Androstenedione for Performance Enhancement: Hard-Hitting Hormone
Androstenedione for Performance Enhancement: Hard-Hitting Hormone or Harmful Hype?
September 1999; Volume 2: 97-100
By Dónal P. O’Mathúna, PhD
Mark mcgwire became a baseball hero in 1998 when he broke Roger Maris’ home run record. During the season, the hero announced that he used androstenedione (or "andro"), which sent sales skyrocketing.1 McGwire put himself center stage in the debate over how natural an athlete’s performance ought to be. Some sports physicians and professional athletes accepted McGwire’s personal use of andro, but criticized him for not warning kids about its potential dangers.2 In response to this criticism, McGwire announced in August 1999 that he stopped taking andro four months earlier.3
Performance enhancing drugs are widely used. More than one million Americans have taken anabolic-androgenic steroids (AAS). Adolescents comprise one quarter of the users.4 After hearing the home run hero’s prior endorsement and looking at his forearms, many young athletes faced difficult decisions. Family members, coaches, and team physicians need to know about andro’s potentially dangerous lure for young athletes.
Background and History
Research in the 1930s showed androstenedione had effects like those of AAS.5 A 1962 study showed dramatic but short-term increases in serum testosterone levels.6 The former East German sports establishment conducted research which led to an androstenedione nasal spray.7 Athletes allegedly used this spray immediately before competition, relying on the spray’s short duration to avoid detection. After the fall of the Berlin Wall, this research was commercialized, resulting in a German patent for androstenedione.8
The 1990 Anabolic Steroids Control Act classified AAS as Schedule III controlled substances, making them more difficult to obtain.9 Androstenedione occurs naturally in Mexican yams and Scotch white pine, allowing its unrestricted sale in the United States in accordance with the 1994 Dietary Supplement Health and Education Act (DSHEA).
Pharmacology
Androstenedione (see Figure 1) is produced in the adrenal glands and gonads as part of the complex network of steroid hormones, being interconverted to testosterone, estrone, estradiol, androsterone, and others.4 Athletes seek the anabolic effects of AAS like androstenedione, including increased muscle mass, organ size, physical aggressiveness, and decreased body fat. Androgenic activity stimulates the development of exaggerated male characteristics, viewed by athletes as an undesirable side effect. Despite the best efforts of chemists, resulting in the synthesis of hundreds of AAS, all AAS retain some androgenic activity.9 Androstenedione’s direct anabolic-androgenic activity is weak.
Mechanism of Action
Androstenedione is promoted as a natural testosterone booster and legal "source" of testosterone. Increased testosterone levels lead to greater muscle mass and strength gains in athletes and non-athletes.10,11 AAS also increase protein synthesis in skeletal muscle and inhibit the catabolic effects of vigorous exercise, allowing faster recovery from intense training.4
Which of the following categories best describes the effects of androstenedione?
a. Anabolic
b. Androgenic
c. Both anabolic and androgenic
d. Neither anabolic nor androgenic
Clinical Studies
In one of two published studies of oral androstenedione, two women took 100 mg androstenedione and blood was drawn at 0, 30, 60, and 90 min.6 One woman’s 60-min testosterone level was 660% higher than baseline, and the other’s was 433% higher. The levels at 90 min remained elevated, but lower than the 60-min levels.
The 1995 German patent for androstenedione nasal spray included the results of human trials, but gave no details about the studies or their subjects.8 Fifteen minutes after taking androstenedione, total serum testosterone levels increased either 40-83% (after 50 mg orally), 111-237% (100 mg orally), or 34-97% (3.5-15 mg nasally). A 48-97% testosterone increase was reported three to four days after discontinuing the nasal spray; an elevated level remained for another six to seven days.
King et al reported the first randomized controlled trial of oral androstenedione and described two separate controlled studies. In the first, 10 healthy men (mean age, 23 years) were randomly assigned to either 100 mg andro-stenedione or placebo.12 Blood taken every 30 min showed androstenedione levels were significantly elevated—175% over baseline at 60 min and 325-350% between 90 and 270 min (P < 0.05). At 360 min, levels had returned to their 60-min level. Serum levels of free and total testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) remained unchanged.
In King’s second study, 20 healthy men (ages 19-29 years) undertook an eight-week resistance training program, and were randomly assigned to androstenedione or placebo.12 Tablets (100 mg androstenedione or placebo) were taken three times daily during weeks 1, 2, 4, 5, 7, and 8 to simulate "washing-out" (a common AAS practice that allegedly prevents tolerance and reduces risks). All subjects were supervised lifting weights for all major muscles three times weekly on nonconsecutive days. Resistance for each muscle was set at 80-85% of a one-repetition maximum (1-RM).
Data for one subject were excluded when blood tests revealed previously undiagnosed diabetes mellitus. Overall body composition, muscle strength, and muscle fiber analysis for all subjects were consistent with a successful conditioning program. However, no significant differences were found between the two groups. Those taking supplements had 100% higher serum androstenedione levels than baseline at weeks 2 and 5 (P < 0.05). At week 8, the level remained elevated, but not significantly (P = 0.07). No significant changes occurred in either free or total testosterone levels within either group during training. In summary, androstenedione supplementation neither increased serum testosterone concentrations nor enhanced the strength gains of resistance training.
Total cholesterol, LDL, VLDL, triglyceride, liver enzyme, total iron, hematocrit, and hemoglobin levels were unchanged in all subjects. LH, FSH, and estriol levels did not change. Estradiol levels were significantly (P < 0.05) higher at weeks 2 (+41%), 5 (+36%), and 8 (+27%) than at baseline. Estrone levels were significantly higher at weeks 2 (+44%) and 5 (+34%) than at baseline. Estrogen increases occurred in all subjects taking androstenedione and none taking placebo. Additionally, serum HDL cholesterol was 12% lower after two weeks of andro-stenedione, and remained lower to week 8 (P < 0.05).
Adverse Effects
Although no adverse effects were reported, the elevated hormone levels found in King’s study raise concerns. Increased serum estrogen levels have been associated with gynecomastia and increased risk of breast cancer in women and pancreatic cancer in men.12 Endogenously elevated androstenedione serum concentration has been observed to increase the risk of prostate cancer,13 though not in every study.14 Elevated androstenedione has been associated with increased risk of pancreatic cancer15 and leads to hirsutism.6 Lowered HDL cholesterol levels are independently associated with higher risk for cardiovascular disease. No studies are available on the adverse effects of long-term androstenedione use.16 The diabetes detected during King’s study was not reported as an adverse effect due to androstenedione.
Regulation
Androstenedione is banned by the National Football League, the National Collegiate Athletic Association, and the International Olympic Committee. The Association of Professional Team Physicians has recommended that it be banned from all competitive sports and taken off the market.17 The American College of Sports Medicine has called for reform of DSHEA because it fails to regulate drugs like androstenedione.18
Drug Interactions
One review reported that AAS in general increase sensitivity to oral anticoagulants and antidiabetic medications, but gave no further details.9 Reports of drug interactions with androstenedione itself were not found.
Formulation
Tablets and capsules contain 50 or 100 mg androstenedione. Manufacturers recommend 100-300 mg/d, though some go as high as 1,200 mg/d.1 Androstenedione is also available as a nasal spray, sublingual spray, and percutaneous gel. The nasal spray patented in Germany delivers 3.5-15 mg androstenedione per pump.8
Conclusion
King’s RCT provides clear evidence of adverse blood chemistry changes, and the scant data available provide no evidence that androstenedione has the effects athletes seek. The older data are poor in quality, but provide some support for a short-duration effect, possibly increasing aggressiveness. The single published RCT conflicts with prior claims that androstenedione boosts testosterone levels. However, the RCT used male non-athletes, and the effects may be different in trained athletes and in females. Further research is needed before King’s efficacy conclusions can be generalized to those more likely to use androstenedione.
Recommendation
Given the lack of demonstrated efficacy and the significant potential for adverse effects, discourage the use of androstenedione.
Dr. O’Mathúna is a Professor of Bioethics and Chemistry at Mt. Carmel College of Nursing, Columbus, OH.
Athletes using androstenedione and other AAS should be closely monitored if they are also taking medication for:
a. depression.
b. bacterial infections.
c. anti-inflammatory effects.
d. diabetes.
References
1. Yesalis CE III. Medical, legal, and societal implications of androstenedione use. JAMA 1999;281: 2043-2044.
2. Johnson K. As drugs in sports proliferate, so do ethical questions. New York Times. August 31, 1998:C9, C12.
3. Fallstrom RB. McGwire says he hasn’t taken andro. Available at: http://search.washingtonpost.com/wp-srv/WAPO/19990805/V000185-080599-idx.html. Accessed August 18, 1999.
4. Sturmi JE, Diorio DJ. Anabolic agents. Clin Sports Med 1998;17:261-282.
5. Kochakian CD. Anabolic-androgenic steroids: A historical perspective and definition. In: Yesalis CE, ed. Anabolic Steroids in Sport and Exercise. Champaign, IL: Human Kinetics Publishing; 1993:3-33.
6. Mahesh VB, Greenblatt RB. The in vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol 1962;41:400-406.
7. Benendonk B. The Gold, The Glory...and The Decay. Horton, Norway: Hilton Publishing; 1993. Cited by: Ketchum B. Androstenedione: The latest hormone supplement. EndurePlus 1997;2:1-2, 10-11.
8. Hacker R, Mattern C, inventors; Arrowdeen Ltd, assignee. German patent DE 42 14953 A1. 1995.
9. Blue JG, Lombardo JA. Steroids and steroid-like compounds. Clin Sports Med 1999;18:667-689.
10. Bhasin S, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996;335:1-7.
11. Kuipers H, et al. Influence of anabolic steroids on body composition, blood pressure, lipid profile and liver functions in body builders. Int J Sports Med 1991;12:413-418.
12. King DS, et al. Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men: A randomized controlled trial. JAMA 1999;281:2020-2028.
13. Barrett-Connor E, et al. A prospective population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Res 1990;50:169-173.
14. Andersson SO, et al. Serum pituitary and sex steroid hormone levels in the etiology of prostatic cancer: A population-based case-controlled study. Br J Cancer 1993;68:97-102.
15. Fernandez-del Castillo C, et al. Pancreatic cancer and androgen metabolism: High androstenedione and low testosterone serum levels. Pancreas 1990;5:515-518.
16. Creatine and androstenedione—two "dietary supplements." Med Lett Drugs Ther 1998;40:105-106.
17. Hormone homers? Univ CA Berkeley Wellness Lett 1999;15(4):6.
18. ACSM recommends that FDA revisit "dietary supplements" [press release]. American College of Sports Medicine; August 31, 1998.
September 1999; Volume 2: 97-100
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