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Sports Medicine

Dehydroepiandrosterone and sport

Dehydroepiandrosterone (DHEA) is a weak androgen, but is one of the main precursors of testosterone. Athletes use it for its androgenic and anticatabolic effects and it has been described as a "wonder drug", although there is little evidence to support these claims. There are no published studies of the long term effects of taking DHEA, particularly in the large doses used by athletes, or of its possible interactions with other agents.

A Brian Corrigan

MJA 1999; 171: 206-208
See also Kennedy

Introduction - Physiology - DHEA and exercise - Medical use - Use by athletes - Screening for DHEA use - Long term effects - Acknowledgements - References - Authors' details
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Introduction In Australia, considerable interest in the use of dehydroepiandrosterone (DHEA) in sports has followed the positive drug tests of two sportsmen, one for DHEA and one for its metabolite, androstenediol. DHEA is a 19-carbon steroid, classified as an androgen,1 albeit a weak one. It is the major steroid hormone secreted by the adrenal glands2,3 and circulates in two forms. One is unconjugated DHEA; the other, present in a much higher concentration, is conjugated as its sulfate, DHEAS. The two are readily interconvertible.4-6

DHEA is one of the main precursors in the biosynthesis of the male and female sex hormones.1 It is formed from the metabolism of cholesterol to pregnenolone and then to DHEA or DHEAS, and can be converted in the tissues to the far more potent androgens testosterone and dihydrotestosterone (Box 1).7

DHEA first burst into prominence nearly 20 years ago when, following animal experiments, it was described as a "wonder drug"8 and "the fountain of youth", with claims that it was an anti-aging, anti-obesity, and anticancer drug. At that time it was available in the United States only on prescription, but in 1985 the Food and Drug Administration (FDA) ordered manufacturers to stop marketing DHEA as a weight-loss product.

In 1994, following intense lobbying by the healthfood industry, an Act of Congress allowed DHEA to be sold in the US as an over-the-counter dietary nutritional supplement.9 The effect of this Act was to shift the burden of proof onto the FDA to prove that a nutritional substance was harmful. The Act also stated that labelling was not to make any unsubstantiated health claims, but this failed to stop the profusion of advertisements on the Internet.10 The fond belief that, if labelled as having "no drug intent", DHEA would be used only as a food supplement, or that it would be used only in small doses, turned out to be just that -- a fond belief. The FDA still does not approve it for any medical indication.9,11

In Australia, DHEA is a banned drug, and a prohibited import under the Customs (Prohibited Imports) Regulations (Cwlth). It has no listed medical uses, and cannot be marketed.

Physiology Circulating levels of DHEA and DHEAS peak in early adulthood, then progressively decline with age.6,12 DHEA has a short half-life of 25 minutes; DHEAS has a half-life of some 10 hours. Most DHEA circulates bound to albumin,13,14 with only minimal binding to sex hormone binding globulin (SHBG) and a smaller amount being free. In contrast, DHEAS is more strongly bound to albumin, only a small amount is free, and none appears bound to SHBG.13 Secretion of DHEA, but not of DHEAS, has a circadian rhythm.1,15,16 DHEAS is present at a plasma concentration much higher than any other adrenal steroid.

Despite its abundance and rapid turnover rate, DHEA's physiological role remains uncertain.14,17,18 A DHEA deficiency state has never been described.19 For men or women who have either adrenal insufficiency or hypopituitarism, although gluco- and mineralocorticosteroid replacement is needed, 50 mg a day of DHEA is sufficient for replacement.12,20


DHEA and exercise
Four studies have been published concerning the effect of physical exercise on DHEA levels. Two of these, involving trained sportsmen, found exercise produced a significant rise in DHEA levels.21,22 The third, with patients in a cardiac rehabilitation program,23 reported no effect. In the other,24 middle-aged women using a treadmill had raised serum DHEA and DHEAS levels.

Medical use DHEA has been described in the treatment of many disorders, including cardiovascular disease,25 breast cancer,26 obesity,27 and as replacement therapy to improve the fall in DHEA levels that occurs in aging men and women.6,28,29 These are all controversial.

DHEA is usually available in 25 mg or 50 mg tablets, which have an average absorption of 50% from the gut.28 It has also been used in an injectable ester form, intramuscular prasterone enanthate 200 mg (Gynodian Depot, Schering), and it has been given as a vaginal pessary. As with other sports drugs, such as steroids, tablets can be readily bought on the black market or on the Internet, but may prove to be counterfeit.30


Use by athletes
The number of athletes who use DHEA as a supplement is unknown (Box 2).31 Athletes use DHEA for several reasons:

  • as an anabolic agent to increase levels of androgens such as androstenediol and testosterone. Its effectiveness as an anabolic or energy-producing agent remains unproven. Nevertheless, an anabolic effect was supported in one study,18 when DHEA was given to healthy young men in a dose of 1600 mg a day orally for four weeks. Fat levels decreased and fat-free body mass increased by an average of 4.5 kg. However, in another study using better technology,32 a ninefold increase in DHEAS levels was induced in eight healthy young men given 1600 mg a day for four weeks in a double-blind crossover study. No effect on bodyweight, lean mass or cholesterol resulted; the authors concluded that "DHEA is not an important regulator of energy or protein metabolism in humans".32 There are no published data on what happens when athletes take long term supraphysiological doses of these agents, nor what might happen if older athletes, such as participants in the Master's Games, used DHEA to achieve the levels found in younger people.

  • as an anticatabolic agent.33 One major proposed mechanism of DHEA's mode of action is to counteract the catabolic effect of corticosteroids, which may be elevated following stress and exhaustion due to sporting events or heavy training schedules.3 DHEA is a powerful antiglucocorticoid33-36 and could accelerate recovery from the stress.

  • as a difficult-to-detect means to increase steroid levels. A positive drug test for anabolic steroids is based on the testosterone (T) to epitestosterone (E) ratio (epitestosterone is an inactive isomer of testosterone produced in the testes). The T/E ratio is around 1:1 in normal individuals, and it rises with exogenous steroid administration. The International Olympic Committee (IOC) uses a cut-off of 6:1 for drug testing; any test result above that is considered to be a positive that requires further investigation. As DHEA is a precursor in testosterone formation, it would increase the concentrations of both T and E, so that the T/E ratio would remain within the normal range. Although the T/E ratio does rise with DHEA use, it usually does so to only a modest degree, usually remaining below the IOC cut-off level.37 However, this is also obviously dependent on the dose and length of time of administration, so that, with a high enough dose, the ratio can be increased.38 Cases of a high T/E ratio have been known after excessive intake, but such an increase in the ratio is more likely to occur with androstenediol than with DHEA.

  • as with most other steroids, DHEA is a neurosteroid39-41 capable of producing marked psychological effects,28,42-44 such as euphoria or anxiety.45


Screening for DHEA use
In Australia, DHEA is an illegal drug that may not be imported, prescribed or administered. However, it is still possible to order it from the Internet. In early 1997, the IOC specifically added it to the list of drugs proscribed because of its androgenic effects. Previously, it would have been banned as "a related substance". Few technical difficulties are associated with detecting DHEA in the urine, but its normal range and a legal level for detection purposes need to be established. In one report, the authors recommend a urinary concentration threshold of 300 mg per litre of DHEA glucuronide for drug-screening purposes.3 Similar figures have been obtained in Australia (Dr R Kazlauskas, Director, Australian Sports Drug Testing Laboratory, personal communication). A screening test might need to rely on urinary ratios between DHEA and other steroids, or else some form of carbon isotope ratio measurement might be developed.46


Long term effects
The long term effects of DHEA are not known, although it does seem to be capable of interfering with many basic hormonal and endocrine systems, including breast, uterine and prostate tumours.47,48 Most of the theories concerning its anticipated effects have been extrapolated from epidemiological or animal studies. There have never been any properly conducted long term clinical trials of its efficacy or side effects in humans, and nothing is known about its interactions with other compounds. For these reasons, it should never be used as a long term treatment in young people such as athletes.


Acknowledgements
I would like to thank Dr John Carter and Dr Michael Kennedy; the Australian Sports Drug Agency, and the librarians at Concord Hospital, for all their help.

References
  1. Williams JD. Textbook of endocrinology. Williams JD, Foster DW, editors. 8th ed. Philadelphia: WB Saunders, 1992; 579-581.
  2. Greenspan FS. Basic and clinical endocrinology. 3rd ed. New Jersey: Prentice-Hall, 1991; 469-471.
  3. Dehennin L, Ferry M, Lafarge P, et al. Oral administration of dehydroepiandrosterone to healthy men: alteration of the urinary androgen profile and consequences for the detection of abuse in sport by gas chromatography-mass spectrometry. Steroids 1998; 63: 80-87.
  4. Bird CE, Masters V, Clark AF. Dehydroepiandrosterone sulfate: kinetics of metabolism in normal young men and women. Clin Invest Med 1984; 7: 119-122.
  5. Haning RV Jr, Carlson IH, Flood CA, et al. Metabolism of dehydroepiandrosterone sulfate (DS) in normal women and women with high DS concentrations. J Clin Endocrinol Metab 1991; 73: 1210-1215.
  6. Herbert J. The age of dehydroepiandrosterone [editorial]. Lancet 1995; 345: 1193-1194.
  7. Labrie F, Belanger A, Simard J, et al. DHEA and peripheral androgen and estrogen formation: intracrinology. Ann N Y Acad Sci 1995; 774: 16-28.
  8. Kent S. DHEA: "miracle" drug? Geriatrics 1982; 37: 157-161.
  9. Skolnick AA. Scientific verdict still out on DHEA. JAMA 1996; 276: 1365-1367.
  10. Kreeger KY. Researchers ponder the benefits of DHEA on many fronts. The Scientist 1997; 11(9): 11,14.
  11. Dehydroepiandrosterone (DHEA). Med Lett Drugs Ther 1996; 38: 91-92.
  12. Young J, Couzinet B, Nahoul K, et al. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrinol Metab 1997; 82: 2578-2585.
  13. Longcope C. Dehydroepiandrosterone metabolism. J Endocrinol 1996; 150 Suppl: S125-S127.
  14. Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994; 343: 1479-1481.
  15. Liu CH, Laughlin G, Fischer U, et al. Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity. J Clin Endocrinol Metab 1990; 71: 900-906.
  16. Baulieu EE. Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab 1996; 81: 3147-3151.
  17. Nestler JE, Kahwash Z. Sex-specific action of insulin to acutely increase the metabolic clearance rate of dehydroepiandrosterone in humans. J Clin Invest 1994; 94: 1484-1489.
  18. Nestler JE, Barlascini CO, Clore JN, et al. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 1988; 66: 57-61.
  19. Regelson W, Loria R, Kalimi M. Dehydroepiandrosterone (DHEA) -- the "mother steroid". I. Immunologic action. Ann N Y Acad Sci 1994; 719: 553-563.
  20. Arlt W, Justl H-G, Callies F, et al. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83: 1928-1932.
  21. Keizer H, Janssen GM, Menheere P, Kranenburg G. Changes in basal plasma testosterone, cortisol, and dehydroepiandrosterone sulfate in previously untrained males and females preparing for a marathon. Int J Sports Med 1989; 10 Suppl 3: S139-S145.
  22. Velardo A, Pantaleoni M, Valerio L, et al. Influence of exercise on dehydroepiandrosterone sulphate and delta 4-androstenedione plasma levels in man. Exp Clin Endocrinol 1991; 97: 99-101.
  23. Milani RV, Lavie CJ, Barbee RW, Littman AB. Lack of effect of exercise training on dehydroepiandrosterone-sulfate. Am J Med Sci 1995; 310: 242-246.
  24. Johnson LG, Kraemer RR, Haltom R, et al. Effects of estrogen replacement therapy on dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol responses to exercise in postmenopausal women. Fertil Steril 1997; 68: 836-843.
  25. Barrett-Connor E, Goodman-Gruen D. The epidemiology of DHEAS and cardiovascular disease. Ann N Y Acad Sci 1995; 774: 259-270.
  26. Bulbrook RD, Hayward JL, Spicer CC, et al. Relation between urinary androgen and corticoid excretion and subsequent breast cancer. Lancet 1971; 2: 395-398.
  27. Clore JN. Dehydroepiandrosterone and body fat. Obes Res 1995; 3 Suppl 4: 613S-616S.
  28. Morales AJ, Nolan JJ, Nelson JC, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78: 1360-1367.
  29. Yen SSC, Morales AJ, Khorram O. Replacement of DHEA in aging men and women. Ann N Y Acad Sci 1995; 774: 128-142.
  30. Lifrak ET, Parker LN. Analysis of nonprescription capsules purported to contain an adrenal androgen. Am J Hosp Pharm 1985; 42: 587-589.
  31. Sturmi JE, Diorio DJ. Anabolic agents. Clin Sports Med 1998; 17: 261-282.
  32. Welle S, Jozefowicz R, Statt M. Failure of dehydroepiandrosterone to influence energy and protein metabolism in humans. J Clin Endocrinol Metab 1990; 71: 1259-1264.
  33. Loria RM. Antiglucocorticoid function of androstenetriol. Psychoneuroendocrinology 1997; 22 Suppl 1: S103-S108.
  34. Kalimi M, Shafagoj Y, Loria R, et al. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 1994; 131: 99-104.
  35. Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA) -- the multifunctional steroid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann N Y Acad Sci 1994; 719: 564-575.
  36. Fleshner M, Pugh CR, Tremblay D, et al. DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis. Behav Neurosci 1997; 111: 512-527.
  37. Bosy TZ, Moore KA, Poklis A. The effect of oral dehydroepiandrosterone (DHEA) on the urine testosterone/epitestosterone (T/E) ratio in human male volunteers. J Anal Toxicol 1998; 22: 455-459.
  38. Bowers LD. Oral dehydroepiandrosterone supplementation can increase the testosterone/epitestosterone ratio. Clin Chem 1999; 45: 295-297.
  39. Baulieu EE. Neurosteroids of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997; 52: 1-32.
  40. Khorram O. DHEA: a hormone with multiple effects. Curr Opin Obstet Gynecol 1996; 8: 351-354.
  41. Dubrovsky B. Natural steroids counteracting some actions of putative depressogenic steroids on the central nervous system: potential therapeutic benefits. Med Hypotheses 1997; 49: 51-55.
  42. Corrigan AB. Anabolic steroids and the mind. Med J Aust 1996; 165: 222-226.
  43. Miller RA. DHEA -- brass ring or red herring? [editorial]. J Am Ger Soc 1977; 45: 1402-1403.
  44. Wang C, Alexander G, Berman N, et al. Testosterone replacement therapy improves mood in hypogonadal men -- a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578-3583.
  45. Imamura M, Prasad C. Modulation of GABA-gated chloride ion influx in the brain by dehydroepiandrosterone and its metabolites. Biochem Biophys Res Commun 1998; 243: 771-775.
  46. Magnay J. Days numbered for testosterone cheats. Sydney Morning Herald 1999; 16 July: 12.
  47. Armsey TD, Green GA. Nutrition supplements: science vs hype. Phys Sportsmed 1997; 25: 77-92.
  48. Dorgan JF, Stanczyk FZ, Longcope C, et al. Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate and 5-androstene-3b,17b-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 1997; 6: 177-181.

Authors' details Institute of Sports Medicine, Concord Hospital, Sydney, NSW.
A Brian Corrigan, AM, FRACP, FRCP, Consultant

Reprints will not be available from the author.
Correspondence: Dr A B Corrigan, Lookout Avenue, Dee Why, NSW 2099.
Email: abc@southernx.com.au

©MJA 1999
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2: DHEA use by Australian athletes

In Australia, there have been two recent instances involving footballers. In the first, a player was given DHEA for presumed chronic fatigue syndrome, although there is no medical evidence that DHEA is of benefit in this condition. At the tribunal hearing, a complicated set of legal arguments resulted in the player being let off without any penalty. However, he was only to play again if he ceased his medication,which he has done, seemingly without any problems.

In the second instance, a footballer used 50mg androstenediol capsules, allegedly because he believed that it was only a food supplement. On testing, a very high testosterone/epitestosterone ratio of 14.5 was found, and he was found guilty, and the maximum penalty imposed.