussion. The non-cellular component of blood is the plasma, made up predominantly of water, but containing a large variety of proteins, minerals, and other substances.

The body produces RBCs in a process known as erythropoeisis. In adults, new RBCs are produced primarily in the bone marrow of the sternum (breast bone), vertebral column, and pelvic bones in a process that takes about a week. Immature RBCs are called reticulocytes and comprise about 1% of the total population of RBCs. RBCs have a lifespan of about 4 months and are then destroyed in the spleen or liver. The typical adult has about 20-30 trillion or so RBCs.

One measure of the amount of RBC’s in the blood is called the hematocrit. If we take a small tube of blood, centrifuge it for a period, we’d be left with cells (mostly RBC’s because they outnumber the other cells, by far) in the bottom of the tube and plasma at the top of the tube. The ratio of cells to plasma, expressed as a percentage, is the hematocrit. At my hospital’s laboratory, the normal range for the hematocrit is 36.2% – 46.3% for adult men and 32.9% – 41.2% for adult women.

The RBCs contain the iron-containing protein, hemoglobin, that allows the red blood cells to carry oxygen to the body’s tissues. Nearly 99% of the blood’s oxygen is bound to the hemoglobin molecules; only about 1% is actually dissolved in the blood’s plasma. In medical school, we learned that the RBCs with hemoglobin are the “box cars” of the train that delivers oxygen to the body’s tissues.

The amount of hemoglobin in the blood can be measured. At my hospital’s laboratory, the normal range is 11.9 – 15.4 g/dL for adult men and 10.6 – 13.5 g/dL for adult women.

There is a feedback mechanism in which low blood oxygen levels stimulate production of Epo by the kidney, which in turn stimulates production of RBCs in the bone marrow.

The Drug

The protein structure of EPO was worked out in the early 1980’s and the agent was commercially available by 1985. The U.S. Food and Drug Administration (FDA) approved epoeitin alpha in June, 1989. Today, the agent is a made by genetic engineering techniques and produced in bacteria. The first commercially available product was Epogen, manufactured by Amgen Pharmaceuticals, but there are now several other formulations that are available.

One common brand of epoeitin alpha is Procrit, manufactured by Janssen Pharmaceuticals. I’ll summarize the information provided by Janssen about their drug in their product insert, but the information will be similar for all of the formulations of epoeitin alpha.

Procrit is used for the treatment of anema due to: chronic kidney disease; the use of Zidovudine in patients with HIV infection; and the use of chemotherapy agents in patients with cancer. It is also indicated for reduction of RBC transfusion in patients undergoing elective, noncardiac, nonvascular surgery. The drug is an injectable agent that can be administered intravenously or by subcutaneous (beneath the skin) injection. The appropriate dosage depends upon the reason for its use.

Procrit produces an increase in the reticulocyte count within 10 days and an increase in the hematocrit and hemoglobin over a 2- to 6-week period. The rate of increase in each of these measured outcomes depends upon the dosage administered.

The use of agents like Procrit must be monitored carefully because there are potentially serious side effects or unwanted consequences, including myocardial infarction (“heart attack”), stroke, venous thromboembolism, thrombosis (clotting) of vascular access, tumor progression or recurrence, and even death. Indeed, the over-use of EPO would be implicated as a possible link to the deaths of 18 Dutch and Belgian cyclists from 1987 to 1990.

EPO as a Performance Enhancing Drug

Dating back to at least the 1960’s athletes were aware of the potentially performance-enhancing effects of blood doping. You may recall that the 1968 Summer Olympic Games were held in Mexico City, at an elevation of 7,350 feet. It was recognized at those Games that athletes from higher altitudes performed well in the endurance events, presumably because of chronic adaptations to altitude that included an increased red blood cell mass. There are many descriptions of athletes using autologous transfusion (of their own banked blood) to enhance athletic performance in the subsequent couple decades. It wasn’t until after the 1984 Olympic Games in Los Angeles that blood doping was banned by the International Olympic Committee (IOC). But as I mentioned above, it was in the mid-1980’s that EPO became available and this would become a new avenue for increasing athletic performance.

The physiologic aspects of blood doping are worth considering for a moment, even in a simplistic fashion. In the endurance sports, athletes are limited by the amount of oxygen that can be delivered and used by the body’s skeletal muscles. We might say that the aerobic capacity is related to the cardiac output (the amount of blood pumped per minute), the hemoglobin mass (the amount of hemoglobin in that blood), and the rate of oxygen extraction in the muscles. In the trained athlete, the hemoglobin mass might be the most easily influenced variable–one that is increased by blood doping or by the use of EPO.

In a previous blog post, I talked about the common heart-related medications that are included in the World Anti-Doping Agency’s Prohibited List. In addition to banning blood doping–the transfusion or administration of blood, blood products, or blood substitutes–the Prohibited List in section S2.1 specifically bans erythropoeisis-stimulating agents such as EPO. All similar agents, as well as genetic methods related to erythropoeisis, are banned as well.

Detection of EPO

When Epo was first available, there was no method for detecting this PED in athletes. As an indirect method, professional cycling first conducted pre-race tests of the hematocrit, banning male athletes with a hematocrit >50% and female athletes with a hematocrit >47%. Keep in mind that in a retrospective study of blood donors in Denmark, 3.9% of non-athletes and 10.4% of elite rowers were found to have a hematocrit >51%. So measurement of the hematocrit alone is not a realistic way to identify use of EPO as a PED.

In 2000, the French national anti-doping laboratory developed a urine test that could identify the difference between an athlete’s naturally-occurring endogenous EPO and synthetic EPO taken as a PED. This test took advantage of the the fact that each EPO type is actually a family of substances, each with the same protein structure but differing glycosylation, producing molecules of differing electric charge which were separable by the technique of electrophoresis.

This test was first used at the 2002 Salt Lake City Olympic Games, where 3 athletes (who had won 8 medals) were disqualified because of the detection of synthetic EPO in the urine.

In 2009, WADA has begun the use of a “biological passport” program to further enhance its ability to identify athletes who have used blood doping or the use of EPO. With this program, longitudinal profiles (over time) are kept of an athlete’s blood-related parameters: hematocrit, hemoglobin, additional RBC parameters, the reticulocyte count, and serum EPO level. At its simplest, the measurements of serum EPO and reticulocyte count INCREASE after administration of synthetic EPO; these same measurements DECREASE after RBC transfusion or stopping the use of synthetic EPO. Unexplained changes in the parameters over time, particularly when linked temporally to competitions, can then be the evidence of doping.

Heart Medications, WADA, and the Athlete

September 8, 2012 By Larry Creswell, MD 1 Comment

I occasionally get questions about athletes’ medications and the issue of doping, usually from amateur athletes who are simply concerned about breaking the rules of their sport. I’m certainly not an expert at all of the aspects of doping rules, detection and enforcement efforts, and participation of various events/sports in organized anti-doping efforts, but it’s worth discussing some important points that will be generally applicable.

Many competitive sports will be involved with the efforts of the World Anti-Doping Agency (WADA). So-called signatories to the WADA Anti-Doping Code agree to a set of policies, rules, and regulations that govern the conduct of their particular sports. Current signatories include all organizations related to the broad Olympic Movement (eg, USA Triathlon, USA Swimming, USA Track & Field); many national sport organizations (eg, U.S. Anti-Doping Agency [USADA]); and various miscellaneous sports organizations (eg, World Karate Organization, World Triathlon Corporation [WTC]). If you participate in activities of these organizations, the rules of the WADA Code apply to you and you should be familiar with these rules.

WADA periodically publishes a Prohibited List that outlines prohibited substances and methods. The most recent List was published in August, 2011 and went into effect on January 1, 2012. There are separate requirements for in- and out-of-competition settings and there are special rules that apply to certain sports.

With heart disease being so common in the American adult population, especially if we include hypertension, it’s worth drawing attention to several items on the Prohibited List:

1. Non-approved substances. Pharmacologic substances that are investigational (ie, not yet approved by a national regulatory agency) are prohibited at all times.

2. Peptide Hormones, Growth Factors, & Related Substances are prohibited at all times. Examples include erythropoeitin (EPO) and insulins.

3. Beta-2 Agonists are used to treat asthma and other pulmonary diseases. These medications are prohibited at all times EXCEPT for salbutamol (eg, Albuterol) or formoterol (eg, Symbicort) used at dosages in accordance with the manufacturer’s recommendations. Athletes who use salbutamol or formoterol are subject to urine testing where levels of >1000 ng/mL or >30 ng/mL, respectively, indicate usage in excess of the manufacturer’s recommendations.

4. Diuretics, in virtually every form, are prohibited at all times. These medications (eg, hydrochlorothiazide [HCTZ], spironolactone, metolazone, acetazolamide) are common and are used alone or in combination with other agents to treat patients with high blood pressure and also in patients with heart failure. They are on the Prohibited List because they can mask the detection of other agents on the List.

5. Stimulants, in all forms, are prohibited during competition EXCEPT for a small group of stimulants included in the 2012 Monitoring Program: caffeine, nicotine, phenylephrine, phenylpropanolamine, pipradol, and synephrine.

6. Narcotics are prohibited during competition.

7. Cannabinoids (ie, marijuana) are prohibited during competition.

8. Alcohol is prohibited during competition for the following sports: aeronautic, archery, automobile, karate, motorcycling, powerboating.

9. Beta-Blockers (eg, atenolol, carvedilol, metoprolol) are prohibited during competition for the following sports: aeronautic, archery (also, out-of-competition), automobile, billiards, boules, bridge, darts, golf, ninepin and tenpin bowling, powerboating, shooting (also, out-of-competition), and skiing/snowboarding.

I suspect that there are many amateur athletes participating in a sport governed by the WADA Code who are using one or more of these substances. Armed with some knowledge about the rules, one logical approach might be to have a discussion with your doctor about alternative(s) to the prohibited medications. Sometimes there might be a viable alternative. Other times, a particular agent may well be the most appropriate choice of medication for a given athlete with a specific medical problem. In that case, there is an oppotunity to obtain a Therapeutic Use Exemption (TUE)–permission to use a prohibited substance because of its medical necessity. Information about the TUE application process is available through WADA. Athletes will file applications with either their sport’s international federation or their country’s anti-doping agency.