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THE PHYSICIAN AND SPORTSMEDICINE - VOL 26 - NO. 11 - NOVEMBER 98


Androstenedione et al: Nonprescription Steroids

When a journalist's peek inside Mark McGwire's locker launched androstenedione into the sports vernacular, the substance was already popular among bodybuilders. Now athletes at all levels—and the rest of the public as well—are hearing about the reputed performance-boosting effects of androstenedione. But what is not so widely known is that androstenedione is just one of several anabolic steroids that are available over the counter.

Bodybuilding enthusiasts call these substances, which are classed as dietary supplements, "prohormones." When athletes search the Internet for information about androstenedione, they see sales pitches for it and several other steroid supplements. The president of a supplement company predicted in Sports Illustrated that McGwire's androstenedione revelation would boost androstenedione annual sales from $5 million to $100 million (1).

Lewis G. Maharam, MD, a sports medicine specialist in private practice in New York City, says he thinks the rising popularity of steroid supplements is the most worrisome drug development in sports. "These drugs are steroids, no question about it," says Maharam, who is president of the New York chapter of the American College of Sports Medicine (ACSM). "And athletes aren't listening to their doctors, they're listening to Mark McGwire." (See Editor's Notes, "Is Mark McGwire a Hero?" page 5.)

Profiling the Drugs

Once ingested, androstenedione converts to testosterone, as do the dietary supplements dehydroepiandrosterone (DHEA) and androstenediol, says Larry D. Bowers, PhD, professor and director of the Athletic Testing and Toxicology Laboratory at Indiana University in Indianapolis. The lab is one of two in the US that are accredited by the International Olympic Committee (IOC). "These supplements are 'prodrugs' for testosterone," he says. Physicians should be aware that two other steroid supplements are available, he says: norandrostenediol and norandrostenedione, which convert to nandrolone, another banned steroid. There are no human studies in the medical literature on the long-term safety of these substances or their ergogenic effects. A 1962 study (4) documents conversion of androstenedione to testosterone in humans.

The anabolic effects of testosterone and nandrolone are well known. William Straw, MD, a family physician in Los Altos, California, and a team physician for the San Francisco Giants and the San Jose Sharks, says androstenedione at the dose recommended by most manufacturers (50 mg twice a day) is weak. "But many athletes don't take it at the recommended dose," says Straw, who is an advisory board member of the Association of Professional Team Physicians (APTP). Bowers adds that the compounds and doses athletes are taking would never be approved for research on ethical grounds.

The supplements are banned by the IOC, the National Collegiate Athletic Association, and the National Football League, but not by Major League Baseball, the National Basketball Association, or the National Hockey League. Use of the hormone supplements can be detected in drug tests: All of the substances raise the testosterone/epitestosterone ratio, Bowers says. "Some athletes aren't doing their homework on these supplements. There have been several positive tests," he says.

Steroid supplements can be expected to produce the same side effects as their prescription counterparts, Bowers says (table 1). Companies that market norandrostenedione and norandrostenediol claim that they cause fewer androgenic and estrogenic side effects than androstenedione and androstenediol. But Straw says, "We know a lot about that class of drugs. There's no safe way of taking them, despite what others may say."


Table 1. Side Effects of Anabolic Steroids


Men
Acne
Gynecomastia
Premature balding
Decreased high-density lipoprotein
Increased low-density lipoprotein
Increased total cholesterol
Thrombolytic disorders
Dependency
Irritability, aggressiveness
Kidney and liver dysfunction
Liver tumors
Peliosis hepatis
Testicular atrophy
Decreased sperm count
Prostatic hypertrophy
Prostatitis

Women
Acne
Clitoral hypertrophy
Decreased breast tissue
Deepened voice
Hirsutism
Irritability, aggressiveness
Kidney and liver dysfunction
Menstrual irregularities

Adolescents
Premature closure of growth plates
Severe facial and body acne


Sources: (1) Catlin D, Wright J, Pope H, et al: Assessing the threat of anabolic steroids. Phys Sportsmed 1993;21(4):37-44. (2) Gary I. Wadler, MD, personal communication, October 1, 1998. (3) United States Olympic Committee: Drug control education. Available at https://www.usoc.org/inside/in_1_3_7_3.html. Accessed September 23, 1998.


Bowers and other sources for this article are most concerned about the impact the supplements could have on adolescents. "Steroids can cause premature closure of the growth plate, and side effects in an adult could be a lot more serious in a teen," he says.

Talking Points for Physicians

Since McGwire admitted he used androstenedione, Maharam has fielded questions about the substance almost every day. He raises the following points in his discussions with young people:

  • Androstenedione and other steroid supplements are anabolic steroids.
  • The supplements can cause you to fail a drug test. US shot putter Randy Barnes, who won a gold medal in the 1996 Olympics, failed an out-of-competition drug test in July after taking androstenedione and is suspended from the sport.
  • Natural doesn't mean safe.
  • These steroid supplements are sold over the counter in this country because the US Food and Drug Administration (FDA) has weak rules.
  • The IOC bans drugs if they tilt the playing field or cause bodily harm. Anabolic steroids, which include these supplements, do both.

In addition, Maharam suggests that physicians talking with athletes about steroid supplements:

  • explain the side effects;
  • address questions that arise about creatine—explain that creatine is related to amino acids, not an anabolic steroid; and
  • be prepared to rebut advertising ploys athletes may have heard, such as the claim that anabolic steroids were the secret behind the past success of East German athletes. Tell athletes the other side of the story: that some East German athletes are suing their coaches and doctors over the long-term side effects.

Maharam says new supplements are emerging so quickly that it's difficult for physicians to stay current on what athletes are taking. When Maraham has a question about a new supplement or drug he calls the USOC drug hot line at (800) 233-0393.

Calls for Action

In September, the ACSM issued a statement urging the FDA to scrutinize supplements such as androstenedione. The Dietary Supplements Health and Education Act of 1994 limits FDA regulation of dietary supplements. "Many physicians feel that some 'supplements' should be considered 'drugs' because they contain known active ingredients, whereas 'dietary supplements' have little or no physiologic effect," ACSM president Paul D. Thompson, MD, stated in a press release. "Unfortunately, most supplements have not been evaluated for either their potential risks or benefits promoted via advertising." Thompson is director of preventive cardiology at Hartford (Connecticut) Hospital, a professor of medicine at the University of Connecticut School of Medicine in Farmington, and an editorial board member of The Physician and Sportsmedicine.

Straw says the APTP also issued a position statement on androstenedione. "We felt it should be banned in all competitive sports and it shouldn't be on the market. The next logical step will be to push the FDA to remove it from the market," he says.

In an editorial in The New England Journal of Medicine (2), editors Marcia Angell, MD, and Jerome P. Kassirer, MD, criticized Congress for weakening the FDA's jurisdiction over dietary supplements. They cited several cases of problems related to supplements. One involved a bodybuilder who had a central nervous system reaction to a supplement containing butyrolactone that he took to stimulate growth-hormone production (3). "The FDA can intervene only after the fact, when it is shown that a product is harmful," Angell and Kassirer noted.

If supplement makers fear their products will be forced from the market, they're using the threat to their advantage. Many ads on the Internet urge athletes, "Buy now, while you still can."

Room for Compromise?

The legal loophole that allows the sale of substances that are "only one enzymatic step away from the real thing" needs to be closed, says Gary I. Wadler, MD, associate professor of clinical medicine at New York University School of Medicine in Manhasset, New York. Wadler was the principal author of a book on doping and sport (5) and won the IOC President's Prize in 1993 for his work on the subject. He contends that as a class, hormones have too many harmful side effects—often occuring months, years, or even decades later—to be sold without a prescription.

Wadler doesn't see a groundswell of support yet for overturning the Dietary Supplement Health and Education Act of 1994, but he says Congress never meant for the act to fuel young people's interest in steroid supplements. He notes that in 1990 legislators were so concerned about anabolic steroid abuse that they reclassified the drugs as controlled substances.

"What I'm suggesting is a reasonable compromise," Wadler says. "Classify these hormone supplements as prescription drugs. This puts the responsibility for safety and efficacy back on the manufacturers' shoulders and interposes physicians in a role they rightfully should have."

References

  1. Hurricane Andro. Sports Illus 1998;89(10):22,24
  2. Angell M, Kassirer JP: Alternative medicine: the risks of untested and unregulated remedies, editorial. N Engl J Med 1998;339(12):839-841
  3. LoVecchio F, Curry SC, Bagnasco T: Butyrolactone-induced central nervous system depression after ingestion of RenewTrient, a "dietary supplement," letter. N Engl J Med 1998;339(12):847-848
  4. Mahesh VB, Greenblatt RB: The in-vive conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol 1962;41:400-406
  5. Wadler GI, Hainline B: Drugs and the Athlete. Philadelphia, Davis Co, 1989

Lisa Schnirring
Minneapolis


Two Reports Clarify EIA Treatment

Two recent studies published in The New England Journal of Medicine provide generally favorable evidence about the long-term use of salmeterol and montelukast to treat active patients who have exercise-induced asthma (EIA).

Salmeterol

In the first study (1), researchers examined whether salmeterol loses its protective effect with long-term use. Twenty patients who had EIA were treated with salmeterol or placebo each morning and evening for a month and were tested after exercise in cold air. For exercise done 30 minutes after dosing, the drug was effective through the whole month. But researchers found a decrease in protection from EIA when exercise was done 9 hours after the dosing.

In an editorial accompanying the two asthma studies (2), John Hansen-Flaschen, MD, and Helena Schotland, MD, pulmonary specialists at the University of Pennsylvania School of Medicine in Philadelphia, wrote that the study challenges two common notions about salmeterol: that a single dose provides 12-hour coverage in adults and that salmeterol loses its effectiveness against EIA over time.

Though the true duration of protection with salmeterol has not been determined, they say it's likely to be longer than that of albuterol. They suggest that salmeterol might be considered the drug of choice for preventing EIA in patients who exercise more than 30 to 60 minutes a day. "Patients should be advised to use salmeterol at least 30 minutes before exercise and to administer a second dose if necessary several hours after they begin exercising," they wrote.

William W. Storms, MD, an allergist in private practice in Colorado Springs, says the salmeterol study is more relevant to the treatment of patients who have chronic asthma than to those who have EIA only. He says the twice-a-day dose used in the study is usual for patients who have chronic asthma, whereas patients who have EIA alone take one dose 30 to 60 minutes before exercise. Thus, he says the reduction in protection that researchers found 9 hours after dosing would not affect patients who take salmeterol solely for EIA.

Given the findings, Storms says patients who have chronic asthma and take salmeterol twice a day may need to take a quick-acting asthma medication before exercise to ensure protection if the exercise is 9 hours postdose.

Storms said the study did not address once-a-day morning dosing, which is intended to provide all-day coverage for school kids who play sports. From his clinical experience, Storms says reduced protection doesn't seem to occur in such instances.

Montelukast

In the second study (3), researchers investigated whether long-term montelukast use protects patients who have mild asthma against exercise-induced bronchospasm (EIB). A group of 110 patients took 10 mg of montelukast or placebo once daily at bedtime for 12 weeks. They underwent exercise and methacholine challenge testing at baseline and at several points in the 12-week study, and again after a 2-week washout interval. The exercise tests were done 20 to 24 hours after dosing, at the end of the dosing interval.

Researchers found that montelukast consistantly protected against EIB over the 12-week test period without causing development of a tolerance or triggering a rebound worsening of lung function after treatment was stopped. After 12 weeks, the average decrease in EIB was 47%, though protection varied from complete in 23% of patients to little or none in 25%. The researchers said the absence of tolerance development distinguishes montelukast from other EIB treatments, such as albuterol.

Storms says the study agrees with his clinical experience. "Montelukast may benefit patients who have EIA, primarily as an additive drug when preexisting treatment is not adequate," he says. He notes that the EIB protection seen with montelukast is less than with albuterol or salmeterol.

In their editorial (2), Hansen-Flaschen and Schotland wrote that montelukast has several advantages over other EIA treatments: once-a-day oral dosing, 20- to 24-hour protection, no known side effects or drug interactions, and Food and Drug Administration indication for children older than 6. However, they said physicians should advise patients that one in four will not respond to montelukast.

Montelukast is a good option for competitive athletes, wrote Hansen-Flaschen and Schotland, because it and other leukotriene modifiers can be used without prior approval from the National Collegiate Athletic Association, the US Olympic Committee, or the International Olympic Committee.

References

  1. Nelson JA, Strauss L, Skowronski M, et al: Effect of long-term salmeterol treatment on exercise-induced asthma. N Engl J Med 1998;339(3):141-145
  2. Hansen-Flaschen J, Schotland H: New treatments for exercise-induced asthma. N Engl J Med 1998;339(3):192-193
  3. Leff JA, Busse WW, Pearlman D, et al: Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339(3):147-152

Lisa Schnirring
Minneapolis


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