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September 2001; Volume 4; 103-107
By Dónal P. O’Mathúna, PhD
Androstenedione (or "andro") was reviewed here shortly after its meteoric rise to fame in 1998.1 That year Mark McGwire broke Roger Maris’ home run record, announcing along the way that he used andro and other dietary supplements as performance-enhancing substances.2 The next year, McGwire stated he no longer used andro, but its reputation and widespread use has persisted.
When McGwire made his announcement, few studies had examined androstenedione’s effectiveness or safety. Many governing sports bodies banned andro as yet another anabolic steroid. Several studies have since demonstrated that androstenedione’s potential harm far outweighs the slim chance of benefit. Athletes and their parents, coaches, and team physicians need to hear about these new results.
Background and History
Androstenedione has been studied as an anabolic-androgenic steroid (AAS) since the 1930s.3 Interest was confined to researchers until the former East German sports establishment looked to it as an alternative to testosterone injections.4 Athletes allegedly used an androstenedione spray, which was later patented in Germany after the fall of Communism.5
Since AASs were classified as Schedule III controlled substances in 1990, more athletes turn to "prohormones," substances allegedly converted into testosterone by the body.6 These products are naturally occurring and can be sold virtually without restriction under the 1994 Dietary Supplement Health and Education Act. Androstenedione occurs naturally in Mexican yams and Scotch white pine. The United States is a primary source of andro for athletes around the world.
Androstenedione is produced in the adrenal glands and gonads as part of the complex network of steroid hormones.7 Androstenedione is the immediate precursor of testosterone (see Figure), although its direct anabolic- androgenic activity is weak. Athletes seek these anabolic effects in addition to increased physical aggressiveness and decreased body fat. Androstenedione is a precursor of testosterone, but also of estrogens, especially in males.8
Mechanism of Action
Androstenedione is alleged to act as a natural testosterone booster. Numerous studies have shown that testosterone increases muscle size, muscle protein synthesis, and muscle strength.9 AASs also inhibit the catabolic effects of vigorous exercise, allowing faster recovery from intense training.7 The question is whether androstenedione produces these effects.
Early research remains the basis of andro promotional materials. The earliest study gave two women 100 mg androstenedione.10 After 60 minutes, one woman’s testosterone level was 660% higher than baseline, and the other’s was 433% higher. At 90 minutes, the levels remained elevated, but lower than at 60 minutes. The 1995 German patent for androstenedione nasal spray gave no methodological details but stated that after 15 minutes total serum testosterone levels increased 40-83% (after 50 mg orally), 111-237% (100 mg orally), or 34-97% (3.5-15 mg nasally).5 Testosterone levels were 48-97% higher 3-4 days after discontinuing the nasal spray and remained elevated for another 6-7 days.
Our earlier review of androstenedione described in detail the only controlled study then available, by King and colleagues.1 King reported two studies, one examining serum changes and the other investigating muscle and strength changes after exercise.11 In the first, 10 healthy men were randomly assigned to either 100 mg androstenedione or placebo. Those taking androstenedione had significantly elevated blood levels of androstenedione, but unchanged levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH).
Several other studies have since examined serum changes. In correspondence, King referenced two unpublished preliminary reports in which 100 mg androstenedione failed to increase testosterone levels.12 An open-label, randomized study gave 42 healthy males (ages 20-40 years) androstenedione (either 100 or 300 mg/d) or placebo for seven days.13 The 300 mg/d group showed a significant 14% increase in testosterone (P < 0.01) which differed significantly from both other groups (P < 0.001). Testosterone levels did not change in those two groups. Estrone and estradiol concentrations were significantly elevated after both 100 and 300 mg/d androstenedione (P < 0.002).
In a randomized, double-blind, cross-over study, eight males (average age 23.8 years) received a single dose of 200 mg androstenedione, 200 mg androstenediol, or placebo.14 Androstenediol is similarly converted into testosterone and is frequently added to "andro" products.15 Testosterone concentrations did not vary significantly, but when analyzed as mean area under the curve (AUC), the androstenedione group had a small but statistically significant elevation in testosterone (P < 0.05). Androstenediol supplementation increased serum androstenedione by 103%, but did not increase testosterone levels.
The impact of exercise on testosterone levels after androstenedione supplementation was examined in 10 men (average age 24 years) with several years of weight-lifting experience.16 This double-blind, cross-over study randomly assigned the men to either 200 mg/d androstenedione or placebo for two days. Testosterone levels initially were unchanged, but after 90 minutes of weight lifting, total and free testosterone levels transiently increased in both groups, but with non-significant differences. Estradiol levels were significantly higher in those taking androstenedione throughout the exercise period (P < 0.05).
Another study found no increase in testosterone levels after androstenedione supplementation (100 mg/d for five days).9 This study also examined changes in protein metabolism in six males (average age 32 years) compared with a non-randomly selected control group. Protein synthesis did increase, but not with statistical significance, and there was an even greater increase in protein breakdown. Estradiol levels were significantly increased (P < 0.05).
Androstenedione’s impact on athletic performance was tested in the second study in King’s original publication.11 Twenty healthy men (ages 19-29 years) were randomly assigned to placebo or androstenedione (100 mg tid for eight weeks, skipping every third week to simulate "wash-out"). All subjects were supervised lifting weights for all major muscles three times weekly. No significant differences between the two groups were found in body composition, muscle size, muscle strength, and testosterone levels. The androstenedione group had significantly elevated estradiol, estrone, and estrogen levels (P < 0.05). Additionally, serum HDL cholesterol was 12% lower in the androstenedione group during weeks 2-8 (P < 0.05).
King’s two studies were replicated using a product containing 300 mg androstenedione, 150 mg dehydroepiandrosterone (DHEA), and four herbs alleged to promote testosterone production and minimize estrogen formation.17 Using identical study designs, results were obtained that were similar to those obtained with pure androstenedione (i.e., 100 mg androstenedione in the herbal product did not elevate testosterone levels in 10 men). In this double-blind, randomized trial, the herbal remedy (including 300 mg/d androstenedione) was administered for eight weeks to 20 men in their twenties who lifted weights three times a week. Serum testosterone, body composition, and muscle strength did not change significantly. The only significant lipid change was a 12% reduction in HDL (P < 0.05); estradiol and estrone levels increased significantly (P < 0.05).
Another double-blind, randomized study involved 40 middle-aged men (mean age 48.1 years) with at least one year of weight-lifting experience.18 Each was assigned to take 50 mg androstenedione, 50 mg DHEA, or placebo bid for 12 weeks. Subjects maintained their usual exercise and dietary patterns. No significant differences were found in lean body mass, strength, or testosterone levels. No adverse effects were reported.
Finally, 50 men (ages 35-65 years) were randomized to receive either placebo, androstenedione (100 mg bid), or androstenediol (100 mg bid).15 They exercised, under supervision, three times a week for 12 weeks. After four weeks, the androstenedione group had significantly elevated testosterone levels compared to androstenediol and placebo, but there were no differences after 12 weeks. The androstenediol group showed no significant increase in total testosterone, but at 12 weeks only, free testosterone levels were significantly elevated (P < 0.05). Both andro supplements led to significantly elevated levels of estradiol and estrone compared to placebo (P < 0.01) and pretreatment baselines (P < 0.03). No significant differences were found between the three groups in body composition or muscle mass. All three groups reported significantly increased muscle strength, with similar gains in each group.
Reduced HDL and elevated LDL were reported as increased cardiac risk profiles. This risk for abnormal
lipid profiles increased 5.2% for androstenediol and 10.48% for androstenedione, and decreased 12.34% with placebo (P = 0.05).18 Lowered HDL cholesterol levels are independently associated with higher risk for cardiovascular disease, as are elevated LDL levels.
No other adverse effects have been reported in studies, although elevated estrogen levels are associated with gynecomastia and increased risk of cardiovascular disease, breast cancer, and hirsutism in women, and pancreatic cancer in men.11 Elevated androstenedione levels are associated with increased risk of prostatic and pancreatic cancer.19,20 No studies are available on the adverse effects of long-term androstenedione use.
The quality of andro products in the United States also is problematic. One study tested nine products.21 Six failed the commonly accepted USP standard of containing between 90% and 110% of labeled quantities. One contained no androstenedione, and one contained 10 mg testosterone without revealing this on its label.
Androstenedione is banned by the National Football League, National Collegiate Athletic Association, and the International Olympic Committee. Consuming these products will, in most cases, lead to positive urine tests for nandrolone, another banned anabolic agent.21 The American College of Sports Medicine has called for regulatory reform because drugs like androstenedione are so readily available.22
One review claimed that all AASs increase sensitivity to oral anticoagulants and antidiabetic medications, but did not elaborate.6 Drug interactions with androstenedione have not been reported.
Tablets and capsules contain 50 or 100 mg androstenedione. Manufacturers recommend 100-300 mg/d, though some recommend 1,200 mg/d.2 Andro-stenedione is available as a nasal spray, sublingual spray, and percutaneous gel. The nasal spray patented in Germany delivers 3.5-15 mg androstenedione per pump.5
Several new androstenedione studies recently have been published. Studies giving 100-200 mg/d androstenedione rarely found increased testosterone levels, but 300 mg/d did increase testosterone levels in some, but not all, studies. However, even 100 mg/d consistently increased estrogen levels and negatively affect- ed blood lipids. Four controlled studies failed to demonstrate any beneficial effects on body composition or strength from androstenedione and related products.
The subjects in these studies differ in important ways from trained athletes who use AASs. Proponents claim anabolic steroids only benefit well-trained athletes because they reverse the catabolic state induced by intense exercise, thus allowing significant gains in strength and lean body mass.7 Recent research has only involved men, whereas early German research involved female athletes. A 1966 study with radioactive tracers found that androstenedione leads to only 0.3% of the testosterone produced in males, but to about 60% of that produced in females.16 Thus, it appears theoretically unlikely that untrained men will experience any anabolic benefit from androstenedione supplements. Androstenedione’s effects may be different in trained athletes and in females.7
Although research is somewhat limited, androstenedione thus far produces none of the advantages athletes seek, and has all the dangers inherent to anabolic steroid abuse. It raises LDL cholesterol and lowers HDL cholesterol. Given the lack of demonstrated efficacy, the significant potential for adverse effects, and concern about product quality, clinicians should actively discourage any use of androstenedione.
Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mount Carmel College of Nursing, Columbus, OH.
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22. American College of Sports Medicine news release, August 31, 1998.